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Abdollahi S, Lotfi AS, Saravani R, Taheri H. An association study of SERPINA1 gene polymorphisms with the risk of metabolic dysfunction-associated steatotic liver disease In an Iranian population: A preliminary case-control study. Biochem Biophys Rep 2025; 42:101974. [PMID: 40176953 PMCID: PMC11964567 DOI: 10.1016/j.bbrep.2025.101974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 03/02/2025] [Accepted: 03/06/2025] [Indexed: 04/05/2025] Open
Abstract
Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a type of fat accumulation in the liver that can lead to cirrhosis and chronic liver disease. MASLD is recognized as the most frequent of liver-associated deaths worldwide. The SERPINA1 gene encodes a serine protease protein that plays a pivotal role in the pathogenesis of liver deficiencies. In this study, we aimed to evaluate the genetic association between rs6647 (M1), rs709932 (M2), and rs1303 (M3) variants in the SERPINA1 gene and the risk of MASLD in an Iranian population. Methods In this case-control study, 120 patients affected by MASLD and 120 healthy subjects participated. The Nephelometry system measured serum levels of α1-antitrypsin (A1AT). Biochemical tests were conducted to assess serum levels of blood parameters using commercially available kits. DNA extraction was performed using the salting-out method, followed by the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method for genotyping. Statistical analysis was performed by SPSS v16.0. Results The findings showed that the rs6647 G allele significantly increased the risk of MASLD. The G allele in codominant, dominant, and over-dominant models caused an increase in the risk of MASLD. Additionally, the rs709932 T allele was more frequent among patients compared to healthy subjects and significantly enhanced the risk of MASLD. The T allele in the codominant and recessive models indicated a high risk for MASLD in our population. The G allele of rs1303 caused an enhancement in the mean serum levels of A1AT in the MASLD group. Conclusions Our results show an association between SERPINA1 gene variants and the risk of MASLD. The rs6647 (M1) and rs709932 (M2) variants of the SERPINA1 gene increased the risk of disorder in our population.
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Affiliation(s)
- Samira Abdollahi
- Department of Clinical Biochemistry, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Abbas Sahebghadam Lotfi
- Department of Clinical Biochemistry, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Ramin Saravani
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
- Department of Clinical Biochemistry, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Hamed Taheri
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
- Department of Internal Medicine, Ali-Ibn-Abitaleb Hospital, Zahedan University of Medical Sciences, Zahedan, Iran
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Remih K, Hufnagel FM, Karl AS, Durkalski-Mauldin V, Lee WM, Karvellas CJ, Su Z, Rule JA, Tomanová P, Krieg L, Karkossa I, Schubert K, von Bergen M, Tacke F, Luckhardt S, Ziegler N, Kannt A, Engel B, Taubert R, Fontana RJ, Strnad P, the US Acute Liver Failure Study Group. Serum proteomics of adults with acute liver failure provides mechanistic insights and attractive prognostic biomarkers. JHEP Rep 2025; 7:101338. [PMID: 40242314 PMCID: PMC11998117 DOI: 10.1016/j.jhepr.2025.101338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 01/17/2025] [Accepted: 01/22/2025] [Indexed: 04/18/2025] Open
Abstract
Background & Aims Acute liver failure (ALF) is defined as rapid onset coagulopathy and encephalopathy in patients without a prior history of liver disease. We performed untargeted and targeted serum proteomics to delineate processes occurring in adult patients with ALF and to identify potential biomarkers. Methods Sera of 319 adult patients with ALF (∼50% acetaminophen [APAP]-related cases) were randomly selected from admission samples of the multicenter USA Acute Liver Failure Study Group consortium and subdivided into discovery/validation cohorts. They were analyzed using untargeted proteomics with mass spectroscopy and a serum cytokine profiling and compared with 30 healthy controls. The primary clinical outcome was 21-day transplant-free survival. Single-cell RNAseq data mapped biomarkers to cells of origin; functional enrichment analysis provided mechanistic insights. Novel prognostic scores were compared with the model for end-stage liver disease and ALFSG prognostic index scores. Results In the discovery cohort, 117 proteins differed between patients with ALF and healthy controls. There were 167 proteins associated with APAP-related ALF, with the majority being hepatocyte-derived. Three hepatocellular proteins (ALDOB, CAT, and PIGR) robustly and reproducibly discriminated APAP from non-APAP cases (AUROCs ∼0.9). In the discovery cohort, 37 proteins were related to 21-day outcome. The key processes associated with survival were acute-phase response and hepatocyte nuclear factor 1α signaling. SERPINA1 and LRG1 were the best individual discriminators of 21-day transplant-free survival in both cohorts. Two models of blood-based proteomic biomarkers outperformed the model for end-stage liver disease and ALFSG prognostic index and were reproduced in the validation cohort (AUROCs 0.83-0.86) for 21-day transplant-free survival. Conclusions Proteomics and cytokine profiling identified new, reproducible biomarkers associated with APAP etiology and 21-day outcome. These biomarkers may improve prognostication and understanding of the etiopathogenesis of ALF but need to be independently validated. Impact and implications Acute liver failure (ALF) is a sudden, and severe condition associated with high fatality. More sensitive and specific prognostic scores are urgently needed to facilitate decision-making regarding liver transplantation in patients with ALF. Our proteomic analysis uncovered marked differences between acetaminophen and non-acetaminophen-related ALF. The identification of routinely measurable biomarkers that are associated with 21-day transplant-free survival and the derivation of novel prognostic scores may facilitate clinical management as well as decisions for/against liver transplantation. Further studies are needed to quantify less abundant proteins. Although we used two cohorts, our findings still need to be independently and prospectively validated.
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Affiliation(s)
- Katharina Remih
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany
| | - Franziska-Maria Hufnagel
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany
| | - Anna Sophie Karl
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany
| | | | - William Martens Lee
- Department of Internal Medicine, Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | | | - Zemin Su
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Jody A. Rule
- Department of Internal Medicine, Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Petra Tomanová
- Department of Econometrics, Prague University of Economics and Business, Prague, Czechia
| | - Laura Krieg
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Isabel Karkossa
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Kristin Schubert
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Martin von Bergen
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany
| | - Sonja Luckhardt
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
| | - Nicole Ziegler
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
| | - Aimo Kannt
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
- Goethe University, Institute of Clinical Pharmacology, Frankfurt am Main, Germany
| | - Bastian Engel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Robert John Fontana
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA
| | - Pavel Strnad
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany
| | - the US Acute Liver Failure Study Group
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA
- Department of Internal Medicine, Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
- Department of Critical Care Medicine, University of Alberta, Edmonton, AB, Canada
- Department of Econometrics, Prague University of Economics and Business, Prague, Czechia
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
- Goethe University, Institute of Clinical Pharmacology, Frankfurt am Main, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA
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Sun Y, Wang J, Zhu Y, Han T, Liu Y, Wang HY. Nanoprobes based on optical imaging techniques for detecting biomarkers in liver injury diseases. Coord Chem Rev 2025; 524:216303. [DOI: 10.1016/j.ccr.2024.216303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Spivak I, Guldiken N, Usachov V, Schaap F, Damink SWO, Bouchecareilh M, Lehmann A, Fu L, Mo F, Ensari GK, Hufnagel F, Fromme M, Preisinger C, Strnad P. Alpha-1 Antitrypsin Inclusions Sequester GRP78 in a Bile Acid-Inducible Manner. Liver Int 2025; 45:e16207. [PMID: 39665869 PMCID: PMC11636636 DOI: 10.1111/liv.16207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 11/24/2024] [Accepted: 11/27/2024] [Indexed: 12/13/2024]
Abstract
BACKGROUND AND AIMS The homozygous PiZ mutation (PIZZ genotype) constitutes the predominant cause of severe alpha-1 antitrypsin (AAT) deficiency and leads to liver disease via hepatocellular AAT aggregation. We systematically analysed the composition of AAT aggregates and studied the impact of bile acids. METHODS AAT inclusions were isolated from livers of PiZ overexpressing mice and PIZZ humans via fluorescence-activated and immunomagnetic sorting (FACS/MACS), while insoluble proteins were obtained via Triton-X extraction. Inclusion composition was evaluated through mass-spectrometry (MS), immunoblotting and immunostaining. Hepatocytes with versus without AAT aggregates were obtained via microdissection. Serum bile acids were assessed in 57 PIZZ subjects and 19 controls. Mice were administered 2% cholic acid (CA)-supplemented chow for 7 days. RESULTS MS identified the key endoplasmic reticulum chaperone 78 kDa glucose-regulated protein (GRP78) in FACS/MACS pulldowns. GRP78 was also enriched in insoluble fractions from PiZ mice versus wild types and detected in insoluble fractions/MACS isolates from PIZZ liver explants. In cultured cells/primary hepatocytes, PiZ overexpression was associated with increased GRP78 mRNA/protein levels. In human livers, hepatocytes with AAT aggregates had higher GRP78 levels than hepatocytes without. PIZZ subjects displayed higher serum bile acid levels than controls and the highest levels were seen in individuals with liver injury/fibrosis. In PiZ mice, CA-mediated bile acid challenge resulted in increased liver injury and translocation of GRP78 into the aggregates. CONCLUSIONS Our results demonstrate that GRP78 is sequestered within AAT inclusions. Bile acid accumulation, as seen in PIZZ subjects with liver disease, may promote GRP78 segregation and thereby augment liver damage. TRIAL REGISTRATION NCT02929940.
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Affiliation(s)
- Igor Spivak
- Medical Department III, Gastroenterology, Metabolic Diseases and Intensive CareUniversity Hospital RWTH AachenAachenGermany
| | - Nurdan Guldiken
- Medical Department III, Gastroenterology, Metabolic Diseases and Intensive CareUniversity Hospital RWTH AachenAachenGermany
| | - Valentyn Usachov
- Medical Department III, Gastroenterology, Metabolic Diseases and Intensive CareUniversity Hospital RWTH AachenAachenGermany
| | - Frank Schaap
- Department of Surgery, Maastricht University Medical Center and NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtNetherlands
- Department of General, Visceral and Transplant SurgeryUniversity Hospital RWTH AachenAachenGermany
| | - Steven W.M. Olde Damink
- Department of Surgery, Maastricht University Medical Center and NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtNetherlands
- Department of General, Visceral and Transplant SurgeryUniversity Hospital RWTH AachenAachenGermany
| | | | | | - Lei Fu
- Medical Department III, Gastroenterology, Metabolic Diseases and Intensive CareUniversity Hospital RWTH AachenAachenGermany
- Department of Science and TechnologyRuikang Hospital Affiliated to Guangxi University of Chinese MedicineNanningChina
| | - Fa‐Rong Mo
- Medical Department III, Gastroenterology, Metabolic Diseases and Intensive CareUniversity Hospital RWTH AachenAachenGermany
| | - Gökce Kobazi Ensari
- Medical Department III, Gastroenterology, Metabolic Diseases and Intensive CareUniversity Hospital RWTH AachenAachenGermany
| | - Franziska Hufnagel
- Medical Department III, Gastroenterology, Metabolic Diseases and Intensive CareUniversity Hospital RWTH AachenAachenGermany
| | - Malin Fromme
- Medical Department III, Gastroenterology, Metabolic Diseases and Intensive CareUniversity Hospital RWTH AachenAachenGermany
| | - Christian Preisinger
- Interdisciplinary Center for Clinical Research (IZKF)University Hospital RWTH AachenAachenGermany
| | - Pavel Strnad
- Medical Department III, Gastroenterology, Metabolic Diseases and Intensive CareUniversity Hospital RWTH AachenAachenGermany
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Volkert I, Fromme M, Schneider C, Candels L, Lindhauer C, Su H, Thorhauge K, Pons M, Mohamed MR, Schneider KM, Strnad P, Trautwein C. Impact of PNPLA3 I148M on alpha-1 antitrypsin deficiency-dependent liver disease progression. Hepatology 2024; 79:898-911. [PMID: 37625151 DOI: 10.1097/hep.0000000000000574] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 07/28/2023] [Indexed: 08/27/2023]
Abstract
BACKGROUND AND AIMS Genetic risk factors are major determinants of chronic liver disease (CLD) progression. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M polymorphism and alpha-1 antitrypsin (AAT) E342K variant, termed PiZ, are major modifiers of metabolic CLD. Both variants are known to affect metabolic CLD through increased endoplasmic reticulum stress, but their combined effect on CLD progression remains largely unknown. Here, we aimed to test our working hypothesis that their combined incidence triggers CLD disease progression. APPROACH AND RESULTS We showed that patients with PiZZ/PNPLA3 I148M from the European alpha-1-antitrypsin deficiency (AATD) liver consortium and the UK Biobank had a trend towards higher liver enzymes, but no increased liver fat accumulation was evident between subgroups. After generating transgenic mice that overexpress the PiZ variant and simultaneously harbor the PNPLA3 I148M knockin (designated as PiZ/PNPLA3 I148M ), we observed that animals with PiZ and PiZ/PNPLA3 I148M showed increased liver enzymes compared to controls during aging. However, no significant difference between PiZ and PiZ/PNPLA3 I148M groups was observed, with no increased liver fat accumulation over time. To further study the impact on CLD progression, a Western-styled diet was administered, which resulted in increased fat accumulation and fibrosis in PiZ and PiZ/PNPLA3 I148M livers compared to controls, but the additional presence of PNPLA3 I148M had no impact on liver phenotype. Notably, the PiZ variant protected PNPLA3 I148M mice from liver damage and obesity after Western-styled diet feeding. CONCLUSION Our results demonstrate that the PNPLA3 polymorphism in the absence of additional metabolic risk factors is insufficient to drive the development of advanced liver disease in severe AATD.
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Affiliation(s)
- Ines Volkert
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Malin Fromme
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Carolin Schneider
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Lena Candels
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Cecilia Lindhauer
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Huan Su
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Katrine Thorhauge
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Monica Pons
- Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autonoma de Barcelona, Barcelona
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | | | | | - Pavel Strnad
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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Fu L, Guldiken N, Remih K, Karl AS, Preisinger C, Strnad P. Serum/Plasma Proteome in Non-Malignant Liver Disease. Int J Mol Sci 2024; 25:2008. [PMID: 38396688 PMCID: PMC10889128 DOI: 10.3390/ijms25042008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/31/2024] [Accepted: 02/03/2024] [Indexed: 02/25/2024] Open
Abstract
The liver is the central metabolic organ and produces 85-90% of the proteins found in plasma. Accordingly, the plasma proteome is an attractive source of liver disease biomarkers that reflects the different cell types present in this organ, as well as the processes such as responses to acute and chronic injury or the formation of an extracellular matrix. In the first part, we summarize the biomarkers routinely used in clinical evaluations and their biological relevance in the different stages of non-malignant liver disease. Later, we describe the current proteomic approaches, including mass spectrometry and affinity-based techniques, that allow a more comprehensive assessment of the liver function but also require complex data processing. The many approaches of analysis and interpretation and their potential caveats are delineated. While these advances hold the promise to transform our understanding of liver diseases and support the development and validation of new liver-related drugs, an interdisciplinary collaboration is needed.
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Affiliation(s)
- Lei Fu
- Department of Internal Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany; (L.F.); (N.G.); (K.R.); (A.S.K.)
| | - Nurdan Guldiken
- Department of Internal Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany; (L.F.); (N.G.); (K.R.); (A.S.K.)
| | - Katharina Remih
- Department of Internal Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany; (L.F.); (N.G.); (K.R.); (A.S.K.)
| | - Anna Sophie Karl
- Department of Internal Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany; (L.F.); (N.G.); (K.R.); (A.S.K.)
| | - Christian Preisinger
- Proteomics Facility, Interdisciplinary Centre for Clinical Research (IZKF), Medical School, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany;
| | - Pavel Strnad
- Department of Internal Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany; (L.F.); (N.G.); (K.R.); (A.S.K.)
