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Quinn C, Rico MC, Merali C, Barrero CA, Perez-Leal O, Mischley V, Karanicolas J, Friedman SL, Merali S. Secreted folate receptor γ drives fibrogenesis in metabolic dysfunction-associated steatohepatitis by amplifying TGFβ signaling in hepatic stellate cells. Sci Transl Med 2023; 15:eade2966. [PMID: 37756380 PMCID: PMC11816833 DOI: 10.1126/scitranslmed.ade2966] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 08/16/2023] [Indexed: 09/29/2023]
Abstract
Hepatic fibrosis is the primary determinant of mortality in patients with metabolic dysfunction-associated steatohepatitis (MASH). Transforming growth factor-β (TGFβ), a master profibrogenic cytokine, is a promising therapeutic target that has not yet been translated into an effective therapy in part because of liabilities associated with systemic TGFβ antagonism. We have identified that soluble folate receptor γ (FOLR3), which is expressed in humans but not in rodents, is a secreted protein that is elevated in the livers of patients with MASH but not in those with metabolic dysfunction-associated steatotic liver disease, those with type II diabetes, or healthy individuals. Global proteomics showed that FOLR3 was the most highly significant MASH-specific protein and was positively correlated with increasing fibrosis stage, consistent with stimulation of activated hepatic stellate cells (HSCs), which are the key fibrogenic cells in the liver. Exposure of HSCs to exogenous FOLR3 led to elevated extracellular matrix (ECM) protein production, an effect synergistically potentiated by TGFβ1. We found that FOLR3 interacts with the serine protease HTRA1, a known regulator of TGFBR, and activates TGFβ signaling. Administration of human FOLR3 to mice induced severe bridging fibrosis and an ECM pattern resembling human MASH. Our study thus uncovers a role of FOLR3 in enhancing fibrosis.
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Affiliation(s)
- Connor Quinn
- Temple University School of Pharmacy, Philadelphia, PA 19140 USA
| | - Mario C. Rico
- Temple University School of Pharmacy, Philadelphia, PA 19140 USA
| | - Carmen Merali
- Temple University School of Pharmacy, Philadelphia, PA 19140 USA
| | | | - Oscar Perez-Leal
- Temple University School of Pharmacy, Philadelphia, PA 19140 USA
| | - Victoria Mischley
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- Drexel University College of Medicine, Philadelphia, PA 19102, USA
| | - John Karanicolas
- Temple University School of Pharmacy, Philadelphia, PA 19140 USA
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Scott L. Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Salim Merali
- Temple University School of Pharmacy, Philadelphia, PA 19140 USA
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Nascè A, Gariani K, Jornayvaz FR, Szanto I. NADPH Oxidases Connecting Fatty Liver Disease, Insulin Resistance and Type 2 Diabetes: Current Knowledge and Therapeutic Outlook. Antioxidants (Basel) 2022; 11:antiox11061131. [PMID: 35740032 PMCID: PMC9219746 DOI: 10.3390/antiox11061131] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/30/2022] [Accepted: 06/03/2022] [Indexed: 12/15/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), characterized by ectopic fat accumulation in hepatocytes, is closely linked to insulin resistance and is the most frequent complication of type 2 diabetes mellitus (T2DM). One of the features connecting NAFLD, insulin resistance and T2DM is cellular oxidative stress. Oxidative stress refers to a redox imbalance due to an inequity between the capacity of production and the elimination of reactive oxygen species (ROS). One of the major cellular ROS sources is NADPH oxidase enzymes (NOX-es). In physiological conditions, NOX-es produce ROS purposefully in a timely and spatially regulated manner and are crucial regulators of various cellular events linked to metabolism, receptor signal transmission, proliferation and apoptosis. In contrast, dysregulated NOX-derived ROS production is related to the onset of diverse pathologies. This review provides a synopsis of current knowledge concerning NOX enzymes as connective elements between NAFLD, insulin resistance and T2DM and weighs their potential relevance as pharmacological targets to alleviate fatty liver disease.
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Affiliation(s)
- Alberto Nascè
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
| | - Karim Gariani
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
| | - François R. Jornayvaz
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Correspondence: (F.R.J.); (I.S.)
| | - Ildiko Szanto
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
- Correspondence: (F.R.J.); (I.S.)
