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Rusu EC, Clavero-Mestres H, Sánchez-Álvarez M, Veciana-Molins M, Bertran L, Monfort-Lanzas P, Aguilar C, Camaron J, Auguet T. Uncovering hepatic transcriptomic and circulating proteomic signatures in MASH: A meta-analysis and machine learning-based biomarker discovery. Comput Biol Med 2025; 191:110170. [PMID: 40220593 DOI: 10.1016/j.compbiomed.2025.110170] [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: 10/20/2024] [Revised: 04/05/2025] [Accepted: 04/05/2025] [Indexed: 04/14/2025]
Abstract
BACKGROUND Metabolic-associated steatohepatitis (MASH), the progressive form of metabolic-associated steatotic liver disease (MASLD), poses significant risks for liver fibrosis and cardiovascular complications. Despite extensive research, reliable biomarkers for MASH diagnosis and progression remain elusive. This study aimed to identify hepatic transcriptomic and circulating proteomic signatures specific to MASH, and to develop a machine learning-based biomarker discovery model. METHODS A systematic review of RNA-Seq and proteomic datasets was conducted, retrieving 7 hepatic transcriptomics and 3 circulating proteomics studies, encompassing 483 liver samples and 169 serum/plasma samples, respectively. Differential gene and protein expression analyses were performed, and pathways were enriched using gene set enrichment analysis. A machine learning (ML) model was developed to identify MASH-specific biomarkers, utilizing biologically significant protein ratios. KEY FINDINGS Hepatic transcriptomic analysis identified 5017 differentially expressed genes (DEGs), with significant enrichment of extracellular matrix (ECM) pathways. Serum proteomics revealed six differentially expressed proteins (DEPs), including complement-related proteins. Integration of transcriptomic and proteomic data highlighted the complement cascade as a key pathway in MASH, with discordant regulation between the liver and circulation. The ML-based biomarker discovery model, utilizing protein ratios, achieved an F1 scores of 0.83 and 0.64 in the training sets and 0.67 in an external validation set. CONCLUSION Our findings indicate ECM deregulation and complement system involvement in MASH progression. The novel ML model incorporating protein ratios offers a potential tool for MASH diagnosis. However, further refinement and validation across larger and more diverse cohorts is needed to generalize these results.
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Affiliation(s)
- Elena Cristina Rusu
- GEMMAIR research Unit (AGAUR) - Applied Medicine (URV). Department of Medicine and Surgery. University Rovira I Virgili (URV), Health Research Institute Pere Virgili (IISPV), 43007, Tarragona, Spain; Institute for Integrative Systems Biology (I2SysBio), University of Valencia and the Spanish National Research Council (CSIC), 46980, Valencia, Spain.
| | - Helena Clavero-Mestres
- GEMMAIR research Unit (AGAUR) - Applied Medicine (URV). Department of Medicine and Surgery. University Rovira I Virgili (URV), Health Research Institute Pere Virgili (IISPV), 43007, Tarragona, Spain.
| | - Mario Sánchez-Álvarez
- GEMMAIR research Unit (AGAUR) - Applied Medicine (URV). Department of Medicine and Surgery. University Rovira I Virgili (URV), Health Research Institute Pere Virgili (IISPV), 43007, Tarragona, Spain.
| | - Marina Veciana-Molins
- GEMMAIR research Unit (AGAUR) - Applied Medicine (URV). Department of Medicine and Surgery. University Rovira I Virgili (URV), Health Research Institute Pere Virgili (IISPV), 43007, Tarragona, Spain.
| | - Laia Bertran
- GEMMAIR research Unit (AGAUR) - Applied Medicine (URV). Department of Medicine and Surgery. University Rovira I Virgili (URV), Health Research Institute Pere Virgili (IISPV), 43007, Tarragona, Spain.
| | - Pablo Monfort-Lanzas
- Institute of Medical Biochemistry, Biocenter, Medical University of Innsbruck, 6020, Innsbruck, Austria; Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, 6020, Innsbruck, Austria.
| | - Carmen Aguilar
- GEMMAIR research Unit (AGAUR) - Applied Medicine (URV). Department of Medicine and Surgery. University Rovira I Virgili (URV), Health Research Institute Pere Virgili (IISPV), 43007, Tarragona, Spain.
| | - Javier Camaron
- Internal Medicine Unit, Joan XXIII University Hospital of Tarragona, 43007, Tarragona, Spain.
| | - Teresa Auguet
- GEMMAIR research Unit (AGAUR) - Applied Medicine (URV). Department of Medicine and Surgery. University Rovira I Virgili (URV), Health Research Institute Pere Virgili (IISPV), 43007, Tarragona, Spain; Internal Medicine Unit, Joan XXIII University Hospital of Tarragona, 43007, Tarragona, Spain.
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De Nardo W, Lee O, Johari Y, Bayliss J, Pensa M, Miotto PM, Keenan SN, Ryan A, Rucinski A, Svinos TM, Ooi GJ, Brown WA, Kemp W, Roberts SK, Parker BL, Montgomery MK, Larance M, Burton PR, Watt MJ. Integrated liver-secreted and plasma proteomics identify a predictive model that stratifies MASH. Cell Rep Med 2025; 6:102085. [PMID: 40250425 DOI: 10.1016/j.xcrm.2025.102085] [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: 11/10/2024] [Revised: 01/30/2025] [Accepted: 03/21/2025] [Indexed: 04/20/2025]
Abstract
Obesity is a major risk factor for metabolic-associated steatotic liver disease (MASLD), which can progress to metabolic-associated steatohepatitis (MASH). There are no validated non-invasive tests to stratify persons with obesity with a greater risk for MASH. Herein, we assess plasma and liver from 266 obese individuals spanning the MASLD spectrum. Ninety-six human livers were precision-cut, and mass spectrometry-based proteomics identifies 3,333 proteins in the liver-secretion medium, of which 107 are differentially secreted in MASH compared with no pathology. The plasma proteome is markedly remodeled in MASH but is not different between patients with steatosis and no pathology. The APASHA model, comprising plasma apolipoprotein F (APOF), proprotein convertase subtilisin/kexin type 9 (PCSK9), afamin (AFM), S100 calcium-binding protein A6 (S100A6), HbA1c, and zinc-alpha-2-glycoprotein (AZGP1), stratifies MASH (area under receiver operating characteristic [AUROC] = 0.88). Our investigations detail the evolution of liver-secreted and plasma proteins with MASLD progression, providing a rich resource defining human liver-secreted proteins and creating a predictive model to stratify patients with obesity at risk of MASH.
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Affiliation(s)
- William De Nardo
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Olivia Lee
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Yazmin Johari
- Department of Surgery, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia; Bariatric Unit, Department of General Surgery, The Alfred Hospital, Melbourne, VIC 3004, Australia
| | - Jacqueline Bayliss
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Marcus Pensa
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Paula M Miotto
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Stacey N Keenan
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Andrew Ryan
- TissuPath, Mount Waverley, VIC 3149, Australia
| | - Amber Rucinski
- Department of Oncology, Bendigo Health, Bendigo, VIC 3550, Australia
| | - Tessa M Svinos
- Department of General Surgery, Barwon Health, Geelong, VIC 3220, Australia
| | - Geraldine J Ooi
- Department of Surgery, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia; Bariatric Unit, Department of General Surgery, The Alfred Hospital, Melbourne, VIC 3004, Australia
| | - Wendy A Brown
- Department of Surgery, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia; Bariatric Unit, Department of General Surgery, The Alfred Hospital, Melbourne, VIC 3004, Australia
| | - William Kemp
- Department of Gastroenterology, The Alfred Hospital and Monash University, Melbourne, VIC 3181, Australia
| | - Stuart K Roberts
- Department of Gastroenterology, The Alfred Hospital and Monash University, Melbourne, VIC 3181, Australia
| | - Benjamin L Parker
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Magdalene K Montgomery
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Mark Larance
- Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Paul R Burton
- Department of Surgery, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia; Bariatric Unit, Department of General Surgery, The Alfred Hospital, Melbourne, VIC 3004, Australia
| | - Matthew J Watt
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia.
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Munk Lauridsen M, Ravnskjaer K, Gluud LL, Sanyal AJ. Disease classification, diagnostic challenges, and evolving clinical trial design in MASLD. J Clin Invest 2025; 135:e189953. [PMID: 40371650 PMCID: PMC12077896 DOI: 10.1172/jci189953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosis and management have evolved rapidly alongside the increasing prevalence of obesity and related complications. Hepatology has expanded its focus beyond late-stage cirrhosis and portal hypertension to earlier, complex MASLD cases in younger patients, necessitating closer collaboration with endocrinology. The renaming of nonalcoholic fatty liver disease (NAFLD) to MASLD reflects its pathophysiology, reduces stigma, and has prompted new research directions. Noninvasive tests such as liver stiffness measurement now play a crucial role in diagnosis, reducing reliance on invasive liver biopsies. However, advanced omics technologies, despite their potential to enhance diagnostic precision and patient stratification, remain underutilized in routine clinical practice. Behavioral factors, including posttraumatic stress disorder (PTSD) and lifestyle choices, influence disease outcomes and must be integrated into patient management strategies. Primary care settings are critical for early screening to prevent progression to advanced disease, yet sizable challenges remain in implementing effective screening protocols. This Review explores these evolving aspects of MASLD diagnosis and management, emphasizing the need for improved diagnostic tools, multidisciplinary collaboration, and holistic care approaches to address existing gaps and ensure comprehensive patient care across all healthcare levels.
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Affiliation(s)
- Mette Munk Lauridsen
- Stravitz-Sanyal Liver Institute, Department of Gastroenterology & Hepatology, Virginia Commonwealth University Medical Clinic, Richmond, Virginia, USA
- University Hospital of Southern Denmark, Liver Research Group, Department of Gastroenterology and Hepatology, Esbjerg, Denmark
| | - Kim Ravnskjaer
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Lise Lotte Gluud
- Gastro Unit, Copenhagen University Hospital, Hvidovre, Denmark, and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Arun J. Sanyal
- Stravitz-Sanyal Liver Institute, Department of Gastroenterology & Hepatology, Virginia Commonwealth University Medical Clinic, Richmond, Virginia, USA
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Bourganou MV, Chondrogianni ME, Kyrou I, Flessa CM, Chatzigeorgiou A, Oikonomou E, Lambadiari V, Randeva HS, Kassi E. Unraveling Metabolic Dysfunction-Associated Steatotic Liver Disease Through the Use of Omics Technologies. Int J Mol Sci 2025; 26:1589. [PMID: 40004054 PMCID: PMC11855544 DOI: 10.3390/ijms26041589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 02/07/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is the most prevalent liver disorder globally, linked to obesity, type 2 diabetes, and cardiovascular risk. Understanding its potential progression from simple steatosis to cirrhosis and hepatocellular carcinoma (HCC) is crucial for patient management and treatment strategies. The disease's complexity requires innovative approaches for early detection and personalized care. Omics technologies-such as genomics, transcriptomics, proteomics, metabolomics, and exposomics-are revolutionizing the study of MASLD. These high-throughput techniques allow for a deeper exploration of the molecular mechanisms driving disease progression. Genomics can identify genetic predispositions, whilst transcriptomics and proteomics reveal changes in gene expression and protein profiles during disease evolution. Metabolomics offers insights into the metabolic alterations associated with MASLD, while exposomics links environmental exposures to MASLD progression and pathology. By integrating data from various omics platforms, researchers can map out the intricate biochemical pathways involved in liver disease progression. This review discusses the roles of omics technologies in enhancing the understanding of disease progression and highlights potential diagnostic and therapeutic targets within the MASLD spectrum, emphasizing the need for non-invasive tools in disease staging and treatment development.
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Affiliation(s)
- Maria V. Bourganou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.V.B.); (M.E.C.); (C.-M.F.)
| | - Maria Eleni Chondrogianni
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.V.B.); (M.E.C.); (C.-M.F.)
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Ioannis Kyrou
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855 Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Centre for Health & Life Sciences, Coventry University, Coventry CV1 5FB, UK
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
- College of Health, Psychology and Social Care, University of Derby, Derby DE22 IGB, UK
| | - Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.V.B.); (M.E.C.); (C.-M.F.)
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece;
| | - Evangelos Oikonomou
- 3rd Department of Cardiology, “Sotiria” Thoracic Diseases Hospital of Athens, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Vaia Lambadiari
- 2nd Department of Internal-Medicine, Diabetes Centre, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Centre for Health & Life Sciences, Coventry University, Coventry CV1 5FB, UK
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.V.B.); (M.E.C.); (C.-M.F.)
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Mocciaro G, George AL, Allison M, Frontini M, Huang‐Doran I, Reiman F, Gribble F, Griffin JL, Vidal‐Puig A, Azzu V, Kay R, Vacca M. Oxidised Apolipoprotein Peptidome Characterises Metabolic Dysfunction-Associated Steatotic Liver Disease. Liver Int 2025; 45:e16200. [PMID: 39822152 PMCID: PMC11740006 DOI: 10.1111/liv.16200] [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: 09/18/2024] [Revised: 11/07/2024] [Accepted: 11/25/2024] [Indexed: 01/19/2025]
Abstract
BACKGROUND Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) encompasses a spectrum of histological conditions ranging from simple steatosis to fibrosing steatohepatitis, and is a risk factor for cardiovascular diseases (CVD). While oxidised apolipoproteins A and B have been linked to obesity and CVD, the association between other oxidised apolipoproteins and MASLD is yet to be established. To fill this gap, we characterised the circulating serum peptidome of patients with MASLD. METHODS We studied the serum of 87 biopsy-confirmed MASLD patients and 20 age- and sex-matched control (CTRL) subjects. We first employed an untargeted LC-MS/MS peptidomics approach (9 CTRL, 32 MASLD) to identify key hits differentially modulated, and subsequently validated the most relevant findings through targeted peptidomics in an enlarged study population (87 MASLD and 20 CTRL). RESULTS Untargeted serum peptidomics identified several oxidised apolipoprotein peptide fragments, including ApoE and ApoC-III, significantly upregulated in MASLD compared to CTRL. Specifically focusing on the oxidative status of intact ApoC-III, studied through its major glycoforms (ApoC-III0, ApoC-IIIi and ApoC-IIIii), we observed a marked reduction in non-oxidised forms of these circulating peptides alongside substantially increased levels of their oxidised proteoforms in MASLD versus controls (but not within the disease stages). Oxidised ApoE and ApoC-III peptide fragments were also significantly correlated with obesity, insulin resistance, dyslipidaemia and transaminases, suggesting a potential link between circulating apolipoprotein oxidation and systemic/hepatic metabolic dysfunction. CONCLUSION Our data reveals a previously unreported oxidised apolipoprotein profile associated with MASLD. The functional and clinical implications of these findings warrant further mechanistic investigation.