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Shafqat F, Ur Rehman S, Khan MS, Niaz K. Liver. ENCYCLOPEDIA OF TOXICOLOGY 2024:897-913. [DOI: 10.1016/b978-0-12-824315-2.00138-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Smith JG, Molendijk J, Blazev R, Chen WH, Zhang Q, Litwin C, Zinna VM, Welz PS, Benitah SA, Greco CM, Sassone-Corsi P, Muñoz-Cánoves P, Parker BL, Koronowski KB. Impact of Bmal1 Rescue and Time-Restricted Feeding on Liver and Muscle Proteomes During the Active Phase in Mice. Mol Cell Proteomics 2023; 22:100655. [PMID: 37793502 PMCID: PMC10651687 DOI: 10.1016/j.mcpro.2023.100655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/01/2023] [Accepted: 09/28/2023] [Indexed: 10/06/2023] Open
Abstract
Molecular clocks and daily feeding cycles support metabolism in peripheral tissues. Although the roles of local clocks and feeding are well defined at the transcriptional level, their impact on governing protein abundance in peripheral tissues is unclear. Here, we determine the relative contributions of local molecular clocks and daily feeding cycles on liver and muscle proteomes during the active phase in mice. LC-MS/MS was performed on liver and gastrocnemius muscle harvested 4 h into the dark phase from WT, Bmal1 KO, and dual liver- and muscle-Bmal1-rescued mice under either ad libitum feeding or time-restricted feeding during the dark phase. Feeding-fasting cycles had only minimal effects on levels of liver proteins and few, if any, on the muscle proteome. In contrast, Bmal1 KO altered the abundance of 674 proteins in liver and 80 proteins in muscle. Local rescue of liver and muscle Bmal1 restored ∼50% of proteins in liver and ∼25% in muscle. These included proteins involved in fatty acid oxidation in liver and carbohydrate metabolism in muscle. For liver, proteins involved in de novo lipogenesis were largely dependent on Bmal1 function in other tissues (i.e., the wider clock system). Proteins regulated by BMAL1 in liver and muscle were enriched for secreted proteins. We found that the abundance of fibroblast growth factor 1, a liver secreted protein, requires BMAL1 and that autocrine fibroblast growth factor 1 signaling modulates mitochondrial respiration in hepatocytes. In liver and muscle, BMAL1 is a more potent regulator of dark phase proteomes than daily feeding cycles, highlighting the need to assess protein levels in addition to mRNA when investigating clock mechanisms. The proteome is more extensively regulated by BMAL1 in liver than in muscle, and many metabolic pathways in peripheral tissues are reliant on the function of the clock system as a whole.
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Affiliation(s)
- Jacob G Smith
- Department of Medical and Life Sciences (MELIS), Pompeu Fabra University (UPF), Parc de Recerca Biomèdica de Barcelona (PRBB), Barcelona, Spain
| | - Jeffrey Molendijk
- Department of Anatomy and Physiology, Centre for Muscle Research, The University of Melbourne, Melbourne, Victoria, Australia
| | - Ronnie Blazev
- Department of Anatomy and Physiology, Centre for Muscle Research, The University of Melbourne, Melbourne, Victoria, Australia
| | - Wan Hsi Chen
- Department of Radiation Oncology, Mays Cancer Center at UT Health San Antonio MD Anderson, Joe R. and Teresa Lozano Long School of Medicine, San Antonio, Texas, USA; Barshop Institute for Longevity and Aging Studies at UT Health San Antonio, San Antonio, Texas, USA
| | - Qing Zhang
- Department of Biochemistry & Structural Biology, University of Texas Health San Antonio, San Antonio, Texas, USA
| | - Christopher Litwin
- Department of Biochemistry & Structural Biology, University of Texas Health San Antonio, San Antonio, Texas, USA
| | - Valentina M Zinna
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Patrick-Simon Welz
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; Hospital del Mar Research Institute Barcelona, Cancer Research Program, Barcelona Biomedical Research Park (PRBB), Barcelona, Spain
| | - Salvador Aznar Benitah
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
| | - Carolina M Greco
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Paolo Sassone-Corsi
- Department of Biological Chemistry, Center for Epigenetics and Metabolism, U1233 INSERM, University of California, Irvine, California, USA
| | - Pura Muñoz-Cánoves
- Department of Medical and Life Sciences (MELIS), Pompeu Fabra University (UPF), Parc de Recerca Biomèdica de Barcelona (PRBB), Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain; Altos Labs, Inc, San Diego Institute of Science, San Diego, California, USA
| | - Benjamin L Parker
- Department of Anatomy and Physiology, Centre for Muscle Research, The University of Melbourne, Melbourne, Victoria, Australia.
| | - Kevin B Koronowski
- Barshop Institute for Longevity and Aging Studies at UT Health San Antonio, San Antonio, Texas, USA; Department of Biochemistry & Structural Biology, University of Texas Health San Antonio, San Antonio, Texas, USA.
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Picker N, Hagiwara M, Baumann S, Marins EG, Wilke T, Ren K, Maywald U, Karki C, Strnad P. Liver disease epidemiology and burden in patients with alterations in plasma protein metabolism: German retrospective insurance claims analysis. World J Hepatol 2023; 15:1127-1139. [PMID: 37970617 PMCID: PMC10642430 DOI: 10.4254/wjh.v15.i10.1127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/11/2023] [Accepted: 09/18/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND Alpha-1 antitrypsin deficiency is a rare genetic disease and a leading cause of inherited alterations in plasma protein metabolism (APPM). AIM To understand the prevalence, burden and progression of liver disease in patients with APPM including alpha-1 antitrypsin deficiency. METHODS We conducted a retrospective analysis of anonymized patient-level claims data from a German health insurance provider (AOK PLUS). The APPM cohort comprised patients with APPM (identified using the German Modification of the International Classification of Diseases-10th Revision [ICD-10-GM] code E88.0 between 01/01/2010-30/09/2020) and incident liver disease (ICD-10-GM codes K74, K70.2-3 and K71.7 between 01/01/2012-30/09/2020). The control cohort comprised patients without APPM but with incident liver disease. Outcomes were incidence/prevalence of liver disease in patients with APPM, demographics/baseline characteristics, diagnostic procedures, progression-free survival (PFS), disease progression and mortality. RESULTS Overall, 2680 and 26299 patients were included in the APPM (fibrosis, 96; cirrhosis, 2584) and control (fibrosis, 1444; cirrhosis, 24855) cohorts, respectively. Per 100000 individuals, annual incidence and prevalence of APPM and liver disease was 10-15 and 36-51, respectively. In the APPM cohort, median survival was 4.7 years [95% confidence interval (CI): 3.5-7.0] and 2.5 years (95%CI: 2.3-2.8) in patients with fibrosis and cirrhosis, respectively. A higher proportion of patients in the APPM cohort experienced disease progression (92.0%) compared with the control cohort (67.2%). Median PFS was shorter in the APPM cohort (0.9 years, 95%CI: 0.7-1.1) compared with the control cohort (3.7 years, 95%CI: 3.6-3.8; P < 0.001). Patients with cirrhosis in the control cohort had longer event-free survival for ascites, hepatic encephalopathy, hepatic failure and esophageal/gastric varices than patients with cirrhosis in the APPM cohort (P < 0.001). Patients with fibrosis in the control cohort had longer event-free survival for ascites, cirrhosis, hepatic failure and esophageal/gastric varices than patients with fibrosis in the APPM cohort (P < 0.001). In the APPM cohort, the most common diagnostic procedures within 12 mo after the first diagnosis of liver disease were imaging procedures (66.3%) and laboratory tests (51.0%). CONCLUSION Among patients with liver disease, those with APPM experience substantial burden and earlier liver disease progression than patients without APPM.
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Affiliation(s)
- Nils Picker
- Real-World Evidence, Cytel Inc. Ingress-Health HWM GmbH, Wismar 23966, Germany
| | - May Hagiwara
- R&D, Global Evidence and Outcomes, Takeda Development Center Americas, Inc., Cambridge, MA 02139, United States
| | - Severin Baumann
- Real-World Evidence, Cytel Inc. Ingress-Health HWM GmbH, Wismar 23966, Germany
| | - Ed G Marins
- Global Medical Affairs, Takeda Development Center Americas, Inc., Cambridge, MA 02139, United States
| | - Thomas Wilke
- IPAM Institute, IPAM E.V., Wismar 23966, Germany
| | - Kaili Ren
- Statistics and Quantitative Sciences, Data Science Institute, Takeda Development Center Americas, Inc., Cambridge, MA 02139, United States
| | - Ulf Maywald
- Drug Department, AOK PLUS, Dresden 01058, Germany
| | - Chitra Karki
- R&D, Global Evidence and Outcomes, Takeda Development Center Americas, Inc., Cambridge, MA 02139, United States
| | - Pavel Strnad
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen 52074, Germany.
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10
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Ye Y, Wu G, Yuan H, Zheng Y, Wang Y, Guo Q. Prognostic role of preoperative lymphocyte/C-reactive protein associated with upper gastrointestinal cancer: a meta-analysis. Front Oncol 2023; 13:1181649. [PMID: 37849797 PMCID: PMC10578962 DOI: 10.3389/fonc.2023.1181649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 09/05/2023] [Indexed: 10/19/2023] Open
Abstract
Purpose The lymphocyte/C-reactive protein (LCR) is a novel immunoinflammatory score and prognostic marker, but the relationship between lymphocyte/C-reactive proteins and clinical outcomes in patients with upper gastrointestinal cancers remains controversial. This study aimed to evaluate the relationship between LCR and the prognosis of upper gastrointestinal cancer by systematic evaluation and meta-analysis. Methods We systematically searched PubMed, EMBASE, Cochrane, and Web of Science databases to obtain related studies on the relationship between LCR and esophageal cancer (EC), gastric cancer (GC), and esophagogastric junction cancers (EGJ), and used hazard ratio (HR), 95% confidence interval (95%CI) to evaluate the prognostic value of LCR. Outcome measures included overall survival (OS) and disease-free survival (DFS). Results Eight retrospective cohort studies with 2838 patients were included. Meta-analysis showed that patients with low LCR cancers had poor overall survival OS and disease-free survival DFS (HR=2.18, 95%CI=1.87-2.55; HR=1.88, 95%CI=1.56-2.26). Subgroup analysis based on cancer type, treatment modality, gender, T stage, TNM stage, country, and LCR threshold showed that lower LCR levels were all associated with worse OS and DFS (P<0.05). Conclusion The LCR can be used as a prognostic marker for patients with upper gastrointestinal cancers, and patients with a lower LCR may have a poor prognosis. Due to the limited number of studies included and mostly retrospective studies, the above findings require validation by more high-quality studies. Systematic Review Registration https://www.crd.york.ac.uk, identifier CRD42023392433.
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Affiliation(s)
- Yongjuan Ye
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Guozhi Wu
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Hao Yuan
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Ya Zheng
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yuping Wang
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Qinghong Guo
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
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11
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Mouliou DS. C-Reactive Protein: Pathophysiology, Diagnosis, False Test Results and a Novel Diagnostic Algorithm for Clinicians. Diseases 2023; 11:132. [PMID: 37873776 PMCID: PMC10594506 DOI: 10.3390/diseases11040132] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/15/2023] [Accepted: 09/19/2023] [Indexed: 10/25/2023] Open
Abstract
The current literature provides a body of evidence on C-Reactive Protein (CRP) and its potential role in inflammation. However, most pieces of evidence are sparse and controversial. This critical state-of-the-art monography provides all the crucial data on the potential biochemical properties of the protein, along with further evidence on its potential pathobiology, both for its pentameric and monomeric forms, including information for its ligands as well as the possible function of autoantibodies against the protein. Furthermore, the current evidence on its potential utility as a biomarker of various diseases is presented, of all cardiovascular, respiratory, hepatobiliary, gastrointestinal, pancreatic, renal, gynecological, andrological, dental, oral, otorhinolaryngological, ophthalmological, dermatological, musculoskeletal, neurological, mental, splenic, thyroid conditions, as well as infections, autoimmune-supposed conditions and neoplasms, including other possible factors that have been linked with elevated concentrations of that protein. Moreover, data on molecular diagnostics on CRP are discussed, and possible etiologies of false test results are highlighted. Additionally, this review evaluates all current pieces of evidence on CRP and systemic inflammation, and highlights future goals. Finally, a novel diagnostic algorithm to carefully assess the CRP level for a precise diagnosis of a medical condition is illustrated.
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12
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Wang H, Pan X, Xiang X, Zhang Y, Chen J, Wen S, Wang J, Gao R, Yang J, Zhi Y, Wen S, Zheng Y, Li T, Ai H, He X, Lu Y, Zhu Y, Li C, Chen Y, Shi G. CRISPR screen identifies the role of RBBP8 in mediating unfolded protein response induced liver damage through regulating protein synthesis. Cell Death Dis 2023; 14:531. [PMID: 37591836 PMCID: PMC10435451 DOI: 10.1038/s41419-023-06046-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 07/20/2023] [Accepted: 08/07/2023] [Indexed: 08/19/2023]
Abstract
Unfolded protein response (UPR) maintains the endoplasmic reticulum (ER) homeostasis, survival, and physiological function of mammalian cells. However, how cells adapt to ER stress under physiological or disease settings remains largely unclear. Here by a genome-wide CRISPR screen, we identified that RBBP8, an endonuclease involved in DNA damage repair, is required for ATF4 activation under ER stress in vitro. RNA-seq analysis suggested that RBBP8 deletion led to impaired cell cycle progression, retarded proliferation, attenuated ATF4 activation, and reduced global protein synthesis under ER stress. Mouse tissue analysis revealed that RBBP8 was highly expressed in the liver, and its expression is responsive to ER stress by tunicamycin intraperitoneal injection. Hepatocytes with RBBP8 inhibition by adenovirus-mediated shRNA were resistant to tunicamycin (Tm)-induced liver damage, cell death, and ER stress response. To study the pathological role of RBBP8 in regulating ATF4 activity, we illustrated that both RBBP8 and ATF4 were highly expressed in liver cancer tissues compared with healthy controls and highly expressed in Ki67-positive proliferating cells within the tumors. Interestingly, overexpression of RBBP8 in vitro promoted ATF4 activation under ER stress, and RBBP8 expression showed a positive correlation with ATF4 expression in liver cancer tissues by co-immunostaining. Our findings provide new insights into the mechanism of how cells adapt to ER stress through the crosstalk between the nucleus and ER and how tumor cells survive under chemotherapy or other anticancer treatments, which suggests potential therapeutic strategies against liver disease by targeting DNA damage repair, UPR or protein synthesis.
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Affiliation(s)
- Heting Wang
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xuya Pan
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaoxin Xiang
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yang Zhang
- Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, USA
- Cancer Biology Program/Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, USA
| | - Jianning Chen
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shiyi Wen
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jin Wang
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Rong Gao
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jifeng Yang
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yaping Zhi
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Siying Wen
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yubao Zheng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ting Li
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Heying Ai
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xuemin He
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yan Lu
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanhua Zhu
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chunliang Li
- Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, USA.
- Cancer Biology Program/Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, USA.
| | - Yanming Chen
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Guojun Shi
- Department of Endocrinology and Metabolism, Medical Center for Comprehensive Weight Control, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, China.
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13
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Strnad P, San Martin J. RNAi therapeutics for diseases involving protein aggregation: fazirsiran for alpha-1 antitrypsin deficiency-associated liver disease. Expert Opin Investig Drugs 2023; 32:571-581. [PMID: 37470509 DOI: 10.1080/13543784.2023.2239707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/23/2023] [Accepted: 07/19/2023] [Indexed: 07/21/2023]
Abstract
INTRODUCTION Therapeutic agents that prevent protein misfolding or promote protein clearance are being studied to treat proteotoxic diseases. Among them, alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the alpha-1 antitrypsin (SERPINA1) gene. Fazirsiran is a small interfering RNA (siRNA) that is intended to address the underlying cause of liver disease associated with AATD through the RNA interference (RNAi) mechanism. AREAS COVERED This article describes the role of misfolded proteins and protein aggregates in disease and options for therapeutic approaches. The RNAi mechanism is discussed, along with how the siRNA therapeutic fazirsiran for the treatment of AATD was developed. We also describe the implications of siRNA therapeutics in extrahepatic diseases. EXPERT OPINION Using RNAi as a therapeutic approach is well suited to treat disease in conditions where an excess of a protein or the effect of an abnormal mutated protein causes disease. The results observed for the first few siRNA therapeutics that were approved or are in development provide an important promise for the development of future drugs that can address such conditions in a specific and targeted way. Current developments should enable the use of RNAi therapeutics outside the liver, where there are many more possible diseases to address.