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Riccio S, Melone R, Vitulano C, Guida P, Maddaluno I, Guarino S, Marzuillo P, Miraglia del Giudice E, Di Sessa A. Advances in pediatric non-alcoholic fatty liver disease: From genetics to lipidomics. World J Clin Pediatr 2022; 11:221-238. [PMID: 35663007 PMCID: PMC9134151 DOI: 10.5409/wjcp.v11.i3.221] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/05/2021] [Accepted: 04/02/2022] [Indexed: 02/06/2023] Open
Abstract
As a result of the obesity epidemic, non-alcoholic fatty liver disease (NAFLD) represents a global medical concern in childhood with a closely related increased cardiometabolic risk. Knowledge on NAFLD pathophysiology has been largely expanded over the last decades. Besides the well-known key NAFLD genes (including the I148M variant of the PNPLA3 gene, the E167K allele of the TM6SF2, the GCKR gene, the MBOAT7-TMC4 rs641738 variant, and the rs72613567:TA variant in the HSD17B13 gene), an intriguing pathogenic role has also been demonstrated for the gut microbiota. More interestingly, evidence has added new factors involved in the "multiple hits" theory. In particular, omics determinants have been highlighted as potential innovative markers for NAFLD diagnosis and treatment. In fact, different branches of omics including metabolomics, lipidomics (in particular sphingolipids and ceramides), transcriptomics (including micro RNAs), epigenomics (such as DNA methylation), proteomics, and glycomics represent the most attractive pathogenic elements in NAFLD development, by providing insightful perspectives in this field. In this perspective, we aimed to provide a comprehensive overview of NAFLD pathophysiology in children, from the oldest pathogenic elements (including genetics) to the newest intriguing perspectives (such as omics branches).
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Affiliation(s)
- Simona Riccio
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Rosa Melone
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Caterina Vitulano
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Pierfrancesco Guida
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Ivan Maddaluno
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Stefano Guarino
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Pierluigi Marzuillo
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Emanuele Miraglia del Giudice
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Anna Di Sessa
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
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Castillo-Castro C, Martagón-Rosado AJ, Ortiz-Lopez R, Garrido-Treviño LF, Villegas-Albo M, Bosques-Padilla FJ. Promising diagnostic biomarkers of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: From clinical proteomics to microbiome. World J Hepatol 2021; 13:1494-1511. [PMID: 34904026 PMCID: PMC8637675 DOI: 10.4254/wjh.v13.i11.1494] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/06/2021] [Accepted: 10/14/2021] [Indexed: 02/06/2023] Open
Abstract
Fatty liver has been present in the lives of patients and physicians for almost two centuries. Vast knowledge has been generated regarding its etiology and consequences, although a long path seeking novel and innovative diagnostic biomarkers for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is still envisioned. On the one hand, proteomics and lipidomics have emerged as potential noninvasive resources for NAFLD diagnosis. In contrast, metabolomics has been able to distinguish between NAFLD and NASH, even detecting degrees of fibrosis. On the other hand, genetic and epigenetic markers have been useful in monitoring disease progression, eventually functioning as target therapies. Other markers involved in immune dysregulation, oxidative stress, and inflammation are involved in the instauration and evolution of the disease. Finally, the fascinating gut microbiome is significantly involved in NAFLD and NASH. This review presents state-of-the-art biomarkers related to NAFLD and NASH and new promises that could eventually be positioned as diagnostic resources for this disease. As is evident, despite great advances in studying these biomarkers, there is still a long path before they translate into clinical benefits.