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Grants
- Wellcome Trust
- MR/S010483/1 Medical Research Council
- This research was supported by NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) funding to V.A., M.A., and M.V.The initial establishment of the cohorts was supported by the Evelyn Trust (funding to M.A. and A.V.P.), Mason Medical Research Trust (funding to V.A.), and the Academy of Medical Sciences (funding to V.A.). V.A. was supported by the University of Cambridge. M.A. is supported by Cambridge University Hospitals NHS Foundation Trust. M.V. is supported by the University of Bari (Horizon Europe Seed cod. id. S06-miRNASH), the Foundation for Liver Research (Intramural Funding), Associazione Italiana Ricerca sul Cancro (IG2022 Grant n. 27521) and Ministry of University and Research on Next Generation EU Funds [COD: P202222FCC, CUP: H53D23009960001, D.D. MUR 1366 (01-09-2023), Title: "System Biology" approaches in HCV Patients with Residual Hepatic Steatosis after Viral Eradication; Cod PE00000003, CUP: H93C22000630001, DD MUR 1550, Title: "ON Foods - Research and innovation network on food and nutrition Sustainability, Safety and Security - Working ON Foods"; Cod: CN00000041, CUP: H93C22000430007, Title PNRR "National Center for Gene Therapy and Drugs based on RNA Technology", M4C2-Investment 1.4; Code: CN00000013, CUP: H93C22000450007, Title PNNR: "National Centre for HPC, Big Data and Quantum Computing").A.V.P. is funded by MRC MDU, MRC Metabolic Diseases Unit (MC_UU_00014/5): Disease Model Core, Biochemistry Assay Lab, Histology Core and British Heart Foundation. M.F. is supported by the British Heart Foundation (FS/18/53/33863) and the British Heart Foundation Cambridge Centre for Research Excellence (RE/18/1/34212). This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. We would like to thank all participants in this study and the NIHR National BioResource. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. JLG is funded by the Medical Research Council (MR/S010483/1; MR/P011705/1; MR/P01836X/1; MR/X012700/1). F.G., F.R., R.K. and A.L.G. were funded by the Wellcome Trust (grants 106262/Z/14/Z, 106263/Z/14/Z), the MRC Metabolic Diseases Unit (grants MRC MC UU 12012/3, MRC MC UU12012/5) and by the NIHR Cambridge Biomedical Research Centre. The mass spectrometers were obtained using the Medical Research Council "Enhancing UK Clinical Research" grant (MR/M009041/1). The views expressed are those of the author(s) and not necessarily those of the relevant funding or supporting institutions. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript
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Affiliation(s)
- Gabriele Mocciaro
- Roger Williams Institute of Liver StudiesFoundation for Liver ResearchLondonUK
| | - Amy L. George
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Michael Allison
- Liver Unit, Cambridge NIHR Biomedical Research CentreCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - Mattia Frontini
- Faculty of Health and Life Sciences, Clinical and Biomedical SciencesUniversity of Exeter Medical SchoolExeterUK
| | - Isabel Huang‐Doran
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Frank Reiman
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Fiona Gribble
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Julian L. Griffin
- The Rowett Institute, Foresterhill CampusUniversity of AberdeenAberdeenUK
| | - Antonio Vidal‐Puig
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Vian Azzu
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
- Liver Unit, Cambridge NIHR Biomedical Research CentreCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - Richard Kay
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Michele Vacca
- Roger Williams Institute of Liver StudiesFoundation for Liver ResearchLondonUK
- University of Bari "Aldo Moro"Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni"BariItaly
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Pirola CJ, Fernández Gianotti T, Sookoian S. The Proteomics of MASLD Progression: Insights From Functional Analysis to Drive the Development of New Therapeutic Solutions. Aliment Pharmacol Ther 2025; 61:614-627. [PMID: 39744897 DOI: 10.1111/apt.18468] [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: 10/15/2024] [Revised: 11/22/2024] [Accepted: 12/19/2024] [Indexed: 01/24/2025]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading chronic liver disease worldwide, with alarming prevalence reaching epidemic proportions. AIMS AND METHODS The objective of this study is to provide a comprehensive review of the latest blood proteomics studies on MASLD and metabolic dysfunction-associated steatohepatitis (MASH), with emphasis on fibrosis. Furthermore, our objective is to conduct an analysis of protein pathways and interactions by integrating proteomics data using functional enrichment analysis of the deregulated proteins. RESULTS Notwithstanding the considerable discrepancies in the methodology and the number of proteins examined in the circulation, the analysis reveals a consistent pattern among the list of proteins that are decreased or increased in the blood of the affected patients. The relevant biological processes (BP) associated with down- and upregulated proteins are high-density lipoprotein remodelling and complement activation, respectively. The protein families identified include not only those expected to be involved in the immune system and cell adhesion and migration but also ligands of glycoproteins expressed in cells that have been subjected to stress and proteins containing the Sushi domain. CONCLUSIONS The application of cutting-edge methodologies to investigate the blood proteome in MASH is yielding insights that facilitate the elucidation of disease mechanisms and the identification of optimal noninvasive biomarkers. However, several challenges remain to be addressed in future research, including the generalisation of results on a global scale, the optimisation of analytical technologies and the implementation of large longitudinal studies to gain insights into the molecular mechanisms that underpin the development of advanced disease.
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Affiliation(s)
- Carlos José Pirola
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- Systems Biology of Complex Diseases, Translational Research in Health Center (CENITRES), Maimónides University, Buenos Aires, Argentina
| | - Tomas Fernández Gianotti
- Systems Biology of Complex Diseases, Translational Research in Health Center (CENITRES), Maimónides University, Buenos Aires, Argentina
| | - Silvia Sookoian
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- Clinical and Molecular Hepatology, Translational Research in Health Center (CENITRES), Maimónides University, Buenos Aires, Argentina
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Sourianarayanane A, Salemi MR, Phinney BS, McCullough AJ. Liver Tissue Proteins Improve the Accuracy of Plasma Proteins as Biomarkers in Diagnosing Metabolic Dysfunction-Associated Steatohepatitis. Proteomics Clin Appl 2024; 18:e202300236. [PMID: 39073724 DOI: 10.1002/prca.202300236] [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: 12/15/2023] [Revised: 06/12/2024] [Accepted: 07/19/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Biomarkers for metabolic dysfunction-associated steatohepatitis (MASH) have been considered based on proteomic and lipidomic data from plasma and liver tissue without clinical benefits. This study evaluated proteomics-based plasma and liver tissue biomarkers collected simultaneously from patients with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS Liver tissue and plasma samples were collected during liver biopsy to diagnose MASLD. Untargeted proteomics was performed on 64 patients. RESULTS Twenty plasma proteins were up- or downregulated in patients with MASH compared with those without MASH. The potential biomarkers utilizing the best combinations of these plasma proteins had an area under the receiver operating curve (AUROC) of 0.671 for detecting those with MASH compared with those without it. However, none of the 20 plasma proteins were represented among the significantly regulated liver tissue proteins in patients with MASH. Ten of them displayed a trend and relevance in liver tissue with MASLD progression. These 10 plasma proteins had an AUROC of 0.793 for MASH identification and higher positive and negative predictive values. CONCLUSION The plasma and liver protein expressions of patients with MASH were not directly comparable. Plasma protein biomarkers that are also expressed in liver tissue can help improve MASH detection.
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Affiliation(s)
- Achuthan Sourianarayanane
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Michelle R Salemi
- Proteomics Core Facility, UC Davis Genome Center, University of California, Davis, California, USA
| | - Brett S Phinney
- Proteomics Core Facility, UC Davis Genome Center, University of California, Davis, California, USA
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Magdy A, Kim HJ, Go H, Lee JM, Sohn HA, Haam K, Jung HJ, Park JL, Yoo T, Kwon ES, Lee DH, Choi M, Kang KW, Kim W, Kim M. DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease. Clin Mol Hepatol 2024; 30:824-844. [PMID: 39048522 PMCID: PMC11540403 DOI: 10.3350/cmh.2024.0229] [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: 04/09/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND/AIMS Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD. METHODS Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction-associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing. RESULTS Methylome and transcriptome analyses of liver biopsies revealed significant (P<0.05) hypermethylation and downregulation of C1R, C1S, C3, C6, C4BPA, and SERPING1, as well as hypomethylation (P<0.0005) and upregulation (P<0.05) of C5AR1, C7, and CD59, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data. CONCLUSION Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD.
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Affiliation(s)
- Amal Magdy
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Hee-Jin Kim
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Hanyong Go
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Jun Min Lee
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Hyun Ahm Sohn
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Keeok Haam
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Hyo-Jung Jung
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Jong-Lyul Park
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Taekyeong Yoo
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Eun-Soo Kwon
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Biomolecular Science, KRIBB School of Bioscience, UST, Daejeon, Korea
| | - Dong Hyeon Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Murim Choi
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Keon Wook Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Mirang Kim
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - on behalf of the Innovative Target Exploration of NAFLD (ITEN) Consortium
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- Department of Biomolecular Science, KRIBB School of Bioscience, UST, Daejeon, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
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9
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Bitterer F, Kupke P, Adenugba A, Evert K, Glehr G, Riquelme P, Scheibert L, Preverin G, Böhm C, Hornung M, Schlitt HJ, Wenzel JJ, Geissler EK, Safinia N, Hutchinson JA, Werner JM. Soluble CD46 as a diagnostic marker of hepatic steatosis. EBioMedicine 2024; 104:105184. [PMID: 38838471 PMCID: PMC11179574 DOI: 10.1016/j.ebiom.2024.105184] [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: 01/05/2024] [Revised: 05/21/2024] [Accepted: 05/21/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) incurs substantial morbidity, mortality and healthcare costs. Detection and clinical intervention at early stages of disease improves prognosis; however, we are currently limited by a lack of reliable diagnostic tests for population screening and monitoring responses to therapy. To address this unmet need, we investigated human invariant Natural Killer T cell (iNKT) activation by fat-loaded hepatocytes, leading to the discovery that circulating soluble CD46 (sCD46) levels accurately predict hepatic steatosis. METHODS sCD46 in plasma was measured using a newly developed immuno-competition assay in two independent cohorts: Prospective living liver donors (n = 156; male = 66, female = 90) and patients with liver tumours (n = 91; male = 58, female = 33). sCD46 levels were statistically evaluated as a predictor of hepatic steatosis. FINDINGS Interleukin-4-secreting (IL-4+) iNKT cells were over-represented amongst intrahepatic lymphocytes isolated from resected human liver samples. IL-4+ iNKT cells preferentially developed in cocultures with a fat-loaded, hepatocyte-like cell line, HepaRG. This was attributed to induction of matrix metalloproteases (MMP) in fat-loaded HepaRG cells and primary human liver organoids, which led to indiscriminate cleavage of immune receptors. Loss of cell-surface CD46 resulted in unrepressed differentiation of IL-4+ iNKT cells. sCD46 levels were elevated in patients with hepatic steatosis. Discriminatory cut-off values for plasma sCD46 were found that accurately classified patients according to histological steatosis grade. INTERPRETATION sCD46 is a reliable clinical marker of hepatic steatosis, which can be conveniently and non-invasively measured in serum and plasma samples, raising the possibility of using sCD46 levels as a diagnostic method for detecting or grading hepatic steatosis. FUNDING F.B. was supported by the Else Kröner Foundation (Award 2016_kolleg.14). G.G. was supported by the Bristol Myers Squibb Foundation for Immuno-Oncology (Award FA-19-009). N.S. was supported by a Wellcome Trust Fellowship (211113/A/18/Z). J.A.H. received funding from the European Union's Horizon 2020 research and innovation programme (Award 860003). J.M.W. received funding from the Else Kröner Foundation (Award 2015_A10).
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Affiliation(s)
- Florian Bitterer
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Paul Kupke
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Akinbami Adenugba
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Katja Evert
- Institute of Pathology, University of Regensburg, Regensburg 93053, Germany
| | - Gunther Glehr
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Paloma Riquelme
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Lena Scheibert
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Giulia Preverin
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Christina Böhm
- Oxford Nanopore Technologies PLC, Oxford Science Park, Oxford OX4 4DQ, United Kingdom
| | - Matthias Hornung
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Hans J Schlitt
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Jürgen J Wenzel
- Institute of Clinical Microbiology and Hygiene, University of Regensburg, Regensburg 93053, Germany
| | - Edward K Geissler
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany
| | - Niloufar Safinia
- Department of Hepatology, King's College London, London SE5 8AF, United Kingdom
| | - James A Hutchinson
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany.
| | - Jens M Werner
- Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany.