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Affiliation(s)
- Pavel Strnad
- Department of Internal Medicine III, University Hospital RWTH (Rheinisch-Westfälisch Technische Hochschule) Aachen, Aachen, Germany
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14
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Halle-Smith JM, Hall L, Hann A, Arshad A, Armstrong MJ, Bangash MN, Murphy N, Cuell J, Isaac JL, Ferguson J, Roberts KJ, Mirza DF, Perera MTPR. Low C-reactive Protein and Urea Distinguish Primary Nonfunction From Early Allograft Dysfunction Within 48 Hours of Liver Transplantation. Transplant Direct 2023; 9:e1484. [PMID: 37250485 PMCID: PMC10212614 DOI: 10.1097/txd.0000000000001484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 03/03/2023] [Indexed: 05/31/2023] Open
Abstract
Primary nonfunction (PNF) is a life-threatening complication of liver transplantation (LT), but in the early postoperative period, it can be difficult to differentiate from early allograft dysfunction (EAD). The aim of this study was to determine if serum biomarkers can distinguish PNF from EAD in the initial 48 h following LT. Materials and Methods A retrospective study of adult patients that underwent LT between January 2010 and April 2020 was performed. Clinical parameters, absolute values and trends of C-reactive protein (CRP), blood urea, creatinine, liver function tests, platelets, and international normalized ratio in the initial 48 h after LT were compared between the EAD and PNF groups. Results There were 1937 eligible LTs, with PNF and EAD occurring in 38 (2%) and 503 (26%) patients, respectively. A low serum CRP and urea were associated with PNF. CRP was able to differentiate between the PNF and EAD on postoperative day (POD)1 (20 versus 43 mg/L; P < 0.001) and POD2 (24 versus 77; P < 0.001). The area under the receiver operating characteristic curve (AUROC) of POD2 CRP was 0.770 (95% confidence interval [CI] 0.645-0.895). The urea value on POD2 (5.05 versus 9.0 mmol/L; P = 0.002) and trend of POD2:1 ratio (0.71 versus 1.32 mmol/L; P < 0.001) were significantly different between the groups. The AUROC of the change in urea from POD1 to 2 was 0.765 (95% CI 0.645-0.885). Aspartate transaminase was significantly different between the groups, with an AUROC of 0.884 (95% CI 0.753-1.00) on POD2. Discussion The biochemical profile immediately following LT can distinguish PNF from EAD; CRP, urea, and aspartate transaminase are more effective than ALT and bilirubin in distinguishing PNF from EAD in the initial postoperative 48 h. Clinicians should consider the values of these markers when making treatment decisions.
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Affiliation(s)
- James M. Halle-Smith
- Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
- College of Medical and Dental Sciences, University of Birmingham, Edgbaston, United Kingdom
| | - Lewis Hall
- College of Medical and Dental Sciences, University of Birmingham, Edgbaston, United Kingdom
| | - Angus Hann
- Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
- College of Medical and Dental Sciences, University of Birmingham, Edgbaston, United Kingdom
| | - Asif Arshad
- Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
| | - Matthew J. Armstrong
- Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
- College of Medical and Dental Sciences, University of Birmingham, Edgbaston, United Kingdom
| | - Mansoor N. Bangash
- Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
- College of Medical and Dental Sciences, University of Birmingham, Edgbaston, United Kingdom
| | - Nick Murphy
- Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
- College of Medical and Dental Sciences, University of Birmingham, Edgbaston, United Kingdom
| | - James Cuell
- Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
| | - John L. Isaac
- Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
| | - James Ferguson
- Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
- College of Medical and Dental Sciences, University of Birmingham, Edgbaston, United Kingdom
| | - Keith J. Roberts
- Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
- College of Medical and Dental Sciences, University of Birmingham, Edgbaston, United Kingdom
| | - Darius F. Mirza
- Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
- College of Medical and Dental Sciences, University of Birmingham, Edgbaston, United Kingdom
| | - M. Thamara P. R. Perera
- Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
- College of Medical and Dental Sciences, University of Birmingham, Edgbaston, United Kingdom
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15
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Rademacher L, Fromme M, Strnad P. Cleaning up alpha-1 antitrypsin deficiency related liver disease. Curr Opin Gastroenterol 2023; 39:163-168. [PMID: 37144533 DOI: 10.1097/mog.0000000000000919] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
PURPOSE OF REVIEW Alpha-1 antitrypsin deficiency (AATD) is one of the most common genetic disorders arising due to mutations in alpha-1 antitrypsin (AAT) gene affecting primarily the lung and the liver. This review summarizes the pathophysiology and clinical manifestation of different AATD genotypes and discusses the recent therapeutic developments. The focus is on the severe, rare homozygous Pi∗ZZ and the common heterozygous Pi∗MZ genotype. RECENT FINDINGS Pi∗ZZ individuals harbor an up to 20 times higher risk of liver fibrosis and cirrhosis than noncarriers and liver transplantation is currently the only available therapeutic option. AATD constitutes a proteotoxic disorder arising from hepatic AAT accumulation and the currently most promising data come from a phase 2, open-label trial of fazirsiran, a hepatocyte-targeted siRNA. Pi∗MZ subjects display an increased risk of advanced liver disease and at the latter stage, a faster deterioration than individuals without AAT mutation. SUMMARY Although the fazirsiran data offer a glimpse of hope to AATD patients, a consensus on appropriate study endpoint, a careful patient selection as well as monitoring of long-term safety will be essential for an approval.
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Affiliation(s)
- Laura Rademacher
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Healthcare Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany
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16
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Gurbuz B, Guldiken N, Reuken P, Fu L, Remih K, Preisinger C, Brůha R, Leníček M, Petrtýl J, Reissing J, Aly M, Fromme M, Zhou B, Karkossa I, Schubert K, von Bergen M, Stallmach A, Bruns T, Strnad P. Biomarkers of hepatocellular synthesis in patients with decompensated cirrhosis. Hepatol Int 2023; 17:698-708. [PMID: 36652164 DOI: 10.1007/s12072-022-10473-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/24/2022] [Indexed: 01/19/2023]
Abstract
BACKGROUND AND AIM Since hepatocytes produce majority of serum proteins, patients with cirrhosis display substantial alterations in the serum proteome. The aim of the current study was to characterize these changes and to study the prognostic utility of hepatocellular proteins available in routine clinical testing. METHODS Sera from 29 healthy controls and 43 patients with cirrhosis were subjected to untargeted proteomic analysis. Unsupervised hierarchical clustering was performed with Perseus software and R. Ingenuity pathway analysis (IPA) suggested upstream regulators that were validated in liver tissues. The behavior and prognostic usefulness of selected biomarkers was investigated in 61 controls and 285 subjects with decompensated cirrhosis. RESULTS Proteomics uncovered 65 and 16 hepatocellular serum proteins that are significantly downregulated or upregulated in patients with cirrhosis vs. controls. Hierarchical clustering revealed two main clusters and six sub-clusters. IPA identified HNF4α and IL-6 as the two major upstream regulators that were confirmed by hepatic gene expression analyses. Among pseudocholinesterase, transferrin, transthyretin, albumin, and apolipoprotein AI (Apo-AI), Apo-AI was the best predictor of 90-days transplant-free survival (AUROC 0.678; p = 0.0001) and remained an independent predictor in multivariable Cox independently of the presence of acute-on-chronic liver failure. CONCLUSION Our study reveals cirrhosis-associated changes in hepatocellular serum proteins and underlying transcription factors. Serum apolipoprotein AI may constitute a useful prognostic adjunct in patients with decompensated cirrhosis.
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Affiliation(s)
- Berivan Gurbuz
- Department of Internal Medicine III and IZKF, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Nurdan Guldiken
- Department of Internal Medicine III and IZKF, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Philipp Reuken
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Lei Fu
- Department of Internal Medicine III and IZKF, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.,Department of Science and Technology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Guangxi Zhuang Autonomous Region, Nanning, 530011, China
| | - Katharina Remih
- Department of Internal Medicine III and IZKF, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Christian Preisinger
- Proteomics Facility, Interdisciplinary Center for Clinical Research (IZKF), University Hospital RWTH, Aachen, Germany
| | - Radan Brůha
- 4th Department of Internal Medicine, First Faculty of Medicine, General University Hospital in Prague, Charles University, Prague, Czech Republic
| | - Martin Leníček
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, General University Hospital in Prague, Charles University, Prague, Czech Republic
| | - Jaromír Petrtýl
- 4th Department of Internal Medicine, First Faculty of Medicine, General University Hospital in Prague, Charles University, Prague, Czech Republic
| | - Johanna Reissing
- Department of Internal Medicine III and IZKF, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Mahmoud Aly
- Department of Internal Medicine III and IZKF, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.,Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat, 12 City, Sadat City, Egypt
| | - Malin Fromme
- Department of Internal Medicine III and IZKF, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Biaohuan Zhou
- Department of Internal Medicine III and IZKF, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.,Department of Surgical Oncology, Fujian Provincial Hospital, Fuzhou, China
| | - Isabel Karkossa
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Kristin Schubert
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Martin von Bergen
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany.,German Centre for Integrative Biodiversity Research, (iDiv) Halle-Jena-Leipzig, Leipzig, Germany.,Faculty of Life Sciences, Institute of Biochemistry, University of Leipzig, Leipzig, Germany
| | - Andreas Stallmach
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Tony Bruns
- Department of Internal Medicine III and IZKF, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.,Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Pavel Strnad
- Department of Internal Medicine III and IZKF, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.
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17
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Chen G, Wei T, Ju F, Li H. Protein quality control and aggregation in the endoplasmic reticulum: From basic to bedside. Front Cell Dev Biol 2023; 11:1156152. [PMID: 37152279 PMCID: PMC10154544 DOI: 10.3389/fcell.2023.1156152] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/10/2023] [Indexed: 05/09/2023] Open
Abstract
Endoplasmic reticulum (ER) is the largest membrane-bound compartment in all cells and functions as a key regulator in protein biosynthesis, lipid metabolism, and calcium balance. Mammalian endoplasmic reticulum has evolved with an orchestrated protein quality control system to handle defective proteins and ensure endoplasmic reticulum homeostasis. Nevertheless, the accumulation and aggregation of misfolded proteins in the endoplasmic reticulum may occur during pathological conditions. The inability of endoplasmic reticulum quality control system to clear faulty proteins and aggregates from the endoplasmic reticulum results in the development of many human disorders. The efforts to comprehensively understand endoplasmic reticulum quality control network and protein aggregation will benefit the diagnostics and therapeutics of endoplasmic reticulum storage diseases. Herein, we overview recent advances in mammalian endoplasmic reticulum protein quality control system, describe protein phase transition model, and summarize the approaches to monitor protein aggregation. Moreover, we discuss the therapeutic applications of enhancing endoplasmic reticulum protein quality control pathways in endoplasmic reticulum storage diseases.
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Affiliation(s)
- Guofang Chen
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tingyi Wei
- Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Precision Medicine, Shanghai, China
| | - Furong Ju
- Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Sha Tin, Hong kong SAR, China
| | - Haisen Li
- School of Life Sciences, Fudan University, Shanghai, China
- AoBio Medical, Shanghai, China
- *Correspondence: Haisen Li,
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18
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Behnke A, Gumpp AM, Rojas R, Sänger T, Lutz-Bonengel S, Moser D, Schelling G, Krumbholz A, Kolassa IT. Circulating inflammatory markers, cell-free mitochondrial DNA, cortisol, endocannabinoids, and N-acylethanolamines in female depressed outpatients. World J Biol Psychiatry 2023; 24:58-69. [PMID: 35532037 DOI: 10.1080/15622975.2022.2070666] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVES Major depressive disorder (MDD) involves peripheral low-grade pro-inflammatory activity. This multi-biomarker case-control study characterises the proinflammatory status in MDD beyond C-reactive protein (CRP) and Interleukin (IL)-6 levels through investigating concomitant alterations of immunoregulatory biomolecules. METHODS In 20 female MDD patients and 24 non-depressed women, circulating levels of CRP, IL-6, cortisol, selected endocannabinoids (ECs; anandamide [AEA], 2-arachidonylglycerol [2-AG]), and N-acylethanolamines (NAEs), as well as circulating cell-free mitochondrial DNA (ccf-mtDNA) were measured. RESULTS We found higher serum CRP and plasma AEA levels in MDD and a positive association of CRP and AEA levels with current depressive symptoms. Blood levels of cortisol, ccf-mtDNA, 2-AG, and NAEs did depend on MDD diagnosis nor correlated with the severity of current depressive symptoms. CRP correlated positively with AEA, and AEA showed positive associations with 2-AG and NAE levels. CONCLUSIONS In this study, female MDD outpatients with mild to moderate disorder severity did not substantially differ from non-depressed controls in the resting levels of multiple immunoregulatory markers in peripheral blood. Instead of investigating resting levels, future research on the role of inflammatory activity in MDD should focus on investigating the reactivity of pathways modulating the immune system upon exposure to physical and psychosocial stressors.
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Affiliation(s)
- Alexander Behnke
- Clinical & Biological Psychology, Institute of Psychology and Education, Ulm University, Ulm, Germany
| | - Anja Maria Gumpp
- Clinical & Biological Psychology, Institute of Psychology and Education, Ulm University, Ulm, Germany
| | - Roberto Rojas
- University Psychotherapeutic Outpatient Clinic, Institute of Psychology and Education, Ulm University, Ulm, Germany
| | - Timo Sänger
- Forensic Molecular Biology, Institute of Forensic Medicine, Medical Centre-University of Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sabine Lutz-Bonengel
- Forensic Molecular Biology, Institute of Forensic Medicine, Medical Centre-University of Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dirk Moser
- Molecular Genetics Lab, Department of Genetic Psychology, Ruhr-Universität Bochum, Bochum, Germany
| | - Gustav Schelling
- Department of Anaesthesiology, Ludwig Maximilians University, Munich, Germany
| | - Aniko Krumbholz
- Institute of Doping Analysis and Sports Biochemistry (IDAS) Dresden, Kreischa, Germany
| | - Iris-Tatjana Kolassa
- Clinical & Biological Psychology, Institute of Psychology and Education, Ulm University, Ulm, Germany
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19
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Weeks O, Miller BM, Pepe-Mooney BJ, Oderberg IM, Freeburg SH, Smith CJ, North TE, Goessling W. Embryonic alcohol exposure disrupts the ubiquitin-proteasome system. JCI Insight 2022; 7:e156914. [PMID: 36477359 PMCID: PMC9746913 DOI: 10.1172/jci.insight.156914] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 10/26/2022] [Indexed: 12/12/2022] Open
Abstract
Ethanol (EtOH) is a commonly encountered teratogen that can disrupt organ development and lead to fetal alcohol spectrum disorders (FASDs); many mechanisms of developmental toxicity are unknown. Here, we used transcriptomic analysis in an established zebrafish model of embryonic alcohol exposure (EAE) to identify the ubiquitin-proteasome system (UPS) as a critical target of EtOH during development. Surprisingly, EAE alters 20S, 19S, and 11S proteasome gene expression and increases ubiquitylated protein load. EtOH and its metabolite acetaldehyde decrease proteasomal peptidase activity in a cell type-specific manner. Proteasome 20S subunit β 1 (psmb1hi2939Tg) and proteasome 26S subunit, ATPase 6 (psmc6hi3593Tg), genetic KOs define the developmental impact of decreased proteasome function. Importantly, loss of psmb1 or psmc6 results in widespread developmental abnormalities resembling EAE phenotypes, including growth restriction, abnormal craniofacial structure, neurodevelopmental defects, and failed hepatopancreas maturation. Furthermore, pharmacologic inhibition of chymotrypsin-like proteasome activity potentiates the teratogenic effects of EAE on craniofacial structure, the nervous system, and the endoderm. Our studies identify the proteasome as a target of EtOH exposure and signify that UPS disruptions contribute to craniofacial, neurological, and endodermal phenotypes in FASDs.