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Affiliation(s)
| | - Alexandro José Martagón-Rosado
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Mexico
- Unidad de Investigación de Enfermedades Metabólicas, Instituto Nacional de Ciencias Médicas y Nutrición, Ciudad de México 14080, Mexico
| | - Rocio Ortiz-Lopez
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Mexico
| | | | - Melissa Villegas-Albo
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Mexico
| | - Francisco Javier Bosques-Padilla
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey 64710, Mexico
- Centro Regional para el Estudio de las Enfermedades Digestivas, Servicio de Gastroenterología, Facultad de Medicina y Hospital Universitario Dr. José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey 64460, Mexico
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Sundararaman N, Go J, Robinson AE, Mato JM, Lu SC, Van Eyk JE, Venkatraman V. PINE: An Automation Tool to Extract and Visualize Protein-Centric Functional Networks. JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY 2020; 31:1410-1421. [PMID: 32463229 PMCID: PMC10362945 DOI: 10.1021/jasms.0c00032] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Recent surges in mass spectrometry-based proteomics studies demand a concurrent rise in speedy and optimized data processing tools and pipelines. Although several stand-alone bioinformatics tools exist that provide protein-protein interaction (PPI) data, we developed Protein Interaction Network Extractor (PINE) as a fully automated, user-friendly, graphical user interface application for visualization and exploration of global proteome and post-translational modification (PTM) based networks. PINE also supports overlaying differential expression, statistical significance thresholds, and PTM sites on functionally enriched visualization networks to gain insights into proteome-wide regulatory mechanisms and PTM-mediated networks. To illustrate the relevance of the tool, we explore the total proteome and its PTM-associated relationships in two different nonalcoholic steatohepatitis (NASH) mouse models to demonstrate different context-specific case studies. The strength of this tool relies in its ability to (1) perform accurate protein identifier mapping to resolve ambiguity, (2) retrieve interaction data from multiple publicly available PPI databases, and (3) assimilate these complex networks into functionally enriched pathways, ontology categories, and terms. Ultimately, PINE can be used as an extremely powerful tool for novel hypothesis generation to understand underlying disease mechanisms.
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Affiliation(s)
- Niveda Sundararaman
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
| | - James Go
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
| | - Aaron E Robinson
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
| | - José M Mato
- CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain
| | - Shelly C Lu
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California 90048, United States
| | - Jennifer E Van Eyk
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
| | - Vidya Venkatraman
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
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Carulli L, Zanca G, Schepis F, Villa E. The OMICs Window into Nonalcoholic Fatty Liver Disease (NAFLD). Metabolites 2019; 9:25. [PMID: 30717274 PMCID: PMC6409793 DOI: 10.3390/metabo9020025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 01/26/2019] [Accepted: 01/30/2019] [Indexed: 12/17/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common cause of hepatic abnormalities worldwide. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD and leads to progressive liver disease, such as cirrhosis and hepatocellular carcinoma. In NASH patient, fibrosis represents the major predictor of liver-related mortality; therefore, it is important to have an early and accurate diagnosis of NASH. The current gold standard for the diagnosis of NASH is still liver biopsy. The development of biomarkers able to predict disease severity, prognosis, as well as response to therapy without the need for a biopsy is the focus of most up-to-date genomic, transcriptomic, proteomic, and metabolomic research. In the future, patients might be diagnosed and treated according to their molecular signatures. In this short review, we discuss how information from genomics, proteomics, and metabolomics contribute to the understanding of NAFLD pathogenesis.
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Affiliation(s)
- Lucia Carulli
- Division of Gastroenterology, Department of Medical Specialties, University of Modena and Reggio Emilia, 41124 Modena, Italy.
| | - Giulia Zanca
- Division of Gastroenterology, Department of Medical Specialties, University of Modena and Reggio Emilia, 41124 Modena, Italy.
| | - Filippo Schepis
- Division of Gastroenterology, Department of Medical Specialties, University of Modena and Reggio Emilia, 41124 Modena, Italy.
| | - Erica Villa
- Division of Gastroenterology, Department of Medical Specialties, University of Modena and Reggio Emilia, 41124 Modena, Italy.