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10
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Sakarin S, Rungsipipat A, Roytrakul S, Jaresitthikunchai J, Phaonakrop N, Charoenlappanit S, Thaisakun S, Surachetpong S. Phosphoproteomics analysis of serum from dogs affected with pulmonary hypertension secondary to degenerative mitral valve disease. PeerJ 2024; 12:e17186. [PMID: 38708342 PMCID: PMC11067895 DOI: 10.7717/peerj.17186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 03/11/2024] [Indexed: 05/07/2024] Open
Abstract
Pulmonary hypertension (PH), a common complication in dogs affected by degenerative mitral valve disease (DMVD), is a progressive disorder characterized by increased pulmonary arterial pressure (PAP) and pulmonary vascular remodeling. Phosphorylation of proteins, impacting vascular function and cell proliferation, might play a role in the development and progression of PH. Unlike gene or protein studies, phosphoproteomic focuses on active proteins that function as end-target proteins within signaling cascades. Studying phosphorylated proteins can reveal active contributors to PH development. Early diagnosis of PH is crucial for effective management and improved clinical outcomes. This study aimed to identify potential serum biomarkers for diagnosing PH in dogs affected with DMVD using a phosphoproteomic approach. Serum samples were collected from healthy control dogs (n = 28), dogs with DMVD (n = 24), and dogs with DMVD and PH (n = 29). Phosphoproteins were enriched from the serum samples and analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Data analysis was performed to identify uniquely expressed phosphoproteins in each group and differentially expressed phosphoproteins among groups. Phosphoproteomic analysis revealed nine uniquely expressed phosphoproteins in the serum of dogs in the DMVD+PH group and 15 differentially upregulated phosphoproteins in the DMVD+PH group compared to the DMVD group. The phosphoproteins previously implicated in PH and associated with pulmonary arterial remodeling, including small nuclear ribonucleoprotein G (SNRPG), alpha-2-macroglobulin (A2M), zinc finger and BTB domain containing 42 (ZBTB42), hemopexin (HPX), serotransferrin (TRF) and complement C3 (C3), were focused on. Their unique expression and differential upregulation in the serum of DMVD dogs with PH suggest their potential as biomarkers for PH diagnosis. In conclusion, this phosphoproteomic study identified uniquely expressed and differentially upregulated phosphoproteins in the serum of DMVD dogs with PH. Further studies are warranted to validate the diagnostic utility of these phosphoproteins.
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Affiliation(s)
- Siriwan Sakarin
- Department of Veterinary Medicine, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand, Bangkok, Thailand
| | - Anudep Rungsipipat
- Center of Excellence for Companion Animal Cancer, Department of Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand, Bangkok, Thailand
| | - Sittiruk Roytrakul
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand, Bangkok, Thailand
| | - Janthima Jaresitthikunchai
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand, Bangkok, Thailand
| | - Narumon Phaonakrop
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand, Bangkok, Thailand
| | - Sawanya Charoenlappanit
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand, Bangkok, Thailand
| | - Siriwan Thaisakun
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand, Bangkok, Thailand
| | - Sirilak Surachetpong
- Department of Veterinary Medicine, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand, Bangkok, Thailand
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11
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Sakarin S, Rungsipipat A, Roytrakul S, Jaresitthikunchai J, Phaonakrop N, Charoenlappanit S, Thaisakun S, Surachetpong SD. Proteomic analysis of the serum in dogs with pulmonary hypertension secondary to myxomatous mitral valve disease: the preliminary study. Front Vet Sci 2024; 11:1327453. [PMID: 38596466 PMCID: PMC11002142 DOI: 10.3389/fvets.2024.1327453] [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: 10/25/2023] [Accepted: 03/01/2024] [Indexed: 04/11/2024] Open
Abstract
Background Pulmonary hypertension (PH) is a common complication in dogs with myxomatous mitral valve disease (MMVD), characterized by elevated blood pressure in pulmonary artery. Echocardiography is a reliable technique for PH diagnosis in veterinary medicine. However, it is limited to use as an early detection method. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has found extensive application in the discovery of serum protein biomarkers for various diseases. The objective of this study was to identify serum proteins in healthy control dogs and MMVD dogs both with and without PH using LC-MS/MS. Materials and methods In this research, a total of 81 small-breed dogs participated, and they were categorized into three groups: the control (n = 28), MMVD (n = 24) and MMVD+PH (n = 29) groups. Serum samples were collected and analyzed by LC-MS/MS. Results Differentially expressed proteins were identified, and the upregulated and downregulated proteins in MMVD+PH group including Myomesin 1 (MYOM1) and Histone deacetylase 7 (HDAC7), Pleckstrin homology domain containing M3 (PLEKHM3), Diacylglycerol lipase alpha (DAGLA) and Tubulin tyrosine ligase like 6 (TTLL6) were selected as proteins of interest in MMVD dogs with PH. Conclusion Different types of proteins have been identified in healthy dogs and MMVD dogs with and without PH. Additional studies are needed to investigate the potential of these proteins as biomarkers for PH in dogs with MMVD.
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Affiliation(s)
- Siriwan Sakarin
- Faculty of Veterinary Science, Department of Veterinary Medicine, Center of Excellence for Companion Animal Cancer, Chulalongkorn University, Bangkok, Thailand
| | - Anudep Rungsipipat
- Faculty of Veterinary Science, Department of Pathology, Chulalongkorn University, Bangkok, Thailand
| | - Sittiruk Roytrakul
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Janthima Jaresitthikunchai
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Narumon Phaonakrop
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Sawanya Charoenlappanit
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Siriwan Thaisakun
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Sirilak Disatian Surachetpong
- Faculty of Veterinary Science, Department of Veterinary Medicine, Center of Excellence for Companion Animal Cancer, Chulalongkorn University, Bangkok, Thailand
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12
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Zhang X, Li X, Xiong X. Applying proteomics in metabolic dysfunction-associated steatotic liver disease: From mechanism to biomarkers. Clin Res Hepatol Gastroenterol 2023; 47:102230. [PMID: 37931846 DOI: 10.1016/j.clinre.2023.102230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/13/2023] [Accepted: 10/18/2023] [Indexed: 11/08/2023]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), which represents the most common cause of liver disease, is emerging as a major health problem around the world. However, the molecular events that underline the pathogenesis and the progression of MASLD remain to be fully elucidated. Advanced stages of MASLD is strongly associated with liver-related outcomes and overall mortality. Despite this, highly accurate, sensitive, and non-invasive diagnostic tools are currently not aviailable, yet no FDA approved drugs for MASLD. The advance of proteomics has enable the study of protein expression, post-translational modifications (PTMs), subcellular distribution, and interactions. In this review, we discuss insights gained from the recent proteomics studies that shed new light on the pathogenesis, diagnosis and potential theraputic targets of MASLD.
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Affiliation(s)
- Xiaofu Zhang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 180 Fenlin Road, Xuhui District, Shanghai 200032, China
| | - Xiaoying Li
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 180 Fenlin Road, Xuhui District, Shanghai 200032, China
| | - Xuelian Xiong
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 180 Fenlin Road, Xuhui District, Shanghai 200032, China.
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13
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Boeriu A, Dobru D, Fofiu C. Non-Invasive Diagnostic of NAFLD in Type 2 Diabetes Mellitus and Risk Stratification: Strengths and Limitations. Life (Basel) 2023; 13:2262. [PMID: 38137863 PMCID: PMC10744403 DOI: 10.3390/life13122262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 10/26/2023] [Accepted: 11/25/2023] [Indexed: 12/24/2023] Open
Abstract
The progressive potential of liver damage in type 2 diabetes mellitus (T2DM) towards advanced fibrosis, end-stage liver disease, and hepatocarcinoma has led to increased concern for quantifying liver injury and individual risk assessment. The combination of blood-based markers and imaging techniques is recommended for the initial evaluation in NAFLD and for regular monitoring to evaluate disease progression. Continued development of ultrasonographic and magnetic resonance imaging methods for accurate quantification of liver steatosis and fibrosis, as well as promising tools for the detection of high-risk NASH, have been noted. In this review, we aim to summarize available evidence regarding the usefulness of non-invasive methods for the assessment of NAFLD in T2DM. We focus on the power and limitations of various methods for diagnosis, risk stratification, and patient monitoring that support their implementation in clinical setting or in research field.
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Affiliation(s)
- Alina Boeriu
- Gastroenterology Department, University of Medicine Pharmacy, Sciences, and Technology “George Emil Palade” Targu Mures, 540142 Targu Mures, Romania;
- Gastroenterology Department, Mures County Clinical Hospital, 540103 Targu Mures, Romania
| | - Daniela Dobru
- Gastroenterology Department, University of Medicine Pharmacy, Sciences, and Technology “George Emil Palade” Targu Mures, 540142 Targu Mures, Romania;
- Gastroenterology Department, Mures County Clinical Hospital, 540103 Targu Mures, Romania
| | - Crina Fofiu
- Gastroenterology Department, University of Medicine Pharmacy, Sciences, and Technology “George Emil Palade” Targu Mures, 540142 Targu Mures, Romania;
- Internal Medicine Department, Bistrita County Clinical Hospital, 420094 Bistrita, Romania
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14
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Jiang Y, Zhuang X, Zhang J, Li M, Du S, Tian J, Yuan Y, Ji G, Hu C. Clinical characterization and proteomic profiling of lean nonalcoholic fatty liver disease. Front Endocrinol (Lausanne) 2023; 14:1171397. [PMID: 38034020 PMCID: PMC10687542 DOI: 10.3389/fendo.2023.1171397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 07/06/2023] [Indexed: 12/02/2023] Open
Abstract
INTRODUCTION Obesity has been historically associated with nonalcoholic fatty liver disease (NAFLD), but it can also occur in lean individuals. However, limited data is available on this special group. To investigate the clinical and proteomic characteristics of lean subjects with NAFLD, and to identify potential clinical variables and plasma proteins for diagnosing NAFLD in lean individuals, we collected clinical data from a large cohort of 2,236 subjects. METHODS Diagnosis of NAFLD relied on detecting pronounced hepatic steatosis through abdominal ultrasonography. Participants were categorized into four groups based on body mass index: overweight NAFLD, overweight control, lean NAFLD, and lean control. Plasma proteomic profiling was performed on samples from 20 subjects in each group. The lean NAFLD group was compared to both lean healthy and obese NAFLD groups across all data. RESULTS AND DISCUSSION The results indicated that the lean NAFLD group exhibited intermediate metabolic profiles, falling between those of the lean healthy and overweight NAFLD groups. Proteomic profiling of plasma in lean subjects with or without NAFLD revealed 45 statistically significant changes in proteins, of which 37 showed high diagnostic value (AUC > 0.7) for lean NAFLD. These potential biomarkers primarily involved lipid metabolism, the immune and complement systems, and platelet degranulation. Furthermore, AFM, GSN, CFH, HGFAC, MMP2, and MMP9 have been previously associated with NAFLD or NAFLD-related factors such as liver damage, insulin resistance, metabolic syndromes, and extracellular homeostasis. Overall, lean individuals with NAFLD exhibit distinct clinical profiles compared to overweight individuals with NAFLD. Despite having worse metabolic profiles than their healthy counterparts, lean NAFLD patients generally experience milder systemic metabolic disturbances compared to obese NAFLD patients. Additionally, the plasma proteomic profile is significantly altered in lean NAFLD, highlighting the potential of differentially expressed proteins as valuable biomarkers or therapeutic targets for diagnosing and treating NAFLD in this population.
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Affiliation(s)
- Yuanye Jiang
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoyu Zhuang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiaqi Zhang
- Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Meng Li
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shengnan Du
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiyun Tian
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yifu Yuan
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Cheng Hu
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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15
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Terracciani F, Falcomatà A, Gallo P, Picardi A, Vespasiani-Gentilucci U. Prognostication in NAFLD: physiological bases, clinical indicators, and newer biomarkers. J Physiol Biochem 2023; 79:851-868. [PMID: 36472795 DOI: 10.1007/s13105-022-00934-0] [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: 05/22/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is becoming an epidemic in Western countries. Notably, while the majority of NAFLD patients will not evolve until advanced liver disease, a minority of them will progress towards liver-related events. Therefore, risk stratification and prognostication are emerging as fundamental in order to optimize human and economic resources for the care of these patients.Liver fibrosis has been clearly recognized as the main predictor of poor hepatic and extrahepatic outcomes. However, a prediction based only on the stage of fibrosis is near-sighted and static, as it does not capture the propensity of disease to further progress, the speed of progression and their changes over time. These determinants, which result from the interaction between genetic predisposition and acquired risk factors (obesity, diabetes, etc.), express themselves in disease activity, and can be synthesized by biomarkers of hepatic inflammation and fibrogenesis.In this review, we present the currently available clinical tools for risk stratification and prognostication in NAFLD specifically with respect to the risk of progression towards hard hepatic outcomes, i.e., liver-related events and death. We also discuss about the genetic and acquired drivers of disease progression, together with the physiopathological bases of their come into action. Finally, we introduce the most promising biomarkers in the direction of repeatedly assessing disease activity over time, mainly in response to future therapeutic interventions.
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Affiliation(s)
- Francesca Terracciani
- Hepatology and Clinical Medicine Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | - Andrea Falcomatà
- Hepatology and Clinical Medicine Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | - Paolo Gallo
- Hepatology and Clinical Medicine Unit, University Campus Bio-Medico of Rome, Rome, Italy.
| | - Antonio Picardi
- Hepatology and Clinical Medicine Unit, University Campus Bio-Medico of Rome, Rome, Italy
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Gîlcă-Blanariu GE, Budur DS, Mitrică DE, Gologan E, Timofte O, Bălan GG, Olteanu VA, Ștefănescu G. Advances in Noninvasive Biomarkers for Nonalcoholic Fatty Liver Disease. Metabolites 2023; 13:1115. [PMID: 37999211 PMCID: PMC10672868 DOI: 10.3390/metabo13111115] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 10/15/2023] [Accepted: 10/24/2023] [Indexed: 11/25/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) currently represents one of the most common liver diseases worldwide. Early diagnosis and disease staging is crucial, since it is mainly asymptomatic, but can progress to nonalcoholic steatohepatitis (NASH) or cirrhosis or even lead to the development of hepatocellular carcinoma. Over time, efforts have been put into developing noninvasive diagnostic and staging methods in order to replace the use of a liver biopsy. The noninvasive methods used include imaging techniques that measure liver stiffness and biological markers, with a focus on serum biomarkers. Due to the impressive complexity of the NAFLD's pathophysiology, biomarkers are able to assay different processes involved, such as apoptosis, fibrogenesis, and inflammation, or even address the genetic background and "omics" technologies. This article reviews not only the currently validated noninvasive methods to investigate NAFLD but also the promising results regarding recently discovered biomarkers, including biomarker panels and the combination of the currently validated evaluation methods and serum markers.