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Affiliation(s)
- Olivia Weeks
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Bess M. Miller
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Brian J. Pepe-Mooney
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Isaac M. Oderberg
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Scott H. Freeburg
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Colton J. Smith
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Trista E. North
- Stem Cell Program, Department of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Cambridge, Massachusetts, USA
| | - Wolfram Goessling
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Cambridge, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
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20
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Wang L, Zhang YL, Jiang C, Duan FF, Yuan ZY, Huang JJ, Bi XW. Novel Signatures Based on the Lymphocyte-to-C-Reactive Protein Ratio Predict the Prognosis of Patients with Early Breast Cancer: A Retrospective Study. J Inflamm Res 2022; 15:3957-3974. [PMID: 35860229 PMCID: PMC9289276 DOI: 10.2147/jir.s364284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 07/07/2022] [Indexed: 01/08/2023] Open
Abstract
Background The value of the lymphocyte-to-C-reactive protein (CRP) ratio (LCR) in early breast cancer (BC) is unclear. We explored the correlation between the LCR and survival of patients with early BC and established effective LCR-based prognostic signatures for predicting prognosis. Methods In this retrospective study, we randomized 623 patients with early-stage BC diagnosed in December 2010 to October 2012 at the Sun Yat-sen University Cancer Center to training and verification datasets. The median follow-up of all patients was 109 months. The survival differences were calculated by Kaplan–Meier method using the Log rank test. For overall survival (OS) and disease-free survival (DFS), the independent factors in the training dataset were identified using univariate and multivariate Cox analyses, in which two-tailed P-values < 0.05 were considered statistically significant. Based on this, we respectively constructed novel signatures for survival prediction and validated the efficiency of signatures through the concordance index (C-index), calibration and receiver operating characteristic (ROC) curves in both datasets. Results The LCR, lymphatic vessel invasion (LVI), progesterone receptor (PR) status, and Ki67 index were independent prognostic factors of OS. And the LCR and LVI are associated to DFS too. High LCR was associated with better OS and DFS. We constructed the prediction signatures based on those independent prognostic factors and calculated the risk scores. Patients in the training dataset with higher risk scores had significantly worse prognosis (P < 0.001). The signature had excellent discrimination capacity, with an OS C-index of 0.785 [95% confidence interval (CI): 0.713–0.857] and 0.750 (95% CI: 0.669–0.832) in the training and verification datasets, respectively. The time–ROC curves also suggest accurate prediction by the signature. Conclusion The LCR was a significant prognostic predictor of OS and DFS in early BC. The LCR-based prognostic signatures could be a useful tool for individualized therapeutic guidance.
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Affiliation(s)
- Li Wang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Yu-Ling Zhang
- Department of Endocrinology, Jiangxi Provincial People's Hospital, Nanchang, People's Republic of China
| | - Chang Jiang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Fang-Fang Duan
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Zhong-Yu Yuan
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Jia-Jia Huang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Xi-Wen Bi
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
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21
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Enrichment Methods for Murine Liver Non-Parenchymal Cells Differentially Affect Their Immunophenotype and Responsiveness towards Stimulation. Int J Mol Sci 2022; 23:ijms23126543. [PMID: 35742987 PMCID: PMC9223567 DOI: 10.3390/ijms23126543] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/07/2022] [Accepted: 06/09/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatocytes comprise the majority of the liver and largely exert metabolic functions, whereas non-parenchymal cells (NPCs)—comprising Kupffer cells, dendritic cells and liver sinusoidal endothelial cells—control the immunological state within this organ. Here, we compared the suitability of two isolation methods for murine liver NPCs. Liver perfusion (LP) with collagenase/DNase I applied via the portal vein leads to efficient liver digestion, whereas the modified liver dissociation (LD) method combines mechanical dissociation of the retrieved organ with enzymatic degradation of the extracellular matrix. In cases of both LP and LD, NPCs were enriched by subsequent gradient density centrifugation. Our results indicate that LP and LD are largely comparable with regards to the yield, purity, and composition of liver NPCs. However, LD-enriched liver NPCs displayed a higher degree of activation after overnight cultivation, and accordingly were less responsive towards stimulation with toll-like receptor ligands that are frequently used as adjuvants, e.g., in nano-vaccines. We conclude that LP is more suitable for obtaining liver NPCs for subsequent in vitro studies, whereas LD as the less laborious method, is more convenient for parallel isolation of larger numbers of samples for ex vivo analysis.
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22
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The Relationship between Plasma Alpha-1-Antitrypsin Polymers and Lung or Liver Function in ZZ Alpha-1-Antitrypsin-Deficient Patients. Biomolecules 2022; 12:biom12030380. [PMID: 35327571 PMCID: PMC8945708 DOI: 10.3390/biom12030380] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/21/2022] [Accepted: 02/25/2022] [Indexed: 12/14/2022] Open
Abstract
Alpha-1-Antitrypsin (AAT) is a protein of the SERPINA1 gene. A single amino acid mutation (Lys342Glu) results in an expression of misfolded Z-AAT protein, which has a high propensity to intra- and extra-cellular polymerization. Here, we asked whether levels of circulating Z-AAT polymers are associated with the severity of lung disease, liver disease, or both. We obtained cross sectional data from the Dutch part of the Alpha1 International Registry of 52 ZZ-AAT patients who performed a pulmonary function test and donated a blood sample on the same day. From the Alpha-1 Liver Aachen Registry, we obtained a cohort of 40 ZZ-AAT patients with available data on their liver function. The levels of plasma Z-AAT polymers were determined using a LG96 monoclonal antibody-based sandwich ELISA. In a Dutch cohort, the median plasma level of Z-AAT polymers of patients diagnosed for pulmonary disease was 947.5 µg/mL (733.6−1218 µg/mL (95% CI)), which did not correlate with airflow obstruction or gas transfer value. In the Alpha-1 liver patient cohort, the median polymer level was 1245.9 µg/mL (753−2034 µg/mL (95% CI)), which correlated with plasma gamma-glutamyl transferase (GGT, rs = 0.57, p = 0.001), glutamate dehydrogenase (GLDH, rs = 0.48, p = 0.002) and triglycerides (TG, rs = 0.48, p = 0.0046). A Wilcoxon rank test showed higher Z-AAT polymer values for the liver over the lung group (p < 0.0001). These correlations support a possible link between plasma Z-AAT polymers and the liver function.
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23
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Duwaerts CC, Maiers JL. ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets. Front Mol Biosci 2022; 8:804097. [PMID: 35174209 PMCID: PMC8841999 DOI: 10.3389/fmolb.2021.804097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 11/18/2021] [Indexed: 11/13/2022] Open
Abstract
The endoplasmic reticulum is a central player in liver pathophysiology. Chronic injury to the ER through increased lipid content, alcohol metabolism, or accumulation of misfolded proteins causes ER stress, dysregulated hepatocyte function, inflammation, and worsened disease pathogenesis. A key adaptation of the ER to resolve stress is the removal of excess or misfolded proteins. Degradation of intra-luminal or ER membrane proteins occurs through distinct mechanisms that include ER-associated Degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD), which includes macro-ER-phagy, micro-ER-phagy, and Atg8/LC-3-dependent vesicular delivery. All three of these processes are critical for removing misfolded or unfolded protein aggregates, and re-establishing ER homeostasis following expansion/stress, which is critical for liver function and adaptation to injury. Despite playing a key role in resolving ER stress, the contribution of these degradative processes to liver physiology and pathophysiology is understudied. Analysis of publicly available datasets from diseased livers revealed that numerous genes involved in ER-related degradative pathways are dysregulated; however, their roles and regulation in disease progression are not well defined. Here we discuss the dynamic regulation of ER-related protein disposal pathways in chronic liver disease and cell-type specific roles, as well as potentially targetable mechanisms for treatment of chronic liver disease.
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Affiliation(s)
- Caroline C. Duwaerts
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Jessica L. Maiers
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
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24
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Morro B, Broughton R, Balseiro P, Handeland SO, Mackenzie S, Doherty MK, Whitfield PD, Shimizu M, Gorissen M, Sveier H, Albalat A. Endoplasmic reticulum stress as a key mechanism in stunted growth of seawater rainbow trout (Oncorhynchus mykiss). BMC Genomics 2021; 22:824. [PMID: 34781893 PMCID: PMC8594166 DOI: 10.1186/s12864-021-08153-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 11/01/2021] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Rainbow trout (Oncorhynchus mykiss) is a salmonid species with a complex life-history. Wild populations are naturally divided into freshwater residents and sea-run migrants. Migrants undergo an energy-demanding adaptation for life in seawater, known as smoltification, while freshwater residents display these changes in an attenuated magnitude and rate. Despite this, in seawater rainbow trout farming all fish are transferred to seawater. Under these circumstances, weeks after seawater transfer, a significant portion of the fish die (around 10%) or experience growth stunting (GS; around 10%), which represents an important profitability and welfare issue. The underlying causes leading to GS in seawater-transferred rainbow trout remain unknown. In this study, we aimed at characterising the GS phenotype in seawater-transferred rainbow trout using untargeted and targeted approaches. To this end, the liver proteome (LC-MS/MS) and lipidome (LC-MS) of GS and fast-growing phenotypes were profiled to identify molecules and processes that are characteristic of the GS phenotype. Moreover, the transcription, abundance or activity of key proteins and hormones related to osmoregulation (Gill Na+, K + -ATPase activity), growth (plasma IGF-I, and liver igf1, igfbp1b, ghr1 and ctsl) and stress (plasma cortisol) were measured using targeted approaches. RESULTS No differences in Gill Na+, K + -ATPase activity and plasma cortisol were detected between the two groups. However, a significant downregulation in plasma IGF-I and liver igf1 transcription pointed at this growth factor as an important pathomechanism for GS. Changes in the liver proteome revealed reactive-oxygen-species-mediated endoplasmic reticulum stress as a key mechanism underlying the GS phenotype. From the lipidomic analysis, key observations include a reduction in triacylglycerols and elevated amounts of cardiolipins, a characteristic lipid class associated with oxidative stress, in GS phenotype. CONCLUSION While the triggers to the activation of endoplasmic reticulum stress are still unknown, data from this study point towards a nutritional deficiency as an underlying driver of this phenotype.
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Affiliation(s)
- Bernat Morro
- Institute of Aquaculture, University of Stirling, Stirling, UK
| | | | - Pablo Balseiro
- NORCE AS, Bergen, Norway.,Department of Biological Sciences, University of Bergen, Bergen, Norway
| | - Sigurd O Handeland
- NORCE AS, Bergen, Norway.,Department of Biological Sciences, University of Bergen, Bergen, Norway
| | - Simon Mackenzie
- Institute of Aquaculture, University of Stirling, Stirling, UK.,NORCE AS, Bergen, Norway
| | - Mary K Doherty
- Institute of Health Research and Innovation, Centre for Health Science, University of the Highlands and Islands, Scotland, UK
| | - Phillip D Whitfield
- Institute of Health Research and Innovation, Centre for Health Science, University of the Highlands and Islands, Scotland, UK.,Institute of Infection, Immunity and Inflammation, University of Glasgow, Scotland, UK
| | - Munetaka Shimizu
- Faculty of Fisheries Sciences, Hokkaido University, Sapporo, Japan
| | - Marnix Gorissen
- Department of Animal Ecology and Physiology, Radboud University, Institute of Water and Wetland Research, Nijmegen, The Netherlands
| | | | - Amaya Albalat
- Institute of Aquaculture, University of Stirling, Stirling, UK.
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25
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Anderson R, Agarwal A, Ghosh A, Guan B, Casteel J, Dvorina N, Baldwin WM, Mazumder B, Nazarko TY, Merrick WC, Buchner DA, Hatzoglou M, Kondratov RV, Komar AA. eIF2A-knockout mice reveal decreased life span and metabolic syndrome. FASEB J 2021; 35:e21990. [PMID: 34665898 PMCID: PMC8848898 DOI: 10.1096/fj.202101105r] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/02/2021] [Accepted: 09/29/2021] [Indexed: 01/07/2023]
Abstract
Eukaryotic initiation factor 2A (eIF2A) is a 65 kDa protein that functions in minor initiation pathways, which affect the translation of only a subset of messenger ribonucleic acid (mRNAs), such as internal ribosome entry site (IRES)-containing mRNAs and/or mRNAs harboring upstream near cognate/non-AUG start codons. These non-canonical initiation events are important for regulation of protein synthesis during cellular development and/or the integrated stress response. Selective eIF2A knockdown in cellular systems significantly inhibits translation of such mRNAs, which rely on alternative initiation mechanisms for their translation. However, there exists a gap in our understanding of how eIF2A functions in mammalian systems in vivo (on the organismal level) and ex vivo (in cells). Here, using an eIF2A-knockout (KO) mouse model, we present evidence implicating eIF2A in the biology of aging, metabolic syndrome and central tolerance. We discovered that eIF2A-KO mice have reduced life span and that eIF2A plays an important role in maintenance of lipid homeostasis, the control of glucose tolerance, insulin resistance and also reduces the abundance of B lymphocytes and dendritic cells in the thymic medulla of mice. We also show the eIF2A KO affects male and female mice differently, suggesting that eIF2A may affect sex-specific pathways. Interestingly, our experiments involving pharmacological induction of endoplasmic reticulum (ER) stress with tunicamycin did not reveal any substantial difference between the response to ER stress in eIF2A-KO and wild-type mice. The identification of eIF2A function in the development of metabolic syndrome bears promise for the further identification of specific eIF2A targets responsible for these changes.