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7
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Wang K, Chen Z, Long L, Tao Y, Wu Q, Xiang M, Liang Y, Xie X, Jiang Y, Xiao Z, Yan Y, Qiu S, Yi B. iTRAQ-based quantitative proteomic analysis of differentially expressed proteins in chemoresistant nasopharyngeal carcinoma. Cancer Biol Ther 2018; 19:809-824. [PMID: 30067426 DOI: 10.1080/15384047.2018.1472192] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a highly prevalent disease in Southeast Asia. The disease is typically diagnosed in the later stages, and chemotherapy resistance often causes treatment failure. To investigate the underlying mechanisms of drug resistance, we searched for chemoresistant-associated proteins in NPC and drug-resistant NPC cell lines using isobaric tags for relative and absolute quantitation combined with nano liquid chromatography-tandem mass spectrometry. The chemoresistant NPC cell lines CNE1DDP and CNE2DDP were resistant to 1 mg/L cisplatin, had resistant indexes of 4.58 and 2.63, respectively, and clearly grew more slowly than the NPC cell lines CNE1 and CNE2. Using three technical replicates, we identified 690 nonredundant proteins, 56 of which were differentially expressed in both groups of cell lines (CNE1 vs. CNE1DDP and CNE2 vs. CNE2DDP). Gene Ontology, KEGG pathway, and miRNA analyses and protein-protein interactions of differentially expressed proteins showed that proteins TRIM29, HSPB1, CLIC1, ANXA1, and STMN1, among others, may play a role in the mechanisms of chemoresistance in clinical therapy. The chemotherapy-resistant proteomic profiles obtained may allow the identification of novel biomarkers for early detection of chemoresistance in NPC and other cancers.
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Affiliation(s)
- Kun Wang
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Zhen Chen
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Lu Long
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Ya Tao
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Qiong Wu
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Manlin Xiang
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Yunlai Liang
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Xulin Xie
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Yuan Jiang
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China.,b Department of Clinical Laboratory , Hunan Cancer Hospital , Changsha , Hunan Province , China
| | - Zhiqiang Xiao
- c The Higher Educational Key Laboratory for Cancer Proteomics and Translational Medicine of Hunan Province , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Yahui Yan
- d Department of pathology , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Shiyang Qiu
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
| | - Bin Yi
- a Department of Clinical Laboratory , Xiangya Hospital, Central South University , Changsha , Hunan Province , China
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Pirola CJ, Sookoian S. Multiomics biomarkers for the prediction of nonalcoholic fatty liver disease severity. World J Gastroenterol 2018; 24:1601-1615. [PMID: 29686467 PMCID: PMC5910543 DOI: 10.3748/wjg.v24.i15.1601] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 03/13/2018] [Accepted: 03/30/2018] [Indexed: 02/06/2023] Open
Abstract
This review intends to uncover how information from large-scale genetic profiling (whole genome sequencing, and whole exome sequencing) of nonalcoholic fatty liver disease (NAFLD), as well as information from circulating transcriptomics (cell-free miRNAs) and metabolomics, contributes to the understanding of NAFLD pathogenesis. A further aim is to address the question of whether OMICs information is ready to be implemented in the clinics. The available evidence suggests that any new knowledge pertaining to molecular signatures associated with NAFLD and nonalcoholic steatohepatitis should be promptly translated into the clinical setting. Nevertheless, rigorous steps that must include validation and replication are mandatory before utilizing OMICs biomarkers in diagnostics to identify patients at risk of advanced disease, including liver cancer.