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Affiliation(s)
- Georgiana-Emmanuela Gîlcă-Blanariu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Daniela Simona Budur
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Dana Elena Mitrică
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Elena Gologan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Oana Timofte
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gheorghe Gh Bălan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Vasile Andrei Olteanu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gabriela Ștefănescu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
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17
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A liver secretome gene signature-based approach for determining circulating biomarkers of NAFLD severity. PLoS One 2022; 17:e0275901. [PMID: 36260611 PMCID: PMC9581378 DOI: 10.1371/journal.pone.0275901] [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: 04/29/2022] [Accepted: 09/25/2022] [Indexed: 11/08/2022] Open
Abstract
Non-invasive biomarkers of non-alcoholic fatty liver disease (NAFLD) supporting diagnosis and monitoring disease progression are urgently needed. The present study aimed to establish a bioinformatics pipeline capable of defining and validating NAFLD biomarker candidates based on paired hepatic global gene expression and plasma bioanalysis from individuals representing different stages of histologically confirmed NAFLD (no/mild, moderate, more advanced NAFLD). Liver secretome gene signatures were generated in a patient cohort of 26 severely obese individuals with the majority having no or mild fibrosis. To this end, global gene expression changes were compared between individuals with no/mild NAFLD and moderate/advanced NAFLD with subsequent filtering for candidate gene products with liver-selective expression and secretion. Four candidate genes, including LPA (lipoprotein A), IGFBP-1 (insulin-like growth factor-binding protein 1), SERPINF2 (serpin family F member 2) and MAT1A (methionine adenosyltransferase 1A), were differentially expressed in moderate/advanced NAFLD, which was confirmed in three independent RNA sequencing datasets from large, publicly available NAFLD studies. The corresponding gene products were quantified in plasma samples but could not discriminate among different grades of NAFLD based on NAFLD activity score. Conclusion: We demonstrate a novel approach based on the liver transcriptome allowing for identification of secreted hepatic gene products as potential circulating diagnostic biomarkers of NAFLD. Using this approach in larger NAFLD patient cohorts may yield potential circulating biomarkers for NAFLD severity.
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18
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Theel W, Boxma-de Klerk BM, Dirksmeier-Harinck F, van Rossum EFC, Kanhai DA, Apers J, van Dalen BM, de Knegt RJ, Holleboom AG, Tushuizen ME, Grobbee DE, Wiebolt J, Castro Cabezas M. Evaluation of nonalcoholic fatty liver disease (NAFLD) in severe obesity using noninvasive tests and imaging techniques. Obes Rev 2022; 23:e13481. [PMID: 35692179 DOI: 10.1111/obr.13481] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 05/25/2022] [Accepted: 05/26/2022] [Indexed: 12/15/2022]
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) and the more severe and inflammatory type, nonalcoholic steatohepatitis (NASH), is increasing rapidly. Especially in high-risk patients, that is those with obesity, metabolic syndrome, and type 2 diabetes mellitus, the prevalence of NAFLD can be as high as 80% while NASH may be present in 20% of these subjects. With the worldwide increase of obesity, it is most likely that these numbers will rise. Since advanced stages of NAFLD and NASH are strongly associated with morbidity and mortality-in particular, cardiovascular disease, liver cirrhosis, and hepatocellular carcinoma-it is of great importance to identify subjects at risk. A great variety of noninvasive tests has been published to diagnose NAFLD and NASH, especially using blood- and imaging-based tests. Liver biopsy remains the gold standard for NAFLD/NASH. This review aims to summarize the different mechanisms leading to NASH and liver fibrosis, the different noninvasive liver tests to diagnose and evaluate patients with severe obesity.
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Affiliation(s)
- Willy Theel
- Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands.,Obesity Center CGG, Rotterdam, The Netherlands
| | - Bianca M Boxma-de Klerk
- Department of Statistics and Education, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands
| | - Femme Dirksmeier-Harinck
- Department of Gastroenterology and Hepatology, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands
| | - Elisabeth F C van Rossum
- Obesity Center CGG, Rotterdam, The Netherlands.,Department of Internal Medicine, Division of Endocrinology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Danny A Kanhai
- Department of Pediatrics, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands
| | - Jan Apers
- Department of Bariatric Surgery, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands
| | - Bas M van Dalen
- Department of Cardiology, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands
| | - Robert J de Knegt
- Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, The Netherlands
| | | | - Maarten E Tushuizen
- Department of Gastroenterology and Hepatology, Leiden UMC, Leiden, The Netherlands
| | - Diederick E Grobbee
- Julius Centre for Health Science and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.,Julius Clinical, Zeist, The Netherlands
| | - Janneke Wiebolt
- Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands.,Obesity Center CGG, Rotterdam, The Netherlands
| | - Manuel Castro Cabezas
- Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands.,Department of Internal Medicine, Division of Endocrinology, Erasmus University Medical Center, Rotterdam, The Netherlands.,Julius Clinical, Zeist, The Netherlands
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19
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Liu CH, Zheng S, Wang S, Wu D, Jiang W, Zeng Q, Wei Y, Zhang Y, Tang H. Urine Proteome in Distinguishing Hepatic Steatosis in Patients with Metabolic-Associated Fatty Liver Disease. Diagnostics (Basel) 2022; 12:diagnostics12061412. [PMID: 35741222 PMCID: PMC9222194 DOI: 10.3390/diagnostics12061412] [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: 04/19/2022] [Revised: 05/21/2022] [Accepted: 06/05/2022] [Indexed: 11/16/2022] Open
Abstract
Background: In patients with metabolic-associated fatty liver disease (MAFLD), hepatic steatosis is the first step of diagnosis, and it is a risk predictor that independently predicts insulin resistance, cardiovascular risk, and mortality. Urine biomarkers have the advantage of being less complex, with a lower dynamic range and fewer technical challenges, in comparison to blood biomarkers. Methods: Hepatic steatosis was measured by magnetic resonance imaging (MRI), which measured the proton density fat fraction (MRI-PDFF). Mild hepatic steatosis was defined as MRI-PDFF 5−10% and severe hepatic steatosis was defined as MRI-PDFF > 10%. Results: MAFLD patients with any kidney diseases were excluded. There were 53 proteins identified by mass spectrometry with significantly different expressions among the healthy control, mild steatosis, and severe steatosis patients. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of these significantly changed urinary molecular features correlated with the liver, resulting in the dysregulation of carbohydrate derivative/catabolic/glycosaminoglycan/metabolic processes, insulin-like growth factor receptor levels, inflammatory responses, the PI3K−Akt signaling pathway, and cholesterol metabolism. Urine alpha-1-acid glycoprotein 1 (ORM1) and ceruloplasmin showed the most significant correlation with the clinical parameters of MAFLD status, including liver fat content, fibrosis, ALT, triglycerides, glucose, HOMA-IR, and C-reactive protein. According to ELISA and western blot (30 urine samples, normalized to urine creatinine), ceruloplasmin (ROC 0.78, p = 0.034) and ORM1 (ROC 0.87, p = 0.005) showed moderate diagnostic accuracy in distinguishing mild steatosis from healthy controls. Ceruloplasmin (ROC 0.79, p = 0.028) and ORM1 (ROC 0.81, p = 0.019) also showed moderate diagnostic accuracy in distinguishing severe steatosis from mild steatosis. Conclusions: Ceruloplasmin and ORM1 are potential biomarkers in distinguishing mild and severe steatosis in MAFLD patients.
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Affiliation(s)
- Chang-Hai Liu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China; (C.-H.L.); (D.W.); (W.J.); (Q.Z.)
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shanshan Zheng
- Key Laboratory of Transplant Engineering and Immunology, MOH, West China-Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu 610041, China; (S.Z.); (S.W.)
| | - Shisheng Wang
- Key Laboratory of Transplant Engineering and Immunology, MOH, West China-Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu 610041, China; (S.Z.); (S.W.)
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China; (C.-H.L.); (D.W.); (W.J.); (Q.Z.)
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wei Jiang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China; (C.-H.L.); (D.W.); (W.J.); (Q.Z.)
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qingmin Zeng
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China; (C.-H.L.); (D.W.); (W.J.); (Q.Z.)
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yi Wei
- Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China;
| | - Yong Zhang
- Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu 610041, China
- Correspondence: (Y.Z.); (H.T.)
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China; (C.-H.L.); (D.W.); (W.J.); (Q.Z.)
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Correspondence: (Y.Z.); (H.T.)
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20
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Cheng Q, Yuan X, Lin S, Zhao Y, Wang H, Zhu F, Wang Y, Xu T, Wu J, Wang K, Zhang J, Sun X, Li C, Liang H, Fang L, Xue B. Serum proteome profiling reveals differentially expressed proteins between subjects with metabolically healthy obesity and nonalcoholic fatty liver disease. J Proteomics 2022; 260:104556. [PMID: 35283354 DOI: 10.1016/j.jprot.2022.104556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 02/21/2022] [Accepted: 03/07/2022] [Indexed: 11/15/2022]
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21
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Ciardullo S, Perseghin G. Advances in fibrosis biomarkers in nonalcoholic fatty liver disease. Adv Clin Chem 2022; 106:33-65. [PMID: 35152974 DOI: 10.1016/bs.acc.2021.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult world population and the degree of liver fibrosis represents the best predictor of the development of liver-related outcomes. Easily applicable and well performing non-invasive fibrosis tests can overcome the limitations of liver biopsy and are of paramount importance to identify at-risk subjects in clinical practice. While tests with optimal performance and ease of use do not exist at this stage, available markers can be divided in three broad groups: simple serum tests, complex serum tests and elastographic methods. Simple scores (such as Fibrosis-4 and NAFLD Fibrosis Score) are based on readily available biochemical data and clinical features, while complex/proprietary tests (such as Fibrotest, Enhanced Liver Fibrosis and Hepascore) directly measure markers of fibrogenesis and fibrolysis, but have higher costs. Elastography techniques estimate the degree of fibrosis from liver stiffness and are based on either ultrasound or magnetic resonance (MR) imaging. MR elastography has better performance compared with sonographic techniques and is not affected by obesity and inflammation, but is highly costly and less available. In general, non-invasive tests are able to exclude the presence of fibrosis, but their positive predictive value is low to moderate and they lead to a high number of indeterminate results. In this context, a combination of different tests might increase accuracy while reducing gray-zone results. Their ability to predict future events and response to treatment is suboptimal and needs to be studied further. Finally, recent studies have tried different approaches, spanning from "omics" to the microbiome and micro-RNAs, with some promising results.
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Affiliation(s)
- Stefano Ciardullo
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, Italy; School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
| | - Gianluca Perseghin
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, Italy; School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy.
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22
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Pelechá M, Villanueva-Bádenas E, Timor-López E, Donato MT, Tolosa L. Cell Models and Omics Techniques for the Study of Nonalcoholic Fatty Liver Disease: Focusing on Stem Cell-Derived Cell Models. Antioxidants (Basel) 2021; 11:86. [PMID: 35052590 PMCID: PMC8772881 DOI: 10.3390/antiox11010086] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/24/2021] [Accepted: 12/28/2021] [Indexed: 12/04/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease in western countries. The molecular mechanisms leading to NAFLD are only partially understood, and effective therapeutic interventions are clearly needed. Therefore, preclinical research is required to improve knowledge about NAFLD physiopathology and to identify new therapeutic targets. Primary human hepatocytes, human hepatic cell lines, and human stem cell-derived hepatocyte-like cells exhibit different hepatic phenotypes and have been widely used for studying NAFLD pathogenesis. In this paper, apart from employing the different in vitro cell models for the in vitro assessment of NAFLD, we also reviewed other approaches (metabolomics, transcriptomics, and high-content screening). We aimed to summarize the characteristics of different cell types and methods and to discuss their major advantages and disadvantages for NAFLD modeling.
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Affiliation(s)
- María Pelechá
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (M.P.); (E.V.-B.); (E.T.-L.)
| | - Estela Villanueva-Bádenas
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (M.P.); (E.V.-B.); (E.T.-L.)
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina y Odontología, Universidad de Valencia, 46010 Valencia, Spain
| | - Enrique Timor-López
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (M.P.); (E.V.-B.); (E.T.-L.)
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina y Odontología, Universidad de Valencia, 46010 Valencia, Spain
| | - María Teresa Donato
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (M.P.); (E.V.-B.); (E.T.-L.)
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina y Odontología, Universidad de Valencia, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Laia Tolosa
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; (M.P.); (E.V.-B.); (E.T.-L.)
- Biomedical Research Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, 28029 Madrid, Spain
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23
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Wang S, Sheng F, Zou L, Xiao J, Li P. Hyperoside attenuates non-alcoholic fatty liver disease in rats via cholesterol metabolism and bile acid metabolism. J Adv Res 2021; 34:109-122. [PMID: 35024184 PMCID: PMC8655136 DOI: 10.1016/j.jare.2021.06.001] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 06/03/2021] [Accepted: 06/04/2021] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) results from increased hepatic total cholesterol (TC) and total triglyceride (TG) accumulation. In our previous study, we found that rats treated with hyperoside became resistant to hepatic lipid accumulation. OBJECTIVES The present study aims to investigate the possible mechanisms responsible for the inhibitory effects of hyperoside on the lipid accumulation in the liver tissues of the NAFLD rats. METHODS Label-free proteomics and metabolomics targeting at bile acid (BA) metabolism were applied to disclose the mechanisms for hyperoside reducing hepatic lipid accumulation among the NAFLD rats. RESULTS In response to hyperoside treatment, several proteins related to the fatty acid degradation pathway, cholesterol metabolism pathway, and bile secretion pathway were altered, including ECI1, Acnat2, ApoE, and BSEP, etc. The expression of nuclear receptors (NRs), including farnesoid X receptor (FXR) and liver X receptor α (LXRα), were increased in hyperoside-treated rats' liver tissue, accompanied by decreased protein expression of catalyzing enzymes in the hepatic de novo lipogenesis and increased protein level of enzymes in the classical and alternative BA synthetic pathway. Liver conjugated BAs were less toxic and more hydrophilic than unconjugated BAs. The BA-targeted metabolomics suggest that hyperoside could decrease the levels of liver unconjugated BAs and increase the levels of liver conjugated BAs. CONCLUSIONS Taken together, the results suggest that hyperoside could improve the condition of NAFLD by regulating the cholesterol metabolism as well as BAs metabolism and excretion. These findings contribute to understanding the mechanisms by which hyperoside lowers the cholesterol and triglyceride in NAFLD rats.