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Affiliation(s)
- Richard Anderson
- Center for Gene Regulation in Health and DiseaseDepartment of Biological, Geological and Environmental SciencesCleveland State UniversityClevelandOhioUSA
| | - Anchal Agarwal
- Center for Gene Regulation in Health and DiseaseDepartment of Biological, Geological and Environmental SciencesCleveland State UniversityClevelandOhioUSA
| | - Arnab Ghosh
- Center for Gene Regulation in Health and DiseaseDepartment of Biological, Geological and Environmental SciencesCleveland State UniversityClevelandOhioUSA
| | - Bo‐Jhih Guan
- Department of Genetics and Genome SciencesCase Western Reserve University School of MedicineClevelandOhioUSA
| | - Jackson Casteel
- Center for Gene Regulation in Health and DiseaseDepartment of Biological, Geological and Environmental SciencesCleveland State UniversityClevelandOhioUSA
| | - Nina Dvorina
- Department of Inflammation and ImmunityCleveland Clinic Lerner College of MedicineClevelandOhioUSA
| | - William M. Baldwin
- Department of Inflammation and ImmunityCleveland Clinic Lerner College of MedicineClevelandOhioUSA
| | - Barsanjit Mazumder
- Center for Gene Regulation in Health and DiseaseDepartment of Biological, Geological and Environmental SciencesCleveland State UniversityClevelandOhioUSA
| | | | - William C. Merrick
- Department of BiochemistryCase Western Reserve University School of MedicineClevelandOhioUSA
| | - David A. Buchner
- Department of Genetics and Genome SciencesCase Western Reserve University School of MedicineClevelandOhioUSA,Department of BiochemistryCase Western Reserve University School of MedicineClevelandOhioUSA
| | - Maria Hatzoglou
- Department of Genetics and Genome SciencesCase Western Reserve University School of MedicineClevelandOhioUSA
| | - Roman V. Kondratov
- Center for Gene Regulation in Health and DiseaseDepartment of Biological, Geological and Environmental SciencesCleveland State UniversityClevelandOhioUSA
| | - Anton A. Komar
- Center for Gene Regulation in Health and DiseaseDepartment of Biological, Geological and Environmental SciencesCleveland State UniversityClevelandOhioUSA,Department of BiochemistryCase Western Reserve University School of MedicineClevelandOhioUSA
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26
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Hakim A, Moll M, Qiao D, Liu J, Lasky‐Su JA, Silverman EK, Vilarinho S, Jiang ZG, Hobbs BD, Cho MH. Heterozygosity of the Alpha 1-Antitrypsin Pi*Z Allele and Risk of Liver Disease. Hepatol Commun 2021; 5:1348-1361. [PMID: 34430780 PMCID: PMC8369947 DOI: 10.1002/hep4.1718] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 01/29/2021] [Accepted: 03/01/2021] [Indexed: 02/04/2023] Open
Abstract
The serpin family A member 1 (SERPINA1) Z allele is present in approximately one in 25 individuals of European ancestry. Z allele homozygosity (Pi*ZZ) is the most common cause of alpha 1-antitrypsin deficiency and is a proven risk factor for cirrhosis. We examined whether heterozygous Z allele (Pi*Z) carriers in United Kingdom (UK) Biobank, a population-based cohort, are at increased risk of liver disease. We replicated findings in Massachusetts General Brigham Biobank, a hospital-based cohort. We also examined variants associated with liver disease and assessed for gene-gene and gene-environment interactions. In UK Biobank, we identified 1,493 cases of cirrhosis, 12,603 Z allele heterozygotes, and 129 Z allele homozygotes among 312,671 unrelated white British participants. Heterozygous carriage of the Z allele was associated with cirrhosis compared to noncarriage (odds ratio [OR], 1.53; P = 1.1×10-04); homozygosity of the Z allele also increased the risk of cirrhosis (OR, 11.8; P = 1.8 × 10-09). The OR for cirrhosis of the Z allele was comparable to that of well-established genetic variants, including patatin-like phospholipase domain containing 3 (PNPLA3) I148M (OR, 1.48; P = 1.1 × 10-22) and transmembrane 6 superfamily member 2 (TM6SF2) E167K (OR, 1.34; P = 2.6 × 10-06). In heterozygotes compared to noncarriers, the Z allele was associated with higher alanine aminotransferase (ALT; P = = 4.6 × 10-46), aspartate aminotransferase (AST; P = 2.2 × 10-27), alkaline phosphatase (P = 3.3 × 10-43), gamma-glutamyltransferase (P = 1.2 × 10-05), and total bilirubin (P = 6.4 × 10-06); Z allele homozygotes had even greater elevations in liver biochemistries. Body mass index (BMI) amplified the association of the Z allele for ALT (P interaction = 0.021) and AST (P interaction = 0.0040), suggesting a gene-environment interaction. Finally, we demonstrated genetic interactions between variants in PNPLA3, TM6SF2, and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13); there was no evidence of epistasis between the Z allele and these variants. Conclusion: SERPINA1 Z allele heterozygosity is an important risk factor for liver disease; this risk is amplified by increasing BMI.
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Affiliation(s)
- Aaron Hakim
- Department of MedicineBeth Israel Deaconess Medical CenterBostonMAUSA
- Division of Gastroenterology and HepatologyBeth Israel Deaconess Medical CenterBostonMAUSA
- Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA
| | - Matthew Moll
- Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA
- Division of Pulmonary and Critical Care MedicineBrigham and Women's HospitalBostonMAUSA
| | - Dandi Qiao
- Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA
| | - Jiangyuan Liu
- Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA
| | - Jessica A. Lasky‐Su
- Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA
| | - Edwin K. Silverman
- Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA
- Division of Pulmonary and Critical Care MedicineBrigham and Women's HospitalBostonMAUSA
| | - Silvia Vilarinho
- Department of Internal MedicineSection of Digestive DiseasesYale School of MedicineNew HavenCTUSA
- Department of PathologyYale School of MedicineNew HavenCTUSA
| | - Z. Gordon Jiang
- Department of MedicineBeth Israel Deaconess Medical CenterBostonMAUSA
- Division of Gastroenterology and HepatologyBeth Israel Deaconess Medical CenterBostonMAUSA
| | - Brian D. Hobbs
- Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA
- Division of Pulmonary and Critical Care MedicineBrigham and Women's HospitalBostonMAUSA
| | - Michael H. Cho
- Department of MedicineBeth Israel Deaconess Medical CenterBostonMAUSA
- Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA
- Division of Pulmonary and Critical Care MedicineBrigham and Women's HospitalBostonMAUSA
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López-López V, Pérez-Sánz F, de Torre-Minguela C, Marco-Abenza J, Robles-Campos R, Sánchez-Bueno F, Pons JA, Ramírez P, Baroja-Mazo A. Proteomics in Liver Transplantation: A Systematic Review. Front Immunol 2021; 12:672829. [PMID: 34381445 PMCID: PMC8350337 DOI: 10.3389/fimmu.2021.672829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 07/12/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Although proteomics has been employed in the study of several models of liver injury, proteomic methods have only recently been applied not only to biomarker discovery and validation but also to improve understanding of the molecular mechanisms involved in transplantation. METHODS The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology and the guidelines for performing systematic literature reviews in bioinformatics (BiSLR). The PubMed, ScienceDirect, and Scopus databases were searched for publications through April 2020. Proteomics studies designed to understand liver transplant outcomes, including ischemia-reperfusion injury (IRI), rejection, or operational tolerance in human or rat samples that applied methodologies for differential expression analysis were considered. RESULTS The analysis included 22 studies after application of the inclusion and exclusion criteria. Among the 497 proteins annotated, 68 were shared between species and 10 were shared between sample sources. Among the types of studies analyzed, IRI and rejection shared a higher number of proteins. The most enriched pathway for liver biopsy samples, IRI, and rejection was metabolism, compared to cytokine-cytokine receptor interactions for tolerance. CONCLUSIONS Proteomics is a promising technique to detect large numbers of proteins. However, our study shows that several technical issues such as the identification of proteoforms or the dynamic range of protein concentration in clinical samples hinder the successful identification of biomarkers in liver transplantation. In addition, there is a need to minimize the experimental variability between studies, increase the sample size and remove high-abundance plasma proteins.
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Affiliation(s)
- Victor López-López
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Digestive and Endocrine Surgery and Transplantation of Abdominal Organs, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain
| | - Fernando Pérez-Sánz
- Biomedical Informatic and Bioinformatic Platform, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain
| | - Carlos de Torre-Minguela
- Digestive and Endocrine Surgery and Transplantation of Abdominal Organs, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain
| | | | - Ricardo Robles-Campos
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Digestive and Endocrine Surgery and Transplantation of Abdominal Organs, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain
| | - Francisco Sánchez-Bueno
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Digestive and Endocrine Surgery and Transplantation of Abdominal Organs, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain
| | - José A. Pons
- Digestive and Endocrine Surgery and Transplantation of Abdominal Organs, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain
- Department of Gastroenterology, Unit of Hepatology, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - Pablo Ramírez
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Digestive and Endocrine Surgery and Transplantation of Abdominal Organs, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain
| | - Alberto Baroja-Mazo
- Digestive and Endocrine Surgery and Transplantation of Abdominal Organs, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain
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Kuscuoglu D, Bewersdorf L, Wenzel K, Gross A, Kobazi Ensari G, Luo Y, Kilic K, Hittatiya K, Golob-Schwarzl N, Leube RE, Preisinger C, George J, Metwally M, Eslam M, Lampertico P, Petta S, Mangia A, Berg T, Boonstra A, Brouwer WP, Abate ML, Loglio A, Sutton A, Nahon P, Schaefer B, Zoller H, Aigner E, Trautwein C, Haybaeck J, Strnad P. Dual proteotoxic stress accelerates liver injury via activation of p62-Nrf2. J Pathol 2021; 254:80-91. [PMID: 33586163 DOI: 10.1002/path.5643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 01/29/2021] [Accepted: 02/10/2021] [Indexed: 02/06/2023]
Abstract
Protein accumulation is the hallmark of various neuronal, muscular, and other human disorders. It is also often seen in the liver as a major protein-secretory organ. For example, aggregation of mutated alpha1-antitrypsin (AAT), referred to as PiZ, is a characteristic feature of AAT deficiency, whereas retention of hepatitis B surface protein (HBs) is found in chronic hepatitis B (CHB) infection. We investigated the interaction of both proteotoxic stresses in humans and mice. Animals overexpressing both PiZ and HBs (HBs-PiZ mice) had greater liver injury, steatosis, and fibrosis. Later they exhibited higher hepatocellular carcinoma load and a more aggressive tumor subtype. Although PiZ and HBs displayed differing solubility properties and distinct distribution patterns, HBs-PiZ animals manifested retention of AAT/HBs in the degradatory pathway and a marked accumulation of the autophagy adaptor p62. Isolation of p62-containing particles revealed retained HBs/AAT and the lipophagy adapter perilipin-2. p62 build-up led to activation of the p62-Nrf2 axis and emergence of reactive oxygen species. Our results demonstrate that the simultaneous presence of two prevalent proteotoxic stresses promotes the development of liver injury due to protein retention and activation of the p62-Nrf2 axis. In humans, the PiZ variant was over-represented in CHB patients with advanced liver fibrosis (unadjusted odds ratio = 9.92 [1.15-85.39]). Current siRNA approaches targeting HBs/AAT should be considered for these individuals. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Deniz Kuscuoglu
- Department of Medicine III, University Hospital Aachen, Aachen, Germany
| | - Lisa Bewersdorf
- Department of Medicine III, University Hospital Aachen, Aachen, Germany
| | - Kathrin Wenzel
- Department of Medicine III, University Hospital Aachen, Aachen, Germany
| | - Annika Gross
- Department of Medicine III, University Hospital Aachen, Aachen, Germany
| | | | - Yizhao Luo
- Department of Medicine III, University Hospital Aachen, Aachen, Germany
| | - Konrad Kilic
- Department of Medicine III, University Hospital Aachen, Aachen, Germany
| | | | | | - Rudolf E Leube
- Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Aachen, Germany
| | - Christian Preisinger
- Proteomics Facility, Interdisciplinary Centre for Clinical Research (IZKF), Medical School, RWTH Aachen University, Aachen, Germany
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, Australia
| | - Mayada Metwally
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, Australia
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, Australia
| | - Pietro Lampertico
- CRC 'A. M. e A. Migliavacca' Center for Liver Disease Division of Gastroenterology and Hepatology Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università di Milano, Milan, Italy
| | - Salvatore Petta
- Sezione di Gastroenterologia e Epatologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Alessandra Mangia
- Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy
| | - Thomas Berg
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Willem P Brouwer
- Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Maria Lorena Abate
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy
| | - Alessandro Loglio
- CRC 'A. M. e A. Migliavacca' Center for Liver Disease Division of Gastroenterology and Hepatology Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università di Milano, Milan, Italy
| | - Angela Sutton
- Centre de Ressources Biologiques (Liver Disease Biobank) Groupe Hospitalier Paris, Seine-Saint-Denis, France
- AP-HP Hôpital Jean Verdier, Service de Biochimie, Bondy, France
- Inserm U1148, Université Paris 13, Bobigny, France
| | - Pierre Nahon
- AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy, France
- Université Paris 13, Sorbonne Paris Cité, 'Equipe Labellisée Ligue Contre le Cancer', Saint-Denis, France
- Inserm, UMR-1162, 'Génomique Fonctionnelle des Tumeur Solides', Paris, France
| | - Benedikt Schaefer
- Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
| | - Heinz Zoller
- Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
| | - Elmar Aigner
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | | | - Johannes Haybaeck
- Department of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria
| | - Pavel Strnad
- Department of Medicine III, University Hospital Aachen, Aachen, Germany
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Trovato M, Sciacchitano S, Facciolà A, Valenti A, Visalli G, Di Pietro A. Interleukin‑6 signalling as a valuable cornerstone for molecular medicine (Review). Int J Mol Med 2021; 47:107. [PMID: 33907833 PMCID: PMC8057292 DOI: 10.3892/ijmm.2021.4940] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/23/2021] [Indexed: 12/14/2022] Open
Abstract
The biological abilities of interleukin-6 (IL-6) have been under investigation for nearly 40 years. IL-6 works through an interaction with the complex peptide IL-6 receptor (IL-6R). IL-6 is built with four α-chain nanostructures, while two different chains, IL-6Rα (gp80) and gp130/IL6β (gp130), are included in IL-6R. The three-dimensional shapes of the six chains composing the IL-6/IL-6R complex are the basis for the nanomolecular roles of IL-6 signalling. Genes, pseudogenes and competitive endogenous RNAs of IL-6 have been identified. In the present review, the roles played by miRNA in the post-transcriptional regulation of IL-6 expression are evaluated. mRNAs are absorbed via the 'sponge' effect to dynamically balance mRNA levels and this has been assessed with regard to IL-6 transcription efficiency. According to current knowledge on molecular and nanomolecular structures involved in active IL-6 signalling, two different IL-6 models have been proposed. IL-6 mainly has functions in inflammatory processes, as well as in cognitive activities. Furthermore, the abnormal production of IL-6 has been found in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; also known as COVID-19). In the present review, both inflammatory and cognitive IL-6 models were analysed by evaluating the cytological and histological locations of IL-6 signalling. The goal of this review was to illustrate the roles of the classic and trans-signalling IL-6 pathways in endocrine glands such as the thyroid and in the central nervous system. Specifically, autoimmune thyroid diseases, disorders of cognitive processes and SARS-CoV-2 virus infection have been examined to determine the contribution of IL-6 to these disease states.
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Affiliation(s)
- Maria Trovato
- Department of Clinical and Experimental Medicine, University Hospital, I‑98125 Messina, Italy
| | | | - Alessio Facciolà
- Department of Clinical and Experimental Medicine, University Hospital, I‑98125 Messina, Italy
| | - Andrea Valenti
- Department of Clinical and Experimental Medicine, University Hospital, I‑98125 Messina, Italy
| | - Giuseppa Visalli
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Policlinico Universitario, I‑98125 Messina, Italy
| | - Angela Di Pietro
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Policlinico Universitario, I‑98125 Messina, Italy
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Jia J, Yang L, Cao Z, Wang M, Ma Y, Ma X, Liu Q, Teng J, Shi H, Liu H, Cheng X, Ye J, Su Y, Sun Y, Chi H, Liu T, Wang Z, Wan L, Yang C, Hu Q. Neutrophil-derived lipocalin-2 in adult-onset Still's disease: a novel biomarker of disease activity and liver damage. Rheumatology (Oxford) 2021; 60:304-315. [PMID: 32766690 PMCID: PMC7785307 DOI: 10.1093/rheumatology/keaa368] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/20/2020] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE Liver damage is a common manifestation and can be life-threatening in adult-onset Still's disease (AOSD), an autoinflammatory disease. The hallmark of AOSD is activation of neutrophils, whose infiltration in liver is suspected to promote tissue injury. Here we aimed to identify a candidate biomarker and to validate its association with liver damage in AOSD. METHODS Transcriptome analysis of neutrophils from treatment-naïve active AOSD patients and healthy donors was performed. Lipocalin-2 (LCN2) expression was assessed in neutrophils, plasma and liver biopsies of AOSD. The correlations of LCN2 with different variables and its ability to identify liver damage from AOSD patients were analysed. RESULTS LCN2, a novel biomarker in hepatic inflammation, was found to be upregulated in AOSD neutrophils by RNA sequencing and confirmed at the mRNA and protein levels. Plasma levels of LCN2 were significantly higher in AOSD patients than healthy controls, RA and SLE patients. Plasma LCN2 levels were closely correlated with inflammatory markers, systemic score, HScore and cytokines. Moreover, LCN2 levels were increased in active AOSD with liver involvement and independently associated with liver dysfunction. Enhanced expression of LCN2 was detected in liver biopsies from three patients with ongoing liver injury. Furthermore, the area under the curve value of LCN2 for identifying AOSD with liver injury from other liver diseases was 0.9694. CONCLUSION Our results reveal that neutrophils-derived LCN2 is higher in plasma and liver tissue in AOSD patients than in healthy controls, and it could serve as a potent biomarker for identifying AOSD with systemic inflammation, especially liver damage caused by hyperinflammation.