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Affiliation(s)
- Carlos J Pirola
- Department of Genetics and Molecular Biology of Complex Diseases. University of Buenos Aires, Institute of Medical Research A Lanari, Buenos Aires, Argentina, National Scientific and Technical Research Council-University of Buenos Aires. Institute of Medical Research (IDIM), CABA 1427, Argentina
| | - Silvia Sookoian
- Clinical and Molecular Hepatology, University of Buenos Aires, Institute of Medical Research A Lanari, Buenos Aires, Argentina, National Scientific and Technical Research Council-University of Buenos Aires. Institute of Medical Research (IDIM), CABA 1427, Argentina
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9
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Wattacheril J, Rose KL, Hill S, Lanciault C, Murray CR, Washington K, Williams B, English W, Spann M, Clements R, Abumrad N, Flynn CR. Non-alcoholic fatty liver disease phosphoproteomics: A functional piece of the precision puzzle. Hepatol Res 2017; 47:1469-1483. [PMID: 28258704 PMCID: PMC5583035 DOI: 10.1111/hepr.12885] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 01/27/2017] [Accepted: 02/28/2017] [Indexed: 12/24/2022]
Abstract
BACKGROUND Molecular signaling events associated with the necroinflammatory changes in nonalcoholic steatohepatitis (NASH) are not well understood. AIMS To understand the molecular basis of NASH, we evaluated reversible phosphorylation events in hepatic tissue derived from Class III obese subjects by phosphoproteomic means with the aim of highlighting key regulatory pathways that distinguish NASH from non-alcoholic fatty liver disease (also known as simple steatosis; SS). MATERIALS & METHODS Class III obese subjects undergoing bariatric surgery underwent liver biopsy (eight normal patients, eight with simple steatosis, and eight NASH patients). Our strategy was unbiased, comparing global differences in liver protein reversible phosphorylation events across the 24 subjects. RESULTS Of the 3078 phosphorylation sites assigned (2465 phosphoserine, 445 phosphothreonine, 165 phosphotyrosine), 53 were altered by a factor of 2 among cohorts, and of those, 12 were significantly increased or decreased by ANOVA (P < 0.05). DISCUSSION Statistical analyses of canonical signaling pathways identified carbohydrate metabolism and RNA post-transcriptional modification among the most over-represented networks. CONCLUSION Collectively, these results raise the possibility of abnormalities in carbohydrate metabolism as an important trigger for the development of NASH, in parallel with already established abnormalities in lipid metabolism.
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Affiliation(s)
- Julia Wattacheril
- Center for Liver Disease and Transplantation, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, United States of America
| | - Kristie L. Rose
- Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Salisha Hill
- Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Christian Lanciault
- Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Clark R. Murray
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Brandon Williams
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Wayne English
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Matthew Spann
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Ronald Clements
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Naji Abumrad
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Charles Robb Flynn
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America,Corresponding author: Charles Flynn, PhD, Assistant Professor, Department of Surgery, Vanderbilt University, MRBIV Room 8465A, 2213 Garland Ave, Nashville, TN 37232,
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Characterizing Blood Metabolomics Profiles Associated with Self-Reported Food Intakes in Female Twins. PLoS One 2016; 11:e0158568. [PMID: 27355821 PMCID: PMC4927065 DOI: 10.1371/journal.pone.0158568] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 06/19/2016] [Indexed: 12/15/2022] Open
Abstract
Using dietary biomarkers in nutritional epidemiological studies may better capture exposure and improve the level at which diet-disease associations can be established and explored. Here, we aimed to identify and evaluate reproducibility of novel biomarkers of reported habitual food intake using targeted and non-targeted metabolomic blood profiling in a large twin cohort. Reported intakes of 71 food groups, determined by FFQ, were assessed against 601 fasting blood metabolites in over 3500 adult female twins from the TwinsUK cohort. For each metabolite, linear regression analysis was undertaken in the discovery group (excluding MZ twin pairs discordant [≥1 SD apart] for food group intake) with each food group as a predictor adjusting for age, batch effects, BMI, family relatedness and multiple testing (1.17x10-6 = 0.05/[71 food groups x 601 detected metabolites]). Significant results were then replicated (non-targeted: P<0.05; targeted: same direction) in the MZ discordant twin group and results from both analyses meta-analyzed. We identified and replicated 180 significant associations with 39 food groups (P<1.17x10-6), overall consisting of 106 different metabolites (74 known and 32 unknown), including 73 novel associations. In particular we identified trans-4-hydroxyproline as a potential marker of red meat intake (0.075[0.009]; P = 1.08x10-17), ergothioneine as a marker of mushroom consumption (0.181[0.019]; P = 5.93x10-22), and three potential markers of fruit consumption (top association: apple and pears): including metabolites derived from gut bacterial transformation of phenolic compounds, 3-phenylpropionate (0.024[0.004]; P = 1.24x10-8) and indolepropionate (0.026[0.004]; P = 2.39x10-9), and threitol (0.033[0.003]; P = 1.69x10-21). With the largest nutritional metabolomics dataset to date, we have identified 73 novel candidate biomarkers of food intake for potential use in nutritional epidemiological studies. We compiled our findings into the DietMetab database (http://www.twinsuk.ac.uk/dietmetab-data/), an online tool to investigate our top associations.
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11
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Nuño-Lámbarri N