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Key Words
- ACC, Acetyl-CoA carboxylase
- AMPK, AMP-activated protein kinase
- Apo, apolipoprotein
- BAs, bile acids
- BSH, bile salt hydrolase
- Bile acid metabolism
- CYP27A1, sterol 27-hydroxylase
- CYP7A1, cholesterol 7α-hydroxylase
- Cholesterol metabolism
- FGF15/19, fibroblast growth factor 15/19
- FXR, farnesoid X receptor
- Hyperoside
- LC-MS, the combination of high-performance liquid chromatography and mass spectrometry
- LXRα, liver X receptor α
- Label-free proteomics
- NAFLD
- NAFLD, non-alcoholic fatty liver disease
- PMSF, phenylmethylsulfonyl fluoride
- QC, quality control
- SDS, sodium dodecyl sulfate
- SHP, small heterodimer partner
- SREBP1, sterol regulatory element-binding protein 1
- SREBP2, sterol regulatory element-binding protein 2
- SREBPs, sterol regulatory element binding proteins
- TC, total cholesterol
- TG, triglyceride
- TGR5, Takeda G-protein-coupled receptor 5
- Targeted metabolomics
- VLDL, very low-density lipoprotein
- WB, Western blot
- pACC, phosphorylated ACC
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Affiliation(s)
- Songsong Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Feiya Sheng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Liang Zou
- School of Medicine, Chengdu University, Chengdu 610106, China
| | - Jianbo Xiao
- Institute of Food Safety and Nutrition, Jinan University, Guangzhou 510632, China
- Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo, Vigo, Spain
| | - Peng Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
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24
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Clinical and Molecular Biomarkers for Diagnosis and Staging of NAFLD. Int J Mol Sci 2021; 22:ijms222111905. [PMID: 34769333 PMCID: PMC8585051 DOI: 10.3390/ijms222111905] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 10/30/2021] [Accepted: 10/30/2021] [Indexed: 12/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic pathology in industrialized countries, affecting about 25% of the general population. NAFLD is a benign condition, however, it could evolve toward more serious diseases, including non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and finally, hepatocellular carcinoma (HCC). Liver biopsy is still the gold standard for NAFLD diagnosis. Due to the risks associated with liver biopsy and the impossibility to apply it on a large scale, it is now necessary to identify non-invasive biomarkers, which may reliably identify patients at higher risk of progression. Therefore, several lines of research have tried to address this issue by identifying novel biomarkers using omics approaches, including lipidomics, metabolomics and RNA molecules' profiling. Thus, in this review, we firstly report the conventional biomarkers used in clinical practice for NAFL and NASH diagnosis as well as fibrosis staging, and secondly, we pay attention to novel biomarkers discovered through omics approaches with a particular focus on RNA biomarkers (microRNAs, long-noncoding RNAs), showing promising diagnostic performance for NAFL/NASH diagnosis and fibrosis staging.
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25
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Zhu Y, Zhang S, Yang C, Xue W, Zhang J, Li J, Zhao J, Xu J, Huang W. [Quantitative analysis of differential proteins in liver tissues of patients with non-alcoholic steatohepatitis using iTRAQ technology]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2021; 41:1381-1387. [PMID: 34658353 DOI: 10.12122/j.issn.1673-4254.2021.09.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To screen differentially expressed proteins (DSPs) in the liver tissues of patients with nonalcoholic steatohepatitis (NASH) using proteomic technologies to identify potential therapeutic targets of NASH. METHODS Liver tissue specimens were obtained from 3 patients with pathologically confirmed NASH and 3 normal control subjects. The total proteins were extracted from the specimens, and iTRAQ reagent was used to label the peptides for liquid chromatography tandem mass spectrometry (LC-MS/MS) detection. The DSPs were identified by comparing the data against UniProt protein database using Mascot2.3.02 software and were annotated and enriched using GO database; KEGG database was used for enrichment of the pathways involving these proteins. Real-time fluorescent quantitative PCR (qPCR) was performed to detect the mRNA expressions of the significant DSPs in NASH. RESULTS By the criteria that a DSP has >1.2 or < 0.8 fold difference between NASH group and the control group and with P < 0.05 as the threshold, a total of 648 significant DSPs in NASH were identified, including 246 up-regulated and 402 down-regulated proteins. GO functional enrichment analysis showed that the DSPs were involved mainly in small molecule metabolism, organic acid metabolism, oxygen acid metabolism and other biological processes, and were enriched in KEGG pathways including the metabolic pathways, complement coagulation cascades, and ribosomes. Among the 25 DEPs with a fold difference >2.0 or < 0.5 (P < 0.05), 6 proteins showed consistent results between qPCR verification and proteomic analysis, including 5 down-regulated proteins: Jumonji protein (JARID2), Lebasillinlike protein (LCA5L), synaptophysin 1 (SYN1) and collagen α-1 (XIII) chain (COL13A1), FYVE, RhoGEF and PH domain protein 5 (FGD5), and 1 upregulated protein glutathione S-transferase Mu 4 (GSTM4). CONCLUSION We identified 648 DEPs inthe liver tissue of patients NASH using iTRAQ technology and bioinformatics methods, and among them JARID2, SYN1, COL13A1, FGD5, and GSTM4 may serve as the key target proteins of NASH.
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Affiliation(s)
- Y Zhu
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - S Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - C Yang
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - W Xue
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - J Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - J Li
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - J Zhao
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - J Xu
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - W Huang
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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Hörber S, Lehmann R, Fritsche L, Machann J, Birkenfeld AL, Häring HU, Stefan N, Heni M, Fritsche A, Peter A. Lifestyle Intervention Improves Prothrombotic Coagulation Profile in Individuals at High Risk for Type 2 Diabetes. J Clin Endocrinol Metab 2021; 106:e3198-e3207. [PMID: 33659996 DOI: 10.1210/clinem/dgab124] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Indexed: 12/18/2022]
Abstract
CONTEXT Patients with obesity and insulin resistance are at higher risk for arterial and venous thrombosis due to a prothrombotic state. OBJECTIVE The present study addressed whether this is reversible by lifestyle intervention and elucidated potential underlying associations. METHODS A total of 100 individuals with impaired glucose tolerance or impaired fasting plasma glucose participated in a 1-year lifestyle intervention, including precise metabolic phenotyping and MRS-based determination of liver fat content as well as a comprehensive analysis of coagulation parameters before and after this intervention. RESULTS During the lifestyle intervention, significant reductions in coagulation factor activities (II, VII, VIII, IX, XI, and XII) were observed. Accordingly, prothrombin time (PT%) and activated partial thromboplastin time (aPTT) were slightly decreased and prolonged, respectively. Moreover, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF), and also protein C and protein S decreased. Fibrinogen, antithrombin, D-dimer, and FXIII remained unchanged. Searching for potential regulators, especially weight loss, but also liver fat reduction, improved insulin sensitivity, and decreased low-grade inflammation were linked to favorable changes in hemostasis parameters. Independent of weight loss, liver fat reduction (FII, protein C, protein S, PAI-1, vWF), improved insulin sensitivity (protein S, PAI-1), and reduced low-grade inflammation (PT%, aPTT, FVIII/IX/XI/XII, vWF) were identified as single potential regulators. CONCLUSION Lifestyle intervention is able to improve a prothrombotic state in individuals at high risk for type 2 diabetes. Besides body weight, liver fat content, insulin sensitivity, and systemic low-grade inflammation are potential mechanisms for improvements in hemostasis and could represent future therapeutic targets.
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Affiliation(s)
- Sebastian Hörber
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Rainer Lehmann
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Louise Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Jürgen Machann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Section on Experimental Radiology, Department of Radiology, University Hospital of Tübingen, Tübingen, Germany
| | - Andreas L Birkenfeld
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, University Hospital of Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, University Hospital of Tübingen, Tübingen, Germany
| | - Norbert Stefan
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, University Hospital of Tübingen, Tübingen, Germany
| | - Martin Heni
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, University Hospital of Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, University Hospital of Tübingen, Tübingen, Germany
| | - Andreas Peter
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
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Yang B, Zhang J, Sun L, Huang T, Kong Y, Li L, Sun Z, Yin M, Li X. Mapping Novel Biomarkers of Liver Injury by Tissue Proteomic Analysis. ACS OMEGA 2021; 6:7127-7138. [PMID: 33748626 PMCID: PMC7970576 DOI: 10.1021/acsomega.1c00152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 02/22/2021] [Indexed: 06/12/2023]
Abstract
Liver damage is a dynamic process, and evaluation of liver injury degree is the key step in disease diagnosis. However, few common markers among different types of liver injury have been reported. Herein, we generated three liver injury mouse models, including Con A-induced, CCl4-injected, and subjected bile duct ligation mouse models, to simulate different types of liver damage in humans and then performed a label-free mass spectrometry to identify differentially expressed proteins in liver tissues. Interestingly, two proteins, G3BP and ABCC6, were conserved regulated in different liver injury models and are proposed to be biomarkers in liver injury, with G3BP upregulated and ABCC6 downregulated. Overall, our study identified two novel biomarkers of liver injury, and they might be used as potential drug targets of liver damage research studies.
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Affiliation(s)
- Bo Yang
- Shanghai
Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences,
School of Life Sciences, East China Normal
University, Shanghai 200241, China
- Interdisciplinary
Research Center on Biology and Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
| | - Jianan Zhang
- Interdisciplinary
Research Center on Biology and Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
- University
of Chinese Academy of Sciences, Beijing 100049, China
| | - Le Sun
- Interdisciplinary
Research Center on Biology and Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
- University
of Chinese Academy of Sciences, Beijing 100049, China
| | - Tingmei Huang
- Shanghai
Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences,
School of Life Sciences, East China Normal
University, Shanghai 200241, China
| | - Yaqi Kong
- Shanghai
Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences,
School of Life Sciences, East China Normal
University, Shanghai 200241, China
| | - Lei Li
- Shanghai
Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences,
School of Life Sciences, East China Normal
University, Shanghai 200241, China
| | - Zhengwang Sun
- Department
of Orthopaedic Surgery, Fudan University
Shanghai Cancer Center, Shanghai 200032, China
| | - Mengchen Yin
- Department
of Orthopaedics, LongHua Hospital, Shanghai
University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaotao Li
- Shanghai
Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences,
School of Life Sciences, East China Normal
University, Shanghai 200241, China
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Proteomic screening of plasma identifies potential noninvasive biomarkers associated with significant/advanced fibrosis in patients with nonalcoholic fatty liver disease. Biosci Rep 2021; 40:221652. [PMID: 31860081 PMCID: PMC6944676 DOI: 10.1042/bsr20190395] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 11/16/2019] [Accepted: 12/19/2019] [Indexed: 12/13/2022] Open
Abstract
Noninvasive biomarkers are clinically useful for evaluating liver fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to compare plasma proteins in patients with early nonalcoholic steatohepatitis (NASH) (F0-F1) versus NASH with significant/advanced fibrosis (F2–F4) to determine whether candidate proteins could be used as potential noninvasive biomarkers. Nineteen biopsy-proven NAFLD patients including ten early NASH patients and nine NASH patients with significant/advanced fibrosis were enrolled in the present study. High-resolution proteomics screening of plasma was performed with the SCIEX TripleTOF 5600 System. Proteins were quantified using two different software platforms, Progenesis Qi and Scaffold Q+, respectively. Progenesis Qi analysis resulted in the discovery of 277 proteins compared with 235 proteins in Scaffold Q+. Five consensus proteins (i.e. Complement component C7; α-2-macroglobulin; Complement component C8 γ chain; Fibulin-1; α-1-antichymotrypsin) were identified. Complement component C7 was three-fold higher in the NASH group with significant/advanced fibrosis (F2–F4) compared with the early NASH (F0-F1) group (q-value = 3.6E-6). Complement component C7 and Fibulin-1 are positively correlated with liver stiffness (P=0.000, P=0.002, respectively); whereas, Complement component C8 γ chain is negatively correlated (P=0.009). High levels of Complement C7 are associated with NASH with significant/advanced fibrosis and Complement C7 is a perfect classifier of patients included in this pilot study. Further studies will be needed in a larger validation cohort to confirm the utility of complement proteins as biomarkers or mechanistic determinants of NASH with significant/advanced fibrosis.
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29
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Wernberg CW, Ravnskjaer K, Lauridsen MM, Thiele M. The Role of Diagnostic Biomarkers, Omics Strategies, and Single-Cell Sequencing for Nonalcoholic Fatty Liver Disease in Severely Obese Patients. J Clin Med 2021; 10:930. [PMID: 33804302 PMCID: PMC7957539 DOI: 10.3390/jcm10050930] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 02/23/2021] [Accepted: 02/24/2021] [Indexed: 12/29/2022] Open
Abstract
Liver disease due to metabolic dysfunction constitute a worldwide growing health issue. Severe obesity is a particularly strong risk factor for non-alcoholic fatty liver disease, which affects up to 93% of these patients. Current diagnostic markers focus on the detection of advanced fibrosis as the major predictor of liver-related morbidity and mortality. The most accurate diagnostic tools use elastography to measure liver stiffness, with diagnostic accuracies similar in normal-weight and severely obese patients. The effectiveness of elastography tools are however hampered by limitations to equipment and measurement quality in patients with very large abdominal circumference and subcutaneous fat. Blood-based biomarkers are therefore attractive, but those available to date have only moderate diagnostic accuracy. Ongoing technological advances in omics technologies such as genomics, transcriptomics, and proteomics hold great promise for discovery of biomarkers and increased pathophysiological understanding of non-alcoholic liver disease and steatohepatitis. Very recent developments have allowed for single-cell sequencing and cell-type resolution of gene expression and function. In the near future, we will therefore likely see a multitude of breakthrough biomarkers, developed from a deepened understanding of the biological function of individual cell types in the healthy and injured liver.