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Affiliation(s)
- Jinchao Jia
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Luyu Yang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University
| | - Zhujun Cao
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Mengyan Wang
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Yuning Ma
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qiaoyan Liu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jialin Teng
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Hui Shi
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Honglei Liu
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Xiaobing Cheng
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Junna Ye
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Yutong Su
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Yue Sun
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Huihui Chi
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Tingting Liu
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Zhihong Wang
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Liyan Wan
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Chengde Yang
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
| | - Qiongyi Hu
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
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Payen VL, Lavergne A, Alevra Sarika N, Colonval M, Karim L, Deckers M, Najimi M, Coppieters W, Charloteaux B, Sokal EM, El Taghdouini A. Single-cell RNA sequencing of human liver reveals hepatic stellate cell heterogeneity. JHEP Rep 2021; 3:100278. [PMID: 34027339 PMCID: PMC8121977 DOI: 10.1016/j.jhepr.2021.100278] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 02/11/2021] [Accepted: 02/28/2021] [Indexed: 02/07/2023] Open
Abstract
Background & Aims The multiple vital functions of the human liver are performed by highly specialised parenchymal and non-parenchymal cells organised in complex collaborative sinusoidal units. Although crucial for homeostasis, the cellular make-up of the human liver remains to be fully elucidated. Here, single-cell RNA-sequencing was used to unravel the heterogeneity of human liver cells, in particular of hepatocytes (HEPs) and hepatic stellate cells (HSCs). Method The transcriptome of ~25,000 freshly isolated human liver cells was profiled using droplet-based RNA-sequencing. Recently published data sets and RNA in situ hybridisation were integrated to validate and locate newly identified cell populations. Results In total, 22 cell populations were annotated that reflected the heterogeneity of human parenchymal and non-parenchymal liver cells. More than 20,000 HEPs were ordered along the portocentral axis to confirm known, and reveal previously undescribed, zonated liver functions. The existence of 2 subpopulations of human HSCs with unique gene expression signatures and distinct intralobular localisation was revealed (i.e. portal and central vein-concentrated GPC3+ HSCs and perisinusoidally located DBH+ HSCs). In particular, these data suggest that, although both subpopulations collaborate in the production and organisation of extracellular matrix, GPC3+ HSCs specifically express genes involved in the metabolism of glycosaminoglycans, whereas DBH+ HSCs display a gene signature that is reminiscent of antigen-presenting cells. Conclusions This study highlights metabolic zonation as a key determinant of HEP transcriptomic heterogeneity and, for the first time, outlines the existence of heterogeneous HSC subpopulations in the human liver. These findings call for further research on the functional implications of liver cell heterogeneity in health and disease. Lay summary This study resolves the cellular landscape of the human liver in an unbiased manner and at high resolution to provide new insights into human liver cell biology. The results highlight the physiological heterogeneity of human hepatic stellate cells.
A cell atlas from the near-native transcriptome of >25,000 human liver cells is presented. Hepatocytes were ordered along the portocentral axis to reveal previously undescribed gene expression patterns and zonated liver functions. Two subpopulations of human hepatic stellate cells (HSCs) are reported, characterised by different spatial distribution in the native tissue. Characteristic gene signatures of HSC subpopulations are suggestive of far-reaching functional differences.
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Key Words
- BSA, bovine serum albumin
- CC, cholangiocyte
- CV, central vein
- DEG, differentially expressed gene
- EC, endothelial cell
- ECM, extracellular matrix
- Extracellular matrix
- FFPE, formaldehyde-fixed paraffin embedded
- GAG, glycosaminoglycan
- GEO, Gene Expression Omnibus
- GO, gene ontology
- HEP, hepatocyte
- HLA, human leukocyte antigen
- HRP, horseradish peroxidase
- HSC, hepatic stellate cell
- Hepatocyte
- ISH, in situ hybridisation
- KLR, killer lectin-like receptor
- LP, lymphoid cell
- Liver cell atlas
- MP, macrophage
- MZ, midzonal
- PC, pericentral
- PP, periportal
- PV, portal vein
- TBS, Tris buffered saline
- TSA, tyramide signal amplification
- UMAP, uniform manifold approximation and projection
- UMI, unique molecular identifier
- VIM, vimentin
- Zonation
- scRNA-seq, single-cell RNA-sequencing
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Affiliation(s)
- Valéry L. Payen
- Laboratory of Pediatric Hepatology and Cell Therapy (PEDI), IREC Institute, Université catholique de Louvain, Brussels, Belgium
- Laboratory of Advanced Drug Delivery and Biomaterials (ADDB), LDRI Institute, Université catholique de Louvain, Brussels, Belgium
| | - Arnaud Lavergne
- Genomics Platform, GIGA Institute, Université de Liège, Liège, Belgium
| | - Niki Alevra Sarika
- Laboratory of Pediatric Hepatology and Cell Therapy (PEDI), IREC Institute, Université catholique de Louvain, Brussels, Belgium
- Laboratory of Advanced Drug Delivery and Biomaterials (ADDB), LDRI Institute, Université catholique de Louvain, Brussels, Belgium
| | - Megan Colonval
- Genomics Platform, GIGA Institute, Université de Liège, Liège, Belgium
| | - Latifa Karim
- Genomics Platform, GIGA Institute, Université de Liège, Liège, Belgium
| | - Manon Deckers
- Genomics Platform, GIGA Institute, Université de Liège, Liège, Belgium
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy (PEDI), IREC Institute, Université catholique de Louvain, Brussels, Belgium
| | - Wouter Coppieters
- Genomics Platform, GIGA Institute, Université de Liège, Liège, Belgium
| | | | - Etienne M. Sokal
- Laboratory of Pediatric Hepatology and Cell Therapy (PEDI), IREC Institute, Université catholique de Louvain, Brussels, Belgium
- Corresponding authors. Address: Laboratory of Pediatric Hepatology and Cell Therapy (PEDI), IREC Institute, Université catholique de Louvain, Avenue Mounier 52 Box B1.52.03, 1200 Brussels, Belgium.
| | - Adil El Taghdouini
- Laboratory of Pediatric Hepatology and Cell Therapy (PEDI), IREC Institute, Université catholique de Louvain, Brussels, Belgium
- Corresponding authors. Address: Laboratory of Pediatric Hepatology and Cell Therapy (PEDI), IREC Institute, Université catholique de Louvain, Avenue Mounier 52 Box B1.52.03, 1200 Brussels, Belgium.
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Alewel DI, Henriquez AR, Colonna CH, Snow SJ, Schladweiler MC, Miller CN, Kodavanti UP. Ozone-induced acute phase response in lung versus liver: the role of adrenal-derived stress hormones. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2021; 84:235-248. [PMID: 33317425 PMCID: PMC8082230 DOI: 10.1080/15287394.2020.1858466] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Acute-phase response (APR) is an innate stress reaction to tissue trauma or injury, infection, and environmental insults like ozone (O3). Regardless of the location of stress, the liver has been considered the primary contributor to circulating acute-phase proteins (APPs); however, the mechanisms underlying APR induction are unknown. Male Wistar-Kyoto rats were exposed to air or O3 (1 ppm, 6-hr/day, 1 or 2 days) and examined immediately after each exposure and after 18-hr recovery for APR proteins and gene expression. To assess the contribution of adrenal-derived stress hormones, lung and liver global gene expression data from sham and adrenalectomized rats exposed to air or O3 were compared for APR transcriptional changes. Data demonstrated serum protein alterations for selected circulating positive and negative APPs following 2 days of O3 exposure and during recovery. At baseline, APP gene expression was several folds higher in the liver relative to the lung. O3-induced increases were significant for lung but not liver for some genes including orosomucoid-1. Further, comparative assessment of mRNA seq data for known APPs in sham rats exhibited marked elevation in the lung but not liver, and a near-complete abolishment of APP mRNA levels in lung tissue of adrenalectomized rats. Thus, the lung appears to play a critical role in O3-induced APP synthesis and requires the presence of circulating adrenal-derived stress hormones. The relative contribution of lung versus liver and the role of neuroendocrine stress hormones need to be considered in future APR studies involving inhaled pollutants.
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Affiliation(s)
- Devin I. Alewel
- Oak Ridge Institute for Science and Education Research Participation Program, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States of America
| | - Andres R. Henriquez
- Oak Ridge Institute for Science and Education Research Participation Program, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States of America
| | - Catherine H. Colonna
- Oak Ridge Institute for Science and Education Research Participation Program, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States of America
| | - Samantha J. Snow
- Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America
| | - Mette C. Schladweiler
- Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America
| | - Colette N. Miller
- Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America
| | - Urmila P. Kodavanti
- Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America
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Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha activity and hepatocyte function in liver diseases. BMC Med 2021; 19:39. [PMID: 33593348 PMCID: PMC7887823 DOI: 10.1186/s12916-021-01917-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 01/18/2021] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4α activity. METHODS Factors regulating transferrin expression in alcoholic hepatitis (AH) were assessed via transcriptomic/methylomic analysis as well as chromatin immunoprecipitation coupled to DNA sequencing. The findings were corroborated in primary hepatocytes. Serum and liver samples from 40 patients with advanced liver disease of multiple etiologies were also studied. RESULTS In patients with advanced liver disease, serum transferrin levels correlated with hepatic transferrin expression (r = 0.51, p = 0.01). Immunohistochemical and biochemical tests confirmed reduced HNF4α and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4α signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGFβ1), tumor necrosis factor α (TNFα), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) negatively associated with transferrin signature. A key regulatory region in transferrin promoter was hypermethylated in patients with AH. In primary hepatocytes, treatment with TGFβ1 or the HNF4α inhibitor BI6015 suppressed transferrin production, while exposure to TNFα, IL-1β, and IL-6 had no effect. The correlation between hepatic HNF4A and transferrin mRNA levels was also seen in advanced liver disease. CONCLUSIONS Serum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4α signaling and liver failure.
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Čaval T, Lin YH, Varkila M, Reiding KR, Bonten MJM, Cremer OL, Franc V, Heck AJR. Glycoproteoform Profiles of Individual Patients' Plasma Alpha-1-Antichymotrypsin are Unique and Extensively Remodeled Following a Septic Episode. Front Immunol 2021; 11:608466. [PMID: 33519818 PMCID: PMC7840657 DOI: 10.3389/fimmu.2020.608466] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 11/24/2020] [Indexed: 01/08/2023] Open
Abstract
Sepsis and septic shock remain the leading causes of death in intensive care units (ICUs), yet the pathogenesis originating from the inflammatory response during sepsis remains ambiguous. Acute-phase proteins are typically highly glycosylated, and the nature of the glycans have been linked to the incidence and severity of such inflammatory responses. To further build upon these findings we here monitored, the longitudinal changes in the plasma proteome and, in molecular detail, glycoproteoform profiles of alpha-1-antichymotrypsin (AACT) extracted from plasma of ten individual septic patients. For each patient we included four different time-points, including post-operative (before sepsis) and following discharge from the ICU. We isolated AACT from plasma depleted for albumin, IgG and serotransferrin and used high-resolution native mass spectrometry to qualitatively and quantitatively monitor the multifaceted glycan microheterogeneity of desialylated AACT, which allowed us to monitor how changes in the glycoproteoform profiles reflected the patient's physiological state. Although we observed a general trend in the remodeling of the AACT glycoproteoform profiles, e.g. increased fucosylation and branching/LacNAc elongation, each patient exhibited unique features and responses, providing a resilient proof-of-concept for the importance of personalized longitudinal glycoproteoform profiling. Importantly, we observed that the AACT glycoproteoform changes induced by sepsis did not readily subside after discharge from ICU.
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Affiliation(s)
- Tomislav Čaval
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, Netherlands
- Netherlands Proteomics Center, Utrecht, Netherlands
| | - Yu-Hsien Lin
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, Netherlands
- Netherlands Proteomics Center, Utrecht, Netherlands
| | - Meri Varkila
- Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, Netherlands
| | - Karli R. Reiding
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, Netherlands
- Netherlands Proteomics Center, Utrecht, Netherlands
| | - Marc J. M. Bonten
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
- Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Olaf L. Cremer
- Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, Netherlands
| | - Vojtech Franc
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, Netherlands
- Netherlands Proteomics Center, Utrecht, Netherlands
| | - Albert J. R. Heck
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, Netherlands
- Netherlands Proteomics Center, Utrecht, Netherlands
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The bile acid induced hepatokine orosomucoid suppresses adipocyte differentiation. Biochem Biophys Res Commun 2020; 534:864-870. [PMID: 33168190 DOI: 10.1016/j.bbrc.2020.10.086] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 10/27/2020] [Indexed: 01/06/2023]
Abstract
Bile acids have recently emerged as key metabolic hormones with beneficial impacts in multiple metabolic diseases. We previously discovered that hepatic bile acid overload distally modulates glucose and fatty acid metabolism in adipose tissues to exert anti-obesity effects. However, the detailed mechanisms that explain the salutary effects of serum bile acid elevation remain unclear. Here, proteomic profiling identified a new hepatokine, Orosomucoid (ORM) that governs liver-adipose tissue crosstalk. Hepatic ORMs were highly induced by both genetic and dietary bile acid overload. To address the direct metabolic effects of ORM, purified ORM proteins were administered during adipogenic differentiation of 3T3-L1 cells and mouse stromal vascular fibroblasts. ORM suppressed adipocyte differentiation and strongly inhibited gene expression of adipogenic transcription factors such as C/EBPβ, KLF5, C/EBPα, and PPARγ. Taken together, our data clearly suggest that bile acid-induced ORM secretion from the liver blocks adipocyte differentiation, potentially linked to anti-obesity effect of bile acids.
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Niemietz C, Bezerra F, Almeida MR, Guo S, Monia BP, Saraiva MJ, Schütz P, Schmidt HHJ, Zibert A. SERPINA1 modulates expression of amyloidogenic transthyretin. Exp Cell Res 2020; 395:112217. [PMID: 32768500 DOI: 10.1016/j.yexcr.2020.112217] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 07/31/2020] [Accepted: 08/01/2020] [Indexed: 12/14/2022]
Abstract
Hereditary transthyretin amyloidosis (ATTR) is caused by amyloid deposition of misfolded transthyretin (TTR) in various tissues. Recently, reduction of circulating serum TTR, achieved via silencing oligonucleotides, was introduced as therapy of ATTR amyloidosis. We explored the impact of Serpin Family A Member 1 (SERPINA1) on TTR mRNA and protein expression. Oncostatin M (OSM) induced SERPINA1 in hepatoma cells and mice, while concomitantly TTR expression was significantly reduced. SERPINA1 knockdown resulted in specific elevated TTR expression in hepatoma cells; however other genes belonging to the group of acute phase proteins were unaffected. In mice, serum TTR was elevated after mSERPINA1 knockdown throughout antisense treatment. Following SERPINA1 knockdown, TTR deposition in several tissues, including dorsal root ganglia and intestine, was found to be increased, however numbers did not exceed significance levels. The data suggest that SERPINA1 is a co-factor of TTR expression. Our findings provide novel insight in the regulation of TTR and reveal a role of SERPINA1 in the pathogenesis of ATTR amyloidosis.
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Affiliation(s)
- Christoph Niemietz
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
| | - Filipa Bezerra
- i3S - Instituto de Investigação e Inovação em Saúde, IBMC - Instituto de Biologia Molecular e Celular,and ICBAS - Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Maria Rosário Almeida
- i3S - Instituto de Investigação e Inovação em Saúde, IBMC - Instituto de Biologia Molecular e Celular,and ICBAS - Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal
| | | | | | - Maria João Saraiva
- i3S - Instituto de Investigação e Inovação em Saúde, IBMC - Instituto de Biologia Molecular e Celular,and ICBAS - Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Paula Schütz
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
| | - Hartmut H-J Schmidt
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
| | - Andree Zibert
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany.
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Ye X, An Q, Chen S, Liu X, Wang N, Li X, Zhao M, Han Y, Zhao Z, Ouyang K, Wang W. The structural characteristics, antioxidant and hepatoprotection activities of polysaccharides from Chimonanthus nitens Oliv. leaves. Int J Biol Macromol 2020; 156:1520-1529. [PMID: 31783077 DOI: 10.1016/j.ijbiomac.2019.11.200] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 10/17/2019] [Accepted: 11/25/2019] [Indexed: 02/07/2023]
Abstract
This work aimed to investigate the structural characteristics, antioxidant activities and hepatoprotection effect of Chimonanthus nitens Oliv. leaves polysaccharides (COP) on alcohol-induced oxidative damage in mice. Physical and chemical analysis showed that COP contained four monosaccharides including arabinose (Ara), mannose (Man), glucose (Glu) and galactose (Gal), with mass percentages of 26.6%, 5.1%, 32.2% and 36.0%, respectively, which was a heteropolysaccharide with both α- and β- configurations. In vivo experiments indicated that oral administration COP significantly reduced the levels of ALT, AST and MDA in serum, and significantly increased the activity of SOD and GSH-Px. Mice pretreated with COP had a higher superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity in liver and lower content of TNF-α, IL-6 and IL-1β in the liver and serum when compared with alcohol exposure. In addition, the liver histopathological changes induced by alcohol returned to normal in the COP pretreatment group. These results suggest that COP has a protective effect on acute liver injury induced by alcohol.
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Affiliation(s)
- Ximei Ye
- Key Lab for Natural Products and Functional Foods of Jiangxi Province, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Qi An
- Key Lab for Natural Products and Functional Foods of Jiangxi Province, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Si Chen
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Xin Liu
- Key Lab for Natural Products and Functional Foods of Jiangxi Province, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Ning Wang
- Key Lab for Natural Products and Functional Foods of Jiangxi Province, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Xiang Li
- Key Lab for Natural Products and Functional Foods of Jiangxi Province, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Meng Zhao
- Key Lab for Natural Products and Functional Foods of Jiangxi Province, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Yi Han
- Key Lab for Natural Products and Functional Foods of Jiangxi Province, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Zitong Zhao
- Key Lab for Natural Products and Functional Foods of Jiangxi Province, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Kehui Ouyang
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Wenjun Wang
- Key Lab for Natural Products and Functional Foods of Jiangxi Province, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China.
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Schneider CV, Hamesch K, Gross A, Mandorfer M, Moeller LS, Pereira V, Pons M, Kuca P, Reichert MC, Benini F, Burbaum B, Voss J, Gutberlet M, Woditsch V, Lindhauer C, Fromme M, Kümpers J, Bewersdorf L, Schaefer B, Eslam M, Bals R, Janciauskiene S, Carvão J, Neureiter D, Zhou B, Wöran K, Bantel H, Geier A, Dirrichs T, Stickel F, Teumer A, Verbeek J, Nevens F, Govaere O, Krawczyk M, Roskams T, Haybaeck J, Lurje G, Chorostowska-Wynimko J, Genesca J, Reiberger T, Lammert F, Krag A, George J, Anstee QM, Trauner M, Datz C, Gaisa NT, Denk H, Trautwein C, Aigner E, Strnad P. Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers. Gastroenterology 2020; 159:534-548.e11. [PMID: 32376409 DOI: 10.1053/j.gastro.2020.04.058] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 03/26/2020] [Accepted: 04/20/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease. METHODS We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank. RESULTS In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals. CONCLUSIONS Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling.
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Affiliation(s)
- Carolin V Schneider
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Karim Hamesch
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; Coordinating Center for alpha-1 antitrypsin deficiency-related liver disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) registry group "Alpha-1 Liver," University Hospital Aachen, Aachen, Germany
| | - Annika Gross
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria; Rare Liver Disease (RALID) Center of the European Reference Network (ERN) RARE-LIVER, Medical University Vienna, Vienna, Austria
| | - Linda S Moeller
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Vitor Pereira
- Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal
| | - Monica Pons
- Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid
| | - Pawel Kuca
- Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland
| | - Matthias C Reichert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Federica Benini
- Gastroenterology Unit, Department of Medicine, Spedali Civili and University, Brescia, Italy
| | - Barbara Burbaum
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Jessica Voss
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Marla Gutberlet
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Vivien Woditsch
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Cecilia Lindhauer
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Malin Fromme
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Julia Kümpers
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Lisa Bewersdorf
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Benedikt Schaefer
- Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia
| | - Robert Bals
- Department of Internal Medicine V, Saarland University Medical Center, Homburg, Germany
| | | | - Joana Carvão
- Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria
| | - Biaohuan Zhou
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Katharina Wöran
- Department of Pathology, Medical University Vienna, Vienna, Austria
| | - Heike Bantel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Andreas Geier
- Department of Hepatology, University of Wuerzburg, Wuerzburg, Germany
| | - Timm Dirrichs
- Department of Diagnostic and Interventional Radiology, RWTH Aachen University Hospital, Aachen, Germany
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zürich, Switzerland
| | - Alexander Teumer
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany
| | - Jef Verbeek
- Department of Gastroenterology & Hepatology, University Hospitals KU Leuven, Leuven, Belgium
| | - Frederik Nevens
- Department of Gastroenterology & Hepatology, University Hospitals KU Leuven, Leuven, Belgium
| | - Olivier Govaere
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Department of Medicine II Saarland University Medical Center Saarland University Homburg Germany Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Tania Roskams
- Department of Pathology, University Hospitals KU Leuven, Leuven, Belgium
| | - Johannes Haybaeck
- Department of Pathology, Neuropathology, and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria; Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Austria
| | - Georg Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany; Department of Surgery, Campus Charité Mitte I Campus Virchow Klinikum Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Joanna Chorostowska-Wynimko
- Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland
| | - Joan Genesca
- Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria; Rare Liver Disease (RALID) Center of the European Reference Network (ERN) RARE-LIVER, Medical University Vienna, Vienna, Austria
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia
| | - Quentin M Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria; Rare Liver Disease (RALID) Center of the European Reference Network (ERN) RARE-LIVER, Medical University Vienna, Vienna, Austria
| | - Christian Datz
- Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Oberndorf, Austria
| | - Nadine T Gaisa
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Helmut Denk
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Christian Trautwein
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; Coordinating Center for alpha-1 antitrypsin deficiency-related liver disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) registry group "Alpha-1 Liver," University Hospital Aachen, Aachen, Germany
| | - Elmar Aigner
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Pavel Strnad
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; Coordinating Center for alpha-1 antitrypsin deficiency-related liver disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) registry group "Alpha-1 Liver," University Hospital Aachen, Aachen, Germany.
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Atkinson SR, Thursz MR, Strnad P. Response to Sainath et al. Am J Gastroenterol 2020; 115:1136-1137. [PMID: 32618669 DOI: 10.14309/ajg.0000000000000697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Stephen R Atkinson
- Department of Hepatology, Imperial College London, London, United Kingdom
| | - Mark R Thursz
- Department of Hepatology, Imperial College London, London, United Kingdom
| | - Pavel Strnad
- Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
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Dash S, Aydin Y, Wu T. Integrated stress response in hepatitis C promotes Nrf2-related chaperone-mediated autophagy: A novel mechanism for host-microbe survival and HCC development in liver cirrhosis. Semin Cell Dev Biol 2020; 101:20-35. [PMID: 31386899 PMCID: PMC7007355 DOI: 10.1016/j.semcdb.2019.07.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/26/2019] [Accepted: 07/30/2019] [Indexed: 02/06/2023]
Abstract
The molecular mechanism(s) how liver damage during the chronic hepatitis C virus (HCV) infection evolve into cirrhosis and hepatocellular carcinoma (HCC) is unclear. HCV infects hepatocyte, the major cell types in the liver. During infection, large amounts of viral proteins and RNA replication intermediates accumulate in the endoplasmic reticulum (ER) of the infected hepatocyte, which creates a substantial amount of stress response. Infected hepatocyte activates a different type of stress adaptive mechanisms such as unfolded protein response (UPR), antioxidant response (AR), and the integrated stress response (ISR) to promote virus-host cell survival. The hepatic stress is also amplified by another layer of innate and inflammatory response associated with cellular sensing of virus infection through the production of interferon (IFN) and inflammatory cytokines. The interplay between various types of cellular stress signal leads to different forms of cell death such as apoptosis, necrosis, and autophagy depending on the intensity of the stress and nature of the adaptive cellular response. How do the adaptive cellular responses decode such death programs that promote host-microbe survival leading to the establishment of chronic liver disease? In this review, we discuss how the adaptive cellular response through the Nrf2 pathway that promotes virus and cell survival. Furthermore, we provide a glimpse of novel stress-induced Nrf2 mediated compensatory autophagy mechanisms in virus-cell survival that degrade tumor suppressor gene and activation of oncogenic signaling during HCV infection. Based on these facts, we hypothesize that the balance between hepatic stress, inflammation and different types of cell death determines liver disease progression outcomes. We propose that a more nuanced understanding of virus-host interactions under excessive cellular stress may provide an answer to the fundamental questions why some individuals with chronic HCV infection remain at risk of developing cirrhosis, cancer and some do not.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA.
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA
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Wu MZ, Fu T, Chen JX, Lin YY, Yang JE, Zhuang SM. LncRNA GOLGA2P10 is induced by PERK/ATF4/CHOP signaling and protects tumor cells from ER stress-induced apoptosis by regulating Bcl-2 family members. Cell Death Dis 2020; 11:276. [PMID: 32332695 PMCID: PMC7181651 DOI: 10.1038/s41419-020-2469-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 01/10/2020] [Accepted: 03/04/2020] [Indexed: 01/16/2023]
Abstract
Elevated endoplasmic reticulum (ER) stress is frequently observed in cancers, whereas sustained ER stress may trigger apoptosis. How cancer cells escape from ER stress-induced apoptosis remain unclear. Here, we found that a pseudogene-derived lncRNA, Golgin A2 pseudogene 10 (GOLGA2P10), was frequently upregulated in HCC tissues and significantly elevated in hepatoma cells treated with ER stress inducers, such as tunicamycin and thapsigargin. Higher GOLGA2P10 level was correlated with shorter recurrence-free survival of HCC patients. Upon ER stress, CHOP directly bound to the promoter of GOLGA2P10 and induced its transcription via the PERK/ATF4/CHOP pathway. Interestingly, the ER stress inducer-stimulated apoptosis was promoted by silencing GOLGA2P10 but was antagonized by overexpressing GOLGA2P10. Both gain- and loss-of-function analyses disclosed that GOLGA2P10 increased BCL-xL protein level, promoted BAD phosphorylation, and conferred tumor cells with resistance to ER stress-induced apoptosis. Moreover, BCL-xL overexpression or BAD knockdown abrogated the apoptosis-promoting effect of GOLGA2P10 silencing. Consistently, the Ser75Ala mutation in BAD, which caused phosphorylation-resistance, further enhanced the promoting effect of BAD in tunicamycin-induced apoptosis. These results suggest that ER stress induces GOLGA2P10 transcription through the PERK/ATF4/CHOP pathway, and upregulation of GOLGA2P10 protects tumor cells from the cytotoxic effect of persistent ER stress in tumor microenvironment by regulating Bcl-2 family members, which highlight GOLGA2P10 as a potential target for anticancer therapy.
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Affiliation(s)
- Meng-Zhi Wu
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou, 510275, P. R. China
| | - Tao Fu
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou, 510275, P. R. China
| | - Jin-Xi Chen
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou, 510275, P. R. China
| | - Ying-Ying Lin
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou, 510275, P. R. China
| | - Jin-E Yang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou, 510275, P. R. China.
| | - Shi-Mei Zhuang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou, 510275, P. R. China.
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Mazuryk O, Gajda-Morszewski P, Brindell M. Versatile Impact of Serum Proteins on Ruthenium(II) Polypyridyl Complexes Properties - Opportunities and Obstacles. Curr Protein Pept Sci 2020; 20:1052-1059. [PMID: 31092177 DOI: 10.2174/1389203720666190513090851] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 01/11/2019] [Accepted: 04/04/2019] [Indexed: 01/20/2023]
Abstract
Ruthenium(II) polypyridyl complexes have been extensively studied for the past few decades as promising anticancer agents. Despite the expected intravenous route of administration, the interaction between Ru(II) polypyridyl compounds and serum proteins is not well characterized and vast majority of the available literature data concerns determination of the binding constant. Ru-protein adducts can modify the biological effects of the Ru complexes influencing their cytotoxic and antimicrobial activity as well as introduce significant changes in their photophysical properties. More extensive research on the interaction between serum proteins and Ru(II) polypyridyl complexes is important for further development of Ru(II) polypyridyl compounds towards their application in anticancer therapy and diagnostics and can open new opportunities for already developed complexes.
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Affiliation(s)
- Olga Mazuryk
- Department of Inorganic Chemistry, Faculty of Chemistry, Jagiellonian University in Krakow, Gronostajowa 2, 30- 387, Krakow, Poland
| | - Przemysław Gajda-Morszewski
- Department of Inorganic Chemistry, Faculty of Chemistry, Jagiellonian University in Krakow, Gronostajowa 2, 30- 387, Krakow, Poland
| | - Małgorzata Brindell
- Department of Inorganic Chemistry, Faculty of Chemistry, Jagiellonian University in Krakow, Gronostajowa 2, 30- 387, Krakow, Poland
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Abstract
OBJECTIVES Severe alcoholic hepatitis (sAH) confers substantial mortality, but the disease course is difficult to predict. As iron parameters are attractive outcome predictors in other liver diseases, we tested their prognostic ability in sAH. METHODS Serum ferritin, transferrin, iron, transferrin saturation, nontransferrin-bound iron, soluble transferrin receptor, and hepcidin were measured in 828 patients with sAH recruited prospectively through the STOPAH trial. The cohort was randomly divided into exploratory (n = 200) and validation sets (n = 628). RESULTS Patients with sAH had diminished serum transferrin but increased transferrin saturation. Among iron parameters, baseline transferrin was the best predictor of 28-day (area under the receiver operated characteristic 0.72 [95% confidence interval 0.67-0.78]) and 90-day survival (area under the receiver operated characteristic 0.65 [0.61-0.70]). Transferrin's predictive ability was comparable with the composite scores, namely model of end-stage liver disease, Glasgow alcoholic hepatitis score, and discriminant function, and was independently associated with survival in multivariable analysis. These results were confirmed in a validation cohort. Transferrin did not correlate with markers of liver synthesis nor with non-transferrin-bound iron or soluble transferrin receptor (as markers of excess unbound iron and functional iron deficiency, respectively). DISCUSSION In patients with sAH, serum transferrin predicts mortality with a performance comparable with commonly used composite scoring systems. Hence, this routinely available parameter might be a useful marker alone or as a component of prognostic models.
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Expression of Transferrin and Albumin in the Sperm-Storage Tubules of Japanese Quail and their Possible Involvement in Long-Term Sperm Storage. J Poult Sci 2020; 57:88-96. [PMID: 32174770 PMCID: PMC7063080 DOI: 10.2141/jpsa.0190049] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Because of the presence of sperm storage tubules (SSTs) in the utero-vaginal junction (UVJ) in the oviduct, once ejaculated sperm enter the female reproductive tract, they can survive for a prolonged period in domestic birds; however, the specific mechanisms involved in sperm maintenance within the SST remain to be elucidated. In this study, we showed that transferrin (TF) and albumin (ALB) are expressed in SSTs. When UVJ extracts were subjected to size-exclusion column chromatography, we obtained fractions that extend sperm longevity in vitro. LC-MS/MS analysis of the two major proteins in the fractions identified these proteins as TF and ALB. Immunohistochemical analysis using specific antisera against TF and ALB indicated that both proteins were localized not only in the SSTs, but also in the surface epithelium of the UVJ. When the ejaculated sperm were incubated with either purified TF or ALB, sperm viability increased after 24 h. These results indicated that oviductal TF and ALB are involved in the process of sperm storage in SSTs and may open a new approach for technological improvement to prolong sperm longevity in vitro.