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Affiliation(s)
- Charlotte W. Wernberg
- Department of Gastroenterology and Hepatology, Hospital Southwest of Jutland, 6700 Esbjerg, Denmark; (C.W.W.); (M.M.L.)
- Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense, Denmark;
| | - Kim Ravnskjaer
- Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense, Denmark;
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark
| | - Mette M. Lauridsen
- Department of Gastroenterology and Hepatology, Hospital Southwest of Jutland, 6700 Esbjerg, Denmark; (C.W.W.); (M.M.L.)
- Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense, Denmark;
| | - Maja Thiele
- Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense, Denmark;
- Center for Liver Research, Department of Hepatology and Gastroenterology, Odense University Hospital, 5000 Odense, Denmark
- Institute for Clinical Research, University of Southern Denmark, 5230 Odense, Denmark
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30
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Kogachi S, Noureddin M. Noninvasive Evaluation for Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Clin Ther 2021; 43:455-472. [PMID: 33581876 DOI: 10.1016/j.clinthera.2021.01.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/26/2020] [Accepted: 01/04/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and has the potential risk for progressing to nonalcoholic steatohepatitis (NASH), which is associated with a greater risk for complications of chronic liver disease. Noninvasive testing has been evaluated for diagnosis, risk stratification, disease progression, and assessing response to therapy. The purpose of this narrative review was to outline the current noninvasive testing modalities for the diagnostic evaluation of NAFLD and NASH, while discussing possible markers that could be used for monitoring response to therapies. METHODS The PubMed and Cochrane databases were searched for relevant articles that evaluated the diagnosis of NAFLD/NASH with serum biomarkers and/or imaging. FINDINGS Serum biomarkers, imaging modalities, and combinations/serial algorithms involved in the diagnosis of NAFLD and NASH are outlined. In addition, noninvasive modalities that have been used for assessing response to therapies in clinical trials are discussed. IMPLICATIONS Liver biopsy currently remains the gold standard for diagnosis and is often used in clinical trials to assess treatment response. However, developing safe and accessible noninvasive modalities for diagnosis and monitoring will have greater impact and relevance, as biopsy may not always be feasible in all clinical settings.
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Affiliation(s)
- Shannon Kogachi
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Mazen Noureddin
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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31
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Huang L, Shao D, Wang Y, Cui X, Li Y, Chen Q, Cui J. Human body-fluid proteome: quantitative profiling and computational prediction. Brief Bioinform 2021; 22:315-333. [PMID: 32020158 PMCID: PMC7820883 DOI: 10.1093/bib/bbz160] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 08/22/2019] [Accepted: 10/18/2019] [Indexed: 12/15/2022] Open
Abstract
Empowered by the advancement of high-throughput bio technologies, recent research on body-fluid proteomes has led to the discoveries of numerous novel disease biomarkers and therapeutic drugs. In the meantime, a tremendous progress in disclosing the body-fluid proteomes was made, resulting in a collection of over 15 000 different proteins detected in major human body fluids. However, common challenges remain with current proteomics technologies about how to effectively handle the large variety of protein modifications in those fluids. To this end, computational effort utilizing statistical and machine-learning approaches has shown early successes in identifying biomarker proteins in specific human diseases. In this article, we first summarized the experimental progresses using a combination of conventional and high-throughput technologies, along with the major discoveries, and focused on current research status of 16 types of body-fluid proteins. Next, the emerging computational work on protein prediction based on support vector machine, ranking algorithm, and protein-protein interaction network were also surveyed, followed by algorithm and application discussion. At last, we discuss additional critical concerns about these topics and close the review by providing future perspectives especially toward the realization of clinical disease biomarker discovery.
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Affiliation(s)
- Lan Huang
- College of Computer Science and Technology in the Jilin University
| | - Dan Shao
- College of Computer Science and Technology in the Jilin University
- College of Computer Science and Technology in Changchun University
| | - Yan Wang
- College of Computer Science and Technology in the Jilin University
| | - Xueteng Cui
- College of Computer Science and Technology in the Changchun University
| | - Yufei Li
- College of Computer Science and Technology in the Changchun University
| | - Qian Chen
- College of Computer Science and Technology in the Jilin University
| | - Juan Cui
- Department of Computer Science and Engineering in the University of Nebraska-Lincoln
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32
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Bayliss J, Ooi GJ, De Nardo W, Shah YJH, Montgomery MK, McLean C, Kemp W, Roberts SK, Brown WA, Burton PR, Watt MJ. Ectodysplasin A Is Increased in Non-Alcoholic Fatty Liver Disease, But Is Not Associated With Type 2 Diabetes. Front Endocrinol (Lausanne) 2021; 12:642432. [PMID: 33746906 PMCID: PMC7970300 DOI: 10.3389/fendo.2021.642432] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
UNLABELLED Ectodysplasin A (EDA) was recently identified as a liver-secreted protein that is increased in the liver and plasma of obese mice and causes skeletal muscle insulin resistance. We assessed if liver and plasma EDA is associated with worsening non-alcoholic fatty liver disease (NAFLD) in obese patients and evaluated plasma EDA as a biomarker for NAFLD. Using a cross-sectional study in a public hospital, patients with a body mass index >30 kg/m2 (n=152) underwent liver biopsy for histopathology assessment and fasting liver EDA mRNA. Fasting plasma EDA levels were also assessed. Non-alcoholic fatty liver (NAFL) was defined as >5% hepatic steatosis and nonalcoholic steatohepatitis (NASH) as NAFLD activity score ≥3. Patients were divided into three groups: No NAFLD (n=45); NAFL (n=65); and NASH (n=42). Liver EDA mRNA was increased in patients with NASH compared with No NAFLD (P=0.05), but not NAFL. Plasma EDA levels were increased in NAFL and NASH compared with No NAFLD (P=0.03). Plasma EDA was related to worsening steatosis (P=0.02) and fibrosis (P=0.04), but not inflammation or hepatocellular ballooning. ROC analysis indicates that plasma EDA is not a reliable biomarker for NAFL or NASH. Plasma EDA was not increased in patients with type 2 diabetes and did not correlate with insulin resistance. Together, we show that plasma EDA is increased in NAFL and NASH, is related to worsening steatosis and fibrosis but is not a reliable biomarker for NASH. Circulating EDA is not associated with insulin resistance in human obesity. CLINICAL TRIAL REGISTRATION https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12615000875505, identifier ACTRN12615000875505.
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Affiliation(s)
- Jacqueline Bayliss
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
| | - Geraldine J. Ooi
- Department of Surgery, Centre for Obesity Research and Education, Monash University, Melbourne, VIC, Australia
| | - William De Nardo
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
| | - Yazmin Johari Halim Shah
- Department of Surgery, Centre for Obesity Research and Education, Monash University, Melbourne, VIC, Australia
| | - Magdalene K. Montgomery
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
| | - Catriona McLean
- Department of Anatomical Pathology, Alfred Health, Melbourne, VIC, Australia
| | - William Kemp
- Department of Gastroenterology, The Alfred Hospital and Monash University, Melbourne, VIC, Australia
| | - Stuart K. Roberts
- Department of Gastroenterology, The Alfred Hospital and Monash University, Melbourne, VIC, Australia
| | - Wendy A. Brown
- Department of Surgery, Centre for Obesity Research and Education, Monash University, Melbourne, VIC, Australia
| | - Paul R. Burton
- Department of Surgery, Centre for Obesity Research and Education, Monash University, Melbourne, VIC, Australia
| | - Matthew J. Watt
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
- *Correspondence: Matthew J. Watt,
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Karlsson C, Wallenius K, Walentinsson A, Greasley PJ, Miliotis T, Hammar M, Iaconelli A, Tapani S, Raffaelli M, Mingrone G, Carlsson B. Identification of Proteins Associated with the Early Restoration of Insulin Sensitivity After Biliopancreatic Diversion. J Clin Endocrinol Metab 2020; 105:5896394. [PMID: 32830851 PMCID: PMC7518464 DOI: 10.1210/clinem/dgaa558] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 08/18/2020] [Indexed: 01/15/2023]
Abstract
CONTEXT Insulin resistance (IR) is a risk factor for type 2 diabetes, diabetic kidney disease, cardiovascular disease and nonalcoholic steatohepatitis. Biliopancreatic diversion (BPD) is the most effective form of bariatric surgery for improving insulin sensitivity. OBJECTIVE To identify plasma proteins correlating with the early restoration of insulin sensitivity after BPD. DESIGN Prospective single-center study including 20 insulin-resistant men with morbid obesity scheduled for BPD. Patient characteristics and blood samples were repeatedly collected from baseline up to 4 weeks postsurgery. IR was assessed by homeostatic model assessment for insulin resistance (HOMA-IR), Matsuda Index, and by studying metabolic profiles during meal tolerance tests. Unbiased proteomic analysis was performed to identify plasma proteins altered by BPD. Detailed plasma profiles were made on a selected set of proteins by targeted multiple reaction monitoring mass spectrometry (MRM/MS). Changes in plasma proteome were evaluated in relation to metabolic and inflammatory changes. RESULTS BPD resulted in improved insulin sensitivity and reduced body weight. Proteomic analysis identified 29 proteins that changed following BPD. Changes in plasma levels of afamin, apolipoprotein A-IV (ApoA4), and apolipoprotein A-II (ApoA2) correlated significantly with changes in IR. CONCLUSION Circulating levels of afamin, ApoA4, and ApoA2 were associated with and may contribute to the rapid improvement in insulin sensitivity after BPD.
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Affiliation(s)
- Cecilia Karlsson
- Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Correspondence and Reprint Requests: Cecilia Karlsson, MD, PhD, Assoc Prof, Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. E-mail:
| | - Kristina Wallenius
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden
| | - Anna Walentinsson
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden
| | - Peter J Greasley
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden
| | - Tasso Miliotis
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden
| | - Mårten Hammar
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden
| | | | - Sofia Tapani
- Early Biometrics and Statistical Innovation, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden
| | - Marco Raffaelli
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Geltrude Mingrone
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Diabetes, King’s College London, London, United Kingdom
| | - Björn Carlsson
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden
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Perakakis N, Stefanakis K, Mantzoros CS. The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease. Metabolism 2020; 111S:154320. [PMID: 32712221 PMCID: PMC7377759 DOI: 10.1016/j.metabol.2020.154320] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/15/2020] [Accepted: 07/18/2020] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifaceted metabolic disorder, whose spectrum covers clinical, histological and pathophysiological developments ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and liver fibrosis, potentially evolving into cirrhosis, hepatocellular carcinoma and liver failure. Liver biopsy remains the gold standard for diagnosing NAFLD, while there are no specific treatments. An ever-increasing number of high-throughput Omics investigations on the molecular pathobiology of NAFLD at the cellular, tissue and system levels produce comprehensive biochemical patient snapshots. In the clinical setting, these applications are considerably enhancing our efforts towards obtaining a holistic insight on NAFLD pathophysiology. Omics are also generating non-invasive diagnostic modalities for the distinct stages of NAFLD, that remain though to be validated in multiple, large, heterogenous and independent cohorts, both cross-sectionally as well as prospectively. Finally, they aid in developing novel therapies. By tracing the flow of information from genomics to epigenomics, transcriptomics, proteomics, metabolomics, lipidomics and glycomics, the chief contributions of these techniques in understanding, diagnosing and treating NAFLD are summarized herein.
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Affiliation(s)
- Nikolaos Perakakis
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA..
| | - Konstantinos Stefanakis
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Christos S Mantzoros
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Rosato V, Masarone M, Aglitti A, Persico M. The diagnostic conundrum in non-alcoholic fatty liver disease. EXPLORATION OF MEDICINE 2020. [DOI: 10.37349/emed.2020.00018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common liver alteration worldwide. It encompasses a spectrum of disorders that range from simple steatosis to a progressive form, defined non-alcoholic steatohepatitis (NASH), that can lead to advanced fibrosis and eventually cirrhosis and hepatocellular carcinoma. On liver histology, NASH is characterized by the concomitant presence of significant fat accumulation and inflammatory reaction with hepatocellular injury. Until now, liver biopsy is still required to differentiate simple steatosis from NASH and evaluate the degree of liver fibrosis. Unfortunately, this technique has well-known limitations, including invasiveness and expensiveness. Moreover, it may be biased by sampling error and intra- or inter-observed variability. Furthermore, due to the increasing prevalence of NAFLD worldwide, to program a systematic screening with liver biopsy is not imaginable. In recent years, different techniques were developed and validated with the aim of non-invasively identifying NASH and assess liver fibrosis degrees. The non-invasive tests range from simple blood-tests analyses to composite scores and complex imaging techniques. Nevertheless, even if they could represent cost-effective strategies for diagnosing NASH, advanced fibrosis and cirrhosis, their accuracy and consequent usefulness are to be discussed. With this aim, in this review the authors summarize the current state of non-invasive assessment of NAFLD. In particular, in addition to the well-established tests, the authors describe the future perspectives in this field, reporting the latest tests based on OMICS, gut-miocrobioma and micro-RNAs. Finally, the authors provide an accurate assessment of how these non-invasive tools perform in clinical practice depending on the clinical context, with the aim of giving the clinicians a useful tool to try to resolve the diagnostic conundrum of NAFLD.