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Janciauskiene S. The Beneficial Effects of Antioxidants in Health And Diseases. CHRONIC OBSTRUCTIVE PULMONARY DISEASES-JOURNAL OF THE COPD FOUNDATION 2020; 7:182-202. [PMID: 32558487 DOI: 10.15326/jcopdf.7.3.2019.0152] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Reactive oxygen and nitrogen species can be generated endogenously (by mitochondria, peroxisomes, and phagocytic cells) and exogenously (by pollutions, UV exposure, xenobiotic compounds, and cigarette smoke). The negative effects of free radicals are neutralized by antioxidant molecules synthesized in our body, like glutathione, uric acid, or ubiquinone, and those obtained from the diet, such as vitamins C, E, and A, and flavonoids. Different microelements like selenium and zinc have no antioxidant action themselves but are required for the activity of many antioxidant enzymes. Furthermore, circulating blood proteins are suggested to account for more than 50% of the combined antioxidant effects of urate, ascorbate, and vitamin E. Antioxidants together constitute a mutually supportive defense against reactive oxygen and nitrogen species to maintain the oxidant/antioxidant balance. This article outlines the oxidative and anti-oxidative molecules involved in the pathogenesis of chronic obstructive lung disease. The role of albumin and alpha-1 antitrypsin in antioxidant defense is also discussed.
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Affiliation(s)
- Sabina Janciauskiene
- Department of Respiratory Medicine, Hannover Medical School, Member of German Centre for Lung Research (DZL), Hannover, Germany; Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland
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Guldiken N, Hamesch K, Schuller SM, Aly M, Lindhauer C, Schneider CV, Fromme M, Trautwein C, Strnad P. Mild Iron Overload as Seen in Individuals Homozygous for the Alpha-1 Antitrypsin Pi*Z Variant Does Not Promote Liver Fibrogenesis in HFE Knockout Mice. Cells 2019; 8:cells8111415. [PMID: 31717526 PMCID: PMC6912453 DOI: 10.3390/cells8111415] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/04/2019] [Accepted: 11/06/2019] [Indexed: 12/31/2022] Open
Abstract
The presence of the homozygous 'Pi*Z' variant of alpha-1 antitrypsin (AAT) ('Pi*ZZ' genotype) predisposes to liver fibrosis development, but the role of iron metabolism in this process remains unknown. Therefore, we assessed iron metabolism and variants in the Homeostatic Iron Regulator gene (HFE) as the major cause of hereditary iron overload in a large cohort of Pi*ZZ subjects without liver comorbidities. The human cohort comprised of 409 Pi*ZZ individuals and 254 subjects without evidence of an AAT mutation who were recruited from ten European countries. All underwent a comprehensive work-up and transient elastography to determine liver stiffness measurements (LSM). The corresponding mouse models (Pi*Z overexpressors, HFE knockouts, and double transgenic [DTg] mice) were used to evaluate the impact of mild iron overload on Pi*Z-induced liver injury. Compared to Pi*Z non-carriers, Pi*ZZ individuals had elevated serum iron, transferrin saturation, and ferritin levels, but relevant iron overload was rare. All these parameters were higher in individuals with signs of significant liver fibrosis (LSM ≥ 7.1 kPa) compared to those without signs of significant liver fibrosis. HFE knockout and DTg mice displayed similar extent of iron overload and of fibrosis. Loss of HFE did not alter the extent of AAT accumulation. In Pi*ZZ individuals, presence of HFE mutations was not associated with more severe liver fibrosis. Taken together, Pi*ZZ individuals display minor alterations in serum iron parameters. Neither mild iron overload seen in these individuals nor the presence of HFE mutations (C282Y and H63D) constitute a major contributor to liver fibrosis development.
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Affiliation(s)
- Nurdan Guldiken
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, D-52074 Aachen, Germany; (N.G.); (K.H.); (S.M.S.); (M.A.); (C.L.); (C.V.S.); (M.F.); (C.T.)
| | - Karim Hamesch
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, D-52074 Aachen, Germany; (N.G.); (K.H.); (S.M.S.); (M.A.); (C.L.); (C.V.S.); (M.F.); (C.T.)
- Coordinating Center for Alpha-1 Antitrypsin Deficiency-Related Liver Disease of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) and the European Association for the Study of the Liver (EASL) Registry Group “Alpha-1 Liver”, Germany
| | - Shari Malan Schuller
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, D-52074 Aachen, Germany; (N.G.); (K.H.); (S.M.S.); (M.A.); (C.L.); (C.V.S.); (M.F.); (C.T.)
| | - Mahmoud Aly
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, D-52074 Aachen, Germany; (N.G.); (K.H.); (S.M.S.); (M.A.); (C.L.); (C.V.S.); (M.F.); (C.T.)
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City 32897, Egypt
| | - Cecilia Lindhauer
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, D-52074 Aachen, Germany; (N.G.); (K.H.); (S.M.S.); (M.A.); (C.L.); (C.V.S.); (M.F.); (C.T.)
| | - Carolin V. Schneider
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, D-52074 Aachen, Germany; (N.G.); (K.H.); (S.M.S.); (M.A.); (C.L.); (C.V.S.); (M.F.); (C.T.)
| | - Malin Fromme
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, D-52074 Aachen, Germany; (N.G.); (K.H.); (S.M.S.); (M.A.); (C.L.); (C.V.S.); (M.F.); (C.T.)
| | - Christian Trautwein
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, D-52074 Aachen, Germany; (N.G.); (K.H.); (S.M.S.); (M.A.); (C.L.); (C.V.S.); (M.F.); (C.T.)
- Coordinating Center for Alpha-1 Antitrypsin Deficiency-Related Liver Disease of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) and the European Association for the Study of the Liver (EASL) Registry Group “Alpha-1 Liver”, Germany
| | - Pavel Strnad
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, D-52074 Aachen, Germany; (N.G.); (K.H.); (S.M.S.); (M.A.); (C.L.); (C.V.S.); (M.F.); (C.T.)
- Coordinating Center for Alpha-1 Antitrypsin Deficiency-Related Liver Disease of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) and the European Association for the Study of the Liver (EASL) Registry Group “Alpha-1 Liver”, Germany
- Correspondence: ; Tel.: +49-(241)-80-35324; Fax: +49-(241)-80-82455
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Hamesch K, Mandorfer M, Pereira VM, Moeller LS, Pons M, Dolman GE, Reichert MC, Schneider CV, Woditsch V, Voss J, Lindhauer C, Fromme M, Spivak I, Guldiken N, Zhou B, Arslanow A, Schaefer B, Zoller H, Aigner E, Reiberger T, Wetzel M, Siegmund B, Simões C, Gaspar R, Maia L, Costa D, Bento-Miranda M, van Helden J, Yagmur E, Bzdok D, Stolk J, Gleiber W, Knipel V, Windisch W, Mahadeva R, Bals R, Koczulla R, Barrecheguren M, Miravitlles M, Janciauskiene S, Stickel F, Lammert F, Liberal R, Genesca J, Griffiths WJ, Trauner M, Krag A, Trautwein C, Strnad P. Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation. Gastroenterology 2019; 157:705-719.e18. [PMID: 31121167 DOI: 10.1053/j.gastro.2019.05.013] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 05/07/2019] [Accepted: 05/09/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation-associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD. METHODS We collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung- and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant. RESULTS Serum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%-36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or γ-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter ≥280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very-low-density lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Z-overexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. CONCLUSIONS In studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosis and impaired lipid secretion. We identified factors associated with significant liver fibrosis in patients, which could facilitate hepatologic assessment and counseling of individuals who carry the Pi*ZZ mutation. ClinicalTrials.gov Number NCT02929940.
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Affiliation(s)
- Karim Hamesch
- Coordinating Center for Alpha1-Antitrypsin Deficiency-Related Liver Disease of the European Reference Network "Rare Liver" and the European Association for the Study of the Liver Registry Group "Alpha1-Liver," University Hospital Aachen, Aachen, Germany; Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria
| | - Vítor M Pereira
- Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal
| | - Linda S Moeller
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Monica Pons
- Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| | - Grace E Dolman
- Department of Hepatology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK
| | - Matthias C Reichert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Carolin V Schneider
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Vivien Woditsch
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Jessica Voss
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Cecilia Lindhauer
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Malin Fromme
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Igor Spivak
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Nurdan Guldiken
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Biaohuan Zhou
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Anita Arslanow
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Benedikt Schaefer
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Heinz Zoller
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Elmar Aigner
- Department of Internal Medicine I, Paracelsus Medical University, Salzburg, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria
| | - Martin Wetzel
- Department of Medicine I, Charité-Universitaetsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Britta Siegmund
- Department of Medicine I, Charité-Universitaetsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Carolina Simões
- Gastroenterology Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal
| | - Rui Gaspar
- Gastroenterology Department, Centro Hospitalar de São João, Faculty of Medicine of Porto University, Porto, Portugal
| | - Luís Maia
- Gastroenterology Department, Centro Hospitalar do Porto, Porto, Portugal
| | - Dalila Costa
- Gastroenterology Department, Hospital de Braga, Braga, Portugal
| | - Mário Bento-Miranda
- Gastroenterology Department, Hospital Universitário de Coimbra, Coimbra, Portugal
| | - Josef van Helden
- Medical Care Centre, Dr Stein and Colleagues, Moenchengladbach, Germany
| | - Eray Yagmur
- Medical Care Centre, Dr Stein and Colleagues, Moenchengladbach, Germany
| | - Danilo Bzdok
- Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany; Jülich Aachen Research Alliance-Brain, Aachen, Germany
| | - Jan Stolk
- Clinic for Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
| | - Wolfgang Gleiber
- Clinic for Pulmonology, University Hospital Frankfurt, Frankfurt, Germany
| | - Verena Knipel
- Department of Pneumology, Cologne Merheim Hospital, Kliniken der Stadt Köln gGmbH, Witten/Herdecke University, Faculty of Health/School of Medicine, Cologne, Germany
| | - Wolfram Windisch
- Department of Pneumology, Cologne Merheim Hospital, Kliniken der Stadt Köln gGmbH, Witten/Herdecke University, Faculty of Health/School of Medicine, Cologne, Germany
| | - Ravi Mahadeva
- Department of Respiratory Medicine, Cambridge National Institute for Health Research, Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Robert Bals
- Department of Medicine V, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Rembert Koczulla
- Clinic for Pneumology, Marburg University Hospital, Marburg, Germany; Institute for Pulmonary Rehabilitation Research, Schoen Clinic Berchtesgadener Land, Member of the Deutsches Zentrum für Lungenforschung, Schönau am Königssee, Germany
| | - Miriam Barrecheguren
- Department of Pneumology, Vall d'Hebron University Hospital, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Barcelona, Spain
| | - Marc Miravitlles
- Department of Pneumology, Vall d'Hebron University Hospital, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Barcelona, Spain
| | - Sabina Janciauskiene
- Clinic for Pneumology, German Center for Lung Research, Medical University Hannover, Hannover, Germany
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Rodrigo Liberal
- Gastroenterology Department, Centro Hospitalar de São João, Faculty of Medicine of Porto University, Porto, Portugal
| | - Joan Genesca
- Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| | - William J Griffiths
- Department of Hepatology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Christian Trautwein
- Coordinating Center for Alpha1-Antitrypsin Deficiency-Related Liver Disease of the European Reference Network "Rare Liver" and the European Association for the Study of the Liver Registry Group "Alpha1-Liver," University Hospital Aachen, Aachen, Germany; Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Pavel Strnad
- Coordinating Center for Alpha1-Antitrypsin Deficiency-Related Liver Disease of the European Reference Network "Rare Liver" and the European Association for the Study of the Liver Registry Group "Alpha1-Liver," University Hospital Aachen, Aachen, Germany; Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany.
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Fromme M, Oliverius M, Strnad P. DEFI-ALFA: The French key to the alpha1 mystery? Liver Int 2019; 39:1019-1021. [PMID: 31127687 DOI: 10.1111/liv.14064] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 01/26/2019] [Accepted: 01/29/2019] [Indexed: 12/29/2022]
Affiliation(s)
- Malin Fromme
- Coordinating Center for Alpha1-Antitrypsin Deficiency-Related Liver Disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) Registry Group "Alpha1-Liver", Aachen, Germany.,Medical Clinic III, Metabolic diseases and Intensive Care, University Hospital RWTH, Gastroenterology, Aachen, Germany
| | - Martin Oliverius
- Department of General Surgery, 3rd Faculty of Medicine, Charles University and Hospital Kralovske Vinohrady, Prague, Czech Republic.,Center for Cardiovascular and Transplant Surgery, Brno, Czech Republic
| | - Pavel Strnad
- Coordinating Center for Alpha1-Antitrypsin Deficiency-Related Liver Disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) Registry Group "Alpha1-Liver", Aachen, Germany.,Medical Clinic III, Metabolic diseases and Intensive Care, University Hospital RWTH, Gastroenterology, Aachen, Germany
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Guillot A, Tacke F. Liver Macrophages: Old Dogmas and New Insights. Hepatol Commun 2019; 3:730-743. [PMID: 31168508 PMCID: PMC6545867 DOI: 10.1002/hep4.1356] [Citation(s) in RCA: 251] [Impact Index Per Article: 41.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 03/28/2019] [Indexed: 12/12/2022] Open
Abstract
Inflammation is a hallmark of virtually all liver diseases, such as liver cancer, fibrosis, nonalcoholic steatohepatitis, alcoholic liver disease, and cholangiopathies. Liver macrophages have been thoroughly studied in human disease and mouse models, unravelling that the hepatic mononuclear phagocyte system is more versatile and complex than previously believed. Liver macrophages mainly consist of liver‐resident phagocytes, or Kupffer cells (KCs), and bone marrow‐derived recruited monocytes. Although both cell populations in the liver demonstrate principal functions of macrophages, such as phagocytosis, danger signal recognition, cytokine release, antigen processing, and the ability to orchestrate immune responses, KCs and recruited monocytes retain characteristic ontogeny markers and remain remarkably distinct on several functional aspects. While KCs dominate the hepatic macrophage pool in homeostasis (“sentinel function”), monocyte‐derived macrophages prevail in acute or chronic injury (“emergency response team”), making them an interesting target for novel therapeutic approaches in liver disease. In addition, recent data acquired by unbiased large‐scale techniques, such as single‐cell RNA sequencing, unraveled a previously unrecognized complexity of human and murine macrophage polarization abilities, far beyond the old dogma of inflammatory (M1) and anti‐inflammatory (M2) macrophages. Despite tremendous progress, numerous challenges remain in deciphering the full spectrum of macrophage activation and its implication in either promoting liver disease progression or repairing injured liver tissue. Being aware of such heterogeneity in cell origin and function is of crucial importance when studying liver diseases, developing novel therapeutic interventions, defining macrophage‐based prognostic biomarkers, or designing clinical trials. Growing knowledge in gene expression modulation and emerging technologies in drug delivery may soon allow shaping macrophage populations toward orchestrating beneficial rather than detrimental inflammatory responses.
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Affiliation(s)
- Adrien Guillot
- Laboratory of Liver Diseases National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Bethesda MD.,Department of Hepatology/Gastroenterology Charité University Medical Center Berlin Germany
| | - Frank Tacke
- Department of Hepatology/Gastroenterology Charité University Medical Center Berlin Germany
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Abstract
PURPOSE OF REVIEW Gallstone disease is one of the most frequent diseases in gastroenterology and treatment by endoscopy and surgery causes high costs in our health-care systems. Family and twin studies have demonstrated that gallstones are, in part, genetically determined. Here we review all recent genome-wide and phenome-wide studies of gallstones in humans and provide an updated 'inventory of human lithogenic genes.' RECENT FINDINGS The largest population attributable risk is conferred by the common variant (p.D19H) of the hepatic and intestinal cholesterol transporter ABCG5/G8. A second ABC transporter, the hepatic phosphatidylcholine translocase ABCB4, increases the risk for gallstone disease, gallbladder cancer and chronic liver diseases in general, whereas the common PNPLA3 risk variant p.I148M decreases gallstone risk. SUMMARY Better understanding of the pathomechanisms of gallstone disease might help to overcome the current invasive treatment of this exceptionally prevalent and economically significant digestive disease by personalized prevention in at-risk patients.
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