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Affiliation(s)
- Valerio Rosato
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Odontostomatology “Scuola Medica Salernitana”- University of Salerno, Street Salvador Allende, 43, Fisciano, 84084 Campania, Italy
| | - Mario Masarone
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Odontostomatology “Scuola Medica Salernitana”- University of Salerno, Street Salvador Allende, 43, Fisciano, 84084 Campania, Italy
| | - Andrea Aglitti
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Odontostomatology “Scuola Medica Salernitana”- University of Salerno, Street Salvador Allende, 43, Fisciano, 84084 Campania, Italy
| | - Marcello Persico
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Odontostomatology “Scuola Medica Salernitana”- University of Salerno, Street Salvador Allende, 43, Fisciano, 84084 Campania, Italy
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Paul J. Recent advances in non-invasive diagnosis and medical management of non-alcoholic fatty liver disease in adult. EGYPTIAN LIVER JOURNAL 2020. [DOI: 10.1186/s43066-020-00043-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Abstract
Background
Number of non-alcoholic fatty liver disease (NAFLD) cases is increasing over time due to alteration of food habit, increase incidence of metabolic syndrome, and lack of exercise. Liver biopsy is the test for diagnosis and staging of NAFLD, but nowadays several biochemical markers, scoring systems, and imaging studies are available to diagnose and stage NAFLD which is linked to end-stage liver disease, hepatocellular cancer, and elevated cardiovascular- and cancer-related morbidity and mortality. Therefore urgent diagnosis and management are required to avoid complications related to NAFLD. This review summarizes recent advances in diagnosis and medical management of non-alcoholic fatty liver disease.
Main text
Recently published studies from PubMed, Red Cross, Copernicus, and also various previous studies were reviewed. We have discussed various non-invasive methods for detection of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), and hepatic fibrosis. Non pharmacological therapies for NAFLD, indications, and approved medications for NAFLD and other commonly used non-approved medications have been discussed in this review article.
Conclusions
Multiple non-invasive tests are available for diagnosis of NAFLD, and its different stages however gold standard test is liver biopsy. NALFD without NASH and significant fibrosis is treated by lifestyle modifications which include moderate to vigorous exercise and diet modification. To improve hepatic steatosis, minimum of 3–5% of body weight loss is necessary, but > 7–10% weight reductions is required for histological improvement in NASH and fibrosis. Pharmacotherapy is indicated when patient is having NASH with significant fibrosis.
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Albhaisi S, Sanyal AJ. Applying Non-Invasive Fibrosis Measurements in NAFLD/NASH: Progress to Date. Pharmaceut Med 2020; 33:451-463. [PMID: 31933238 DOI: 10.1007/s40290-019-00305-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has now become a worldwide health issue due to the obesity epidemic, affecting approximately 90% of the obese population and 15-40% of the general population. It is the most common form of chronic liver disease in the United States. NAFLD constitutes a spectrum of diseases ranging in severity from mild, such as fatty liver, progressing into nonalcoholic steatohepatitis (NASH), then fibrosis, and ending with cirrhosis. NASH and increasing fibrosis stage are associated with increased morbidity and mortality; the fibrosis stage is therefore a critical element of risk stratification needed to determine therapeutic approach and also the response to treatment. Liver biopsy is considered the 'gold standard' in the diagnosis of NAFLD. However, it is not practical for widespread clinical use because it is invasive, costly, and associated with complications including occasional death. These limitations have driven the development of noninvasive tests that can accurately predict the fibrosis stage in those with NAFLD. In this review, we provide a concise overview of different non-invasive measurements used for NAFLD/NASH.
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Affiliation(s)
- Somaya Albhaisi
- Department of Internal Medicine, Virginia Commonwealth University, Box 980102, Richmond, VA, 23298, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Box 980341, Richmond, VA, 23298, USA.
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Liu F, Seto WK, Wong DKH, Huang FY, Cheung KS, Mak LY, Sharma R, Zhang S, Fung J, Lai CL, Yuen MF. Plasma Fibronectin Levels Identified via Quantitative Proteomics Profiling Predicts Hepatitis B Surface Antigen Seroclearance in Chronic Hepatitis B. J Infect Dis 2020; 220:940-950. [PMID: 31056649 DOI: 10.1093/infdis/jiz223] [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: 01/05/2019] [Accepted: 05/01/2019] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Seroclearance of hepatitis B surface antigen (HBsAg) is a potentially achievable target of chronic hepatitis B (CHB). Plasma proteins relevant to HBsAg seroclearance remain undetermined. METHODS We prospectively recruited treatment-naive CHB patients with spontaneous HBsAg seroclearance and matched HBsAg-positive controls. Plasma protein profiling was performed using isobaric tags for relative and absolute quantitation-based proteomics, with the expression of candidate proteins validated in a separate cohort. The predictive value of fibronectin was assessed at 3 years, 1 year (Year -1) before, and at the time (Year 0) of HBsAg seroclearance. RESULTS Four hundred eighty-seven plasma proteins were identified via proteomics, with 97 proteins showing altered expression. In the verification cohort (n = 90), median plasma fibronectin levels in patients with HBsAg seroclearance was higher than in controls (P = .009). In the longitudinal cohort (n = 164), patients with HBsAg seroclearance, compared with controls, had a higher median fibronectin levels at Year -1 (413.26 vs 227.95 µg/mL) and Year 0 (349.45 vs 208.72 µg/mL) (both P < .001). In patients with an annual HBsAg log reduction >0.5, Year -1 fibronectin level achieved an area under the receiving operator characteristic of 0.884 in predicting HBsAg seroclearance. CONCLUSIONS Using proteomics-based technology, plasma fibronectin may be associated with HBsAg seroclearance and a potential predictor of "functional cure".
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Affiliation(s)
- Fen Liu
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China.,State Key Laboratory for Liver Research, The University of Hong Kong, China.,Department of Medicine, The University of Hong Kong-Shenzhen Hospital, China
| | - Danny Ka-Ho Wong
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China.,State Key Laboratory for Liver Research, The University of Hong Kong, China
| | - Fung-Yu Huang
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China
| | - Ka-Shing Cheung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China
| | - Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China
| | - Rakesh Sharma
- Proteomics and Metabolomics Core Facility, Li Ka Shing Faculty of Medicine, The University of Hong Kong
| | - Saisai Zhang
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China
| | - James Fung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China.,State Key Laboratory for Liver Research, The University of Hong Kong, China
| | - Ching-Lung Lai
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China.,State Key Laboratory for Liver Research, The University of Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China.,State Key Laboratory for Liver Research, The University of Hong Kong, China
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Piazzolla VA, Mangia A. Noninvasive Diagnosis of NAFLD and NASH. Cells 2020; 9:E1005. [PMID: 32316690 PMCID: PMC7226476 DOI: 10.3390/cells9041005] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/09/2020] [Accepted: 04/14/2020] [Indexed: 02/07/2023] Open
Abstract
The aim of this review is to outline emerging biomarkers that can serve as early diagnostic tools to identify patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) and, among them, the subgroup of best candidates for clinical trials on emerging compounds. Regarding possible predictors of NAFLD, a number of studies evaluated a combination of serum biomarkers either available in routine practice (or investigational) or proprietary and expensive. So far, magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) appears to be the most accurate for fatty liver diagnosis. In clinical practice, the main question is how to diagnose NASH early. There are new promising biomarkers that can help in diagnosing early stages of NASH, yet they include variables not routinely tested. In the setting of NASH, most studies confirm that, in spite of several well-known limitations, transient elastography or point shear wave elastography can help in enriching the pool of patients that should be screened for investigational treatments. Newer multiomics biomarkers including those focusing on microbiota can be useful but require methods to be standardized and implemented. To date, one biomarker alone is not able to non- or minimally invasively identify patients with NASH and mild to moderate fibrosis.
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Affiliation(s)
| | - Alessandra Mangia
- Liver Unit, Department of Medical Sciences, IRCCS Fondazione, “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy;
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Veyel D, Wenger K, Broermann A, Bretschneider T, Luippold AH, Krawczyk B, Rist W, Simon E. Biomarker discovery for chronic liver diseases by multi-omics - a preclinical case study. Sci Rep 2020; 10:1314. [PMID: 31992752 PMCID: PMC6987209 DOI: 10.1038/s41598-020-58030-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 01/09/2020] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a major cause of liver fibrosis with increasing prevalence worldwide. Currently there are no approved drugs available. The development of new therapies is difficult as diagnosis and staging requires biopsies. Consequently, predictive plasma biomarkers would be useful for drug development. Here we present a multi-omics approach to characterize the molecular pathophysiology and to identify new plasma biomarkers in a choline-deficient L-amino acid-defined diet rat NASH model. We analyzed liver samples by RNA-Seq and proteomics, revealing disease relevant signatures and a high correlation between mRNA and protein changes. Comparison to human data showed an overlap of inflammatory, metabolic, and developmental pathways. Using proteomics analysis of plasma we identified mainly secreted proteins that correlate with liver RNA and protein levels. We developed a multi-dimensional attribute ranking approach integrating multi-omics data with liver histology and prior knowledge uncovering known human markers, but also novel candidates. Using regression analysis, we show that the top-ranked markers were highly predictive for fibrosis in our model and hence can serve as preclinical plasma biomarkers. Our approach presented here illustrates the power of multi-omics analyses combined with plasma proteomics and is readily applicable to human biomarker discovery.
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Affiliation(s)
- Daniel Veyel
- Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Sciences, Birkendorfer Str. 65, D-88397, Biberach Riss, Germany
| | - Kathrin Wenger
- Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Sciences, Birkendorfer Str. 65, D-88397, Biberach Riss, Germany
| | - Andre Broermann
- Boehringer Ingelheim Pharma GmbH & Co. KG, CardioMetabolic Diseases Research, Birkendorfer Str. 65, D-88397, Biberach Riss, Germany
| | - Tom Bretschneider
- Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Sciences, Birkendorfer Str. 65, D-88397, Biberach Riss, Germany
| | - Andreas H Luippold
- Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Sciences, Birkendorfer Str. 65, D-88397, Biberach Riss, Germany
| | - Bartlomiej Krawczyk
- Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Sciences, Birkendorfer Str. 65, D-88397, Biberach Riss, Germany
| | - Wolfgang Rist
- Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Sciences, Birkendorfer Str. 65, D-88397, Biberach Riss, Germany.
| | - Eric Simon
- Boehringer Ingelheim Pharma GmbH & Co. KG, Computational Biology, Birkendorfer Str. 65, D-88397, Biberach Riss, Germany.
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Ægidius HM, Veidal SS, Feigh M, Hallenborg P, Puglia M, Pers TH, Vrang N, Jelsing J, Kornum BR, Blagoev B, Rigbolt KTG. Multi-omics characterization of a diet-induced obese model of non-alcoholic steatohepatitis. Sci Rep 2020; 10:1148. [PMID: 31980690 PMCID: PMC6981216 DOI: 10.1038/s41598-020-58059-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 01/07/2020] [Indexed: 02/07/2023] Open
Abstract
To improve the understanding of the complex biological processes underlying the development of non-alcoholic steatohepatitis (NASH), a multi-omics approach combining bulk RNA-sequencing based transcriptomics, quantitative proteomics and single-cell RNA-sequencing was used to characterize tissue biopsies from histologically validated diet-induced obese (DIO) NASH mice compared to chow-fed controls. Bulk RNA-sequencing and proteomics showed a clear distinction between phenotypes and a good correspondence between mRNA and protein level regulations, apart from specific regulatory events discovered by each technology. Transcriptomics-based gene set enrichment analysis revealed changes associated with key clinical manifestations of NASH, including impaired lipid metabolism, increased extracellular matrix formation/remodeling and pro-inflammatory responses, whereas proteomics-based gene set enrichment analysis pinpointed metabolic pathway perturbations. Integration with single-cell RNA-sequencing data identified key regulated cell types involved in development of NASH demonstrating the cellular heterogeneity and complexity of NASH pathogenesis.
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Affiliation(s)
| | | | | | - Philip Hallenborg
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Michele Puglia
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Tune H Pers
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Niels Vrang
- Gubra, Hørsholm Kongevej 11B, Hørsholm, Denmark
| | | | - Birgitte R Kornum
- Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
| | - Blagoy Blagoev
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
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Allam AS, Salama MM, Nasser HM, Kabiel WAY, Elsayed EH. Comparison between NAFLD fibrosis score and retinoic acid serum level in NAFLD. EGYPTIAN LIVER JOURNAL 2020. [DOI: 10.1186/s43066-019-0014-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Abstract
Background
Non-alcoholic fatty liver disease (NAFLD) is described by the abnormal accumulation of fats in livers of individuals without significant alcohol intake. It includes a spectrum of diseases from simple steatosis to steatohepatitis (NASH) with fibrosis and cirrhosis. The prevalence of NAFLD is rising in association with increasing obesity worldwide. Retinoic acid (RA), a metabolite of vitamin A, mediates the functions of vitamin A required for growth and development. Also, RA has been shown to reduce adiposity not only in fat cells but also in the liver through increasing triglyceride hydrolysis and fat oxidation. This could put a future trial of preventing NASH and cirrhosis development by vitamin A supplementation. This work aimed to study the role of retinoic acid in NAFLD, whether it can differentiate simple steatosis from NASH and correlate the result with the NAFLD fibrosis score. It is a cross-sectional study done on 180 patients divided into three groups. Group 1 is composed of 80 patients with simple steatosis and normal ALT; group 2 is composed of 80 patients with NASH and high ALT in addition to group 3 with 20 healthy subjects served as a control group. All patients were proven to have fatty liver by ultrasonography. Serum RA was assayed by using enzyme-linked immunosorbent assay (ELISA) technique, and the NAFLD fibrosis score was calculated and compared with the retinoic acid level.
Result
Serum RA level was significantly decreased in the patient groups as compared to the controls; the lowest serum level was observed among the NASH group, followed by the steatosis group. NAFLD fibrosis score was calculated, and it was higher in the NASH group than in the steatosis group. Besides, there was a significant negative correlation between retinoic acid and NAFLD score among the patient groups.
Conclusion
Serum RA level was lower in patients with simple steatosis and NASH. RA had a high statistically significant difference in differentiation between the patient groups and the control group. The results were comparable to the NAFLD fibrosis score. Thus, retinoic acid could be used for diagnosis and accessing the degree of NAFLD.
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Singh SP, Barik RK. NonInvasive Biomarkers in Nonalcoholic Fatty Liver Disease: Are We There Yet? J Clin Exp Hepatol 2020; 10:88-98. [PMID: 32025168 PMCID: PMC6995889 DOI: 10.1016/j.jceh.2019.09.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 09/15/2019] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD encompasses a spectrum of disease ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. However, despite the growing recognition of this important disease burden, there are significant challenges to accurately and noninvasively diagnose the various forms of NAFLD, especially to differentiate benign steatosis from the progressive NASH. This is of utmost importance because although liver biopsy is considered the current imperfect 'gold' standard for diagnosing NASH and staging fibrosis, it is an invasive procedure with significant limitations. Although, a number of noninvasive markers have been or are currently undergoing investigation, until date, no highly sensitive and specific tests are available to differentiate NASH from simple steatosis. At the moment, further investigations are needed before prediction models or blood-based biomarkers become available and acceptable for routine clinical care. There is a great need for developing inexpensive, easily accessible, highly sensitive and specific biomarkers that permit not only the identification of patients at high risk of adverse outcomes, but also the monitoring of disease progression and response after therapeutic interventions.
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Affiliation(s)
- Shivaram P. Singh
- Address for correspondence: Shivaram Prasad Singh, Professor, Dept. of Gastroenterology, S.C.B. Medical College, Cuttack, Odisha, 753007, India.
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Huang B, Yao Y, Li Y, Yang H, Liu H, Liu H, Li D, Shu W, Chen M. Proteomics approach to investigate dynamic protein profile involved in high fat diet-induced fatty liver disease in rats. J Toxicol Pathol 2019; 32:223-232. [PMID: 31719749 PMCID: PMC6831498 DOI: 10.1293/tox.2018-0045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Accepted: 03/19/2019] [Indexed: 12/15/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a disorder of the liver found worldwide. The
molecular mechanisms underlying NAFLD initiation and progression, however, remain poorly
understood. In this study, fluorescence difference gel electrophoresis (DIGE) combined
with mass spectrometry was performed to profile the intracellular processes in the rat
liver at the proteome level when rats were fed a high-fat diet for 8 weeks. Dynamic
changes of 27 protein spots were observed. Among them, upregulation of 14 spots and
downregulation of 13 spots were observed during the eight weeks of the high fat
diet-induction period. These spots were analyzed by matrix-assisted laser
desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF), and
ultimately 24 proteins were identified with more than 95% confidence. Gene ontology (GO)
annotation indicated that these proteins were implicated in the metabolism of
carbohydrates, lipids, and amino acids. Four proteins were validated by western blot.
Further functional studies on these dynamically changing proteins may lead to a better
understanding of the mechanisms of high fat diet-induced fatty liver disease.
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Affiliation(s)
- Baohua Huang
- State Key Laboratory for Chemistry and Molecular Engineering of Medical Resources, Guangxi Normal University, 15 Yucai Road, Guilin city, Guangxi Province, 541004, China
| | - Yanling Yao
- State Key Laboratory for Chemistry and Molecular Engineering of Medical Resources, Guangxi Normal University, 15 Yucai Road, Guilin city, Guangxi Province, 541004, China
| | - Yaping Li
- State Key Laboratory for Chemistry and Molecular Engineering of Medical Resources, Guangxi Normal University, 15 Yucai Road, Guilin city, Guangxi Province, 541004, China
| | - Hua Yang
- State Key Laboratory for Chemistry and Molecular Engineering of Medical Resources, Guangxi Normal University, 15 Yucai Road, Guilin city, Guangxi Province, 541004, China
| | - Huchen Liu
- State Key Laboratory for Chemistry and Molecular Engineering of Medical Resources, Guangxi Normal University, 15 Yucai Road, Guilin city, Guangxi Province, 541004, China
| | - Heng Liu
- Department of Cell Biology and Genetics, Guangxi Medical University, 22 Shuangyong Road, Nanning city, Guangxi Province, 530021, China
| | - Dongming Li
- Department of Cell Biology and Genetics, Guangxi Medical University, 22 Shuangyong Road, Nanning city, Guangxi Province, 530021, China
| | - Wei Shu
- Department of Cell Biology and Genetics, Guangxi Medical University, 22 Shuangyong Road, Nanning city, Guangxi Province, 530021, China
| | - Ming Chen
- State Key Laboratory for Chemistry and Molecular Engineering of Medical Resources, Guangxi Normal University, 15 Yucai Road, Guilin city, Guangxi Province, 541004, China
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Accuracy of proton magnetic resonance for diagnosing non-alcoholic steatohepatitis: a meta-analysis. Sci Rep 2019; 9:15002. [PMID: 31628409 PMCID: PMC6802098 DOI: 10.1038/s41598-019-51302-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 09/28/2019] [Indexed: 12/19/2022] Open
Abstract
Liver biopsy is the reference standard test to differentiate between non-alcoholic steatohepatitis (NASH) and simple steatosis (SS) in non-alcoholic fatty liver disease (NAFLD), but noninvasive diagnostics are warranted. The diagnostic accuracy in NASH using MR imaging modality have not yet been clearly identified. This study was assessed the accuracy of magnetic resonance imaging (MRI) method for diagnosing NASH. Data were extracted from research articles obtained after a literature search from multiple electronic databases. Random-effects meta-analyses were performed to obtain overall effect size of the area under the receiver operating characteristic(ROC) curve, sensitivity, specificity, likelihood ratios(LR), diagnostic odds ratio(DOR) of MRI method in detecting histopathologically-proven SS(or non-NASH) and NASH. Seven studies were analyzed 485 patients, which included 207 SS and 278 NASH. The pooled sensitivity was 87.4% (95% CI, 76.4–95.3) and specificity was 74.3% (95% CI, 62.4–84.6). Pooled positive LR was 2.59 (95% CI, 1.96–3.42) and negative LR was 0.17 (95% CI, 0.07–0.38). DOR was 21.57 (95% CI, 7.27–63.99). The area under the curve of summary ROC was 0.89. Our meta-analysis shows that the MRI-based diagnostic methods are valuable additions in detecting NASH.
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Overview of the Pathogenesis, Genetic, and Non-Invasive Clinical, Biochemical, and Scoring Methods in the Assessment of NAFLD. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16193570. [PMID: 31554274 PMCID: PMC6801903 DOI: 10.3390/ijerph16193570] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/16/2019] [Accepted: 09/20/2019] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. It represents a range of disorders, including simple steatosis, nonalcoholic steatohepatitis (NASH), and liver cirrhosis, and its prevalence continues to rise. In some cases, hepatocellular carcinoma (HCC) may develop. The develop;ment of non-invasive diagnostic and screening tools is needed, in order to reduce the frequency of liver biopsies. The most promising methods are those able to exclude advanced fibrosis and quantify steatosis. In this study, new perspective markers for inflammation, oxidative stress, apoptosis, and fibrogenesis; emerging scoring models for detecting hepatic steatosis and fibrosis; and new genetic, epigenetic, and multiomic studies are discussed. As isolated biochemical parameters are not specific or sensitive enough to predict the presence of NASH and fibrosis, there is a tendency to use various markers and combine them into mathematical algorithms. Several predictive models and scoring systems have been developed. Current data suggests that panels of markers (NAFLD fibrosis score, Fib-4 score, BARD score, and others) are useful diagnostic modalities to minimize the number of liver biopsies. The review unveils pathophysiological aspects related to new trends in current non-invasive biochemical, genetic, and scoring methods, and provides insight into their diagnostic accuracies and suitability in clinical practice.
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is an increasingly dominant cause of liver disease worldwide. The progressive subtype, nonalcoholic steatohepatitis, is a leading indication for liver transplantation and a noteworthy cause of hepatocellular carcinoma. The overall prevalence of NAFLD is on the rise, and even more concerning data modeling predicts that an increasing percentage of those with NAFLD will develop advanced disease. This increased volume of patients with advanced liver disease will impose a significant health care burden in terms of resources and cost. Thus, the identification of patients with established fibrosis or at high risk of developing advanced liver disease is critical to effectively intervene and prevent overall and liver-related morbidity and mortality. Herein, we provide a framework to consider for the identification of patients with NAFLD at high risk of nonalcoholic steatohepatitis with advanced fibrosis and provide a critical assessment of currently accessible diagnostic and treatment modalities.
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Niu L, Geyer PE, Wewer Albrechtsen NJ, Gluud LL, Santos A, Doll S, Treit PV, Holst JJ, Knop FK, Vilsbøll T, Junker A, Sachs S, Stemmer K, Müller TD, Tschöp MH, Hofmann SM, Mann M. Plasma proteome profiling discovers novel proteins associated with non-alcoholic fatty liver disease. Mol Syst Biol 2019; 15:e8793. [PMID: 30824564 PMCID: PMC6396370 DOI: 10.15252/msb.20188793] [Citation(s) in RCA: 189] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/27/2019] [Accepted: 01/28/2019] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects 25% of the population and can progress to cirrhosis with limited treatment options. As the liver secretes most of the blood plasma proteins, liver disease may affect the plasma proteome. Plasma proteome profiling of 48 patients with and without cirrhosis or NAFLD revealed six statistically significantly changing proteins (ALDOB, APOM, LGALS3BP, PIGR, VTN, and AFM), two of which are already linked to liver disease. Polymeric immunoglobulin receptor (PIGR) was significantly elevated in both cohorts by 170% in NAFLD and 298% in cirrhosis and was further validated in mouse models. Furthermore, a global correlation map of clinical and proteomic data strongly associated DPP4, ANPEP, TGFBI, PIGR, and APOE with NAFLD and cirrhosis. The prominent diabetic drug target DPP4 is an aminopeptidase like ANPEP, ENPEP, and LAP3, all of which are up-regulated in the human or mouse data. Furthermore, ANPEP and TGFBI have potential roles in extracellular matrix remodeling in fibrosis. Thus, plasma proteome profiling can identify potential biomarkers and drug targets in liver disease.
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Affiliation(s)
- Lili Niu
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Philipp E Geyer
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Nicolai J Wewer Albrechtsen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Lise L Gluud
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - Alberto Santos
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sophia Doll
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Peter V Treit
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Tina Vilsbøll
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Anders Junker
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Stephan Sachs
- Helmholtz Diabetes Center at Helmholtz Centre Munich & Division of Metabolic Diseases, Institute for Diabetes and Obesity, Technische Universität München, Munich, Germany
| | - Kerstin Stemmer
- Helmholtz Diabetes Center at Helmholtz Centre Munich & Division of Metabolic Diseases, Institute for Diabetes and Obesity, Technische Universität München, Munich, Germany
| | - Timo D Müller
- Helmholtz Diabetes Center at Helmholtz Centre Munich & Division of Metabolic Diseases, Institute for Diabetes and Obesity, Technische Universität München, Munich, Germany
| | - Matthias H Tschöp
- Helmholtz Diabetes Center at Helmholtz Centre Munich & Division of Metabolic Diseases, Institute for Diabetes and Obesity, Technische Universität München, Munich, Germany
| | - Susanna M Hofmann
- Institute for Diabetes and Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Medizinische Klinik und Poliklinik IV, Klinikum der LMU, München, Germany
| | - Matthias Mann
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
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Prevention of hepatic stellate cell activation using JQ1- and atorvastatin-loaded chitosan nanoparticles as a promising approach in therapy of liver fibrosis. Eur J Pharm Biopharm 2019; 134:96-106. [DOI: 10.1016/j.ejpb.2018.11.018] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 10/09/2018] [Accepted: 11/20/2018] [Indexed: 01/14/2023]
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50
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Lee K, Haddad A, Osme A, Kim C, Borzou A, Ilchenko S, Allende D, Dasarathy S, McCullough A, Sadygov RG, Kasumov T. Hepatic Mitochondrial Defects in a Nonalcoholic Fatty Liver Disease Mouse Model Are Associated with Increased Degradation of Oxidative Phosphorylation Subunits. Mol Cell Proteomics 2018; 17:2371-2386. [PMID: 30171159 DOI: 10.1074/mcp.ra118.000961] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 08/21/2018] [Indexed: 12/11/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic mitochondrial dysfunction characterized by reduced ATP synthesis. We applied the 2H2O-metabolic labeling approach to test the hypothesis that the reduced stability of oxidative phosphorylation proteins contributes to mitochondrial dysfunction in a diet-induced mouse model of NAFLD. A high fat diet containing cholesterol (a so-called Western diet (WD)) led to hepatic oxidative stress, steatosis, inflammation and mild fibrosis, all markers of NAFLD, in low density cholesterol (LDL) receptor deficient (LDLR-/-) mice. In addition, compared with controls (LDLR-/- mice on normal diet), livers from NAFLD mice had reduced citrate synthase activity and ATP content, suggesting mitochondrial impairment. Proteome dynamics study revealed that mitochondrial defects are associated with reduced average half-lives of mitochondrial proteins in NAFLD mice (5.41 ± 0.46 versus 5.15 ± 0.49 day, p < 0.05). In particular, the WD reduced stability of oxidative phosphorylation subunits, including cytochrome b-c1 complex subunit 1 (5.9 ± 0.1 versus 3.4 ± 0.8 day), ATP synthase subunit α (6.3 ± 0.4 versus 5.5 ± 0.4 day) and ATP synthase F(0) complex subunit B1 of complex V (8.5 ± 0.6 versus 6.5 ± 0.2 day) (p < 0.05). These changes were associated with impaired complex III and F0F1-ATP synthase activities. Markers of mitophagy were increased, but proteasomal degradation activity were reduced in NAFLD mice liver, suggesting that ATP deficiency because of reduced stability of oxidative phosphorylation complex subunits contributed to inhibition of ubiquitin-proteasome and activation of mitophagy. In conclusion, the 2H2O-metabolic labeling approach shows that increased degradation of hepatic oxidative phosphorylation subunits contributed to mitochondrial impairment in NAFLD mice.
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Affiliation(s)
- Kwangwon Lee
- Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272
| | - Andrew Haddad
- Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272
| | - Abdullah Osme
- Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272
| | - Chunki Kim
- Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272
| | - Ahmad Borzou
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555
| | - Sergei Ilchenko
- Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272
| | - Daniela Allende
- Department of Pathology, Cleveland Clinic Foundation, Cleveland, Ohio 44195
| | | | - Arthur McCullough
- Department of Hepatology, Cleveland Clinic Foundation, Cleveland, Ohio 44195
| | - Rovshan G Sadygov
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555
| | - Takhar Kasumov
- Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272; Department of Hepatology, Cleveland Clinic Foundation, Cleveland, Ohio 44195.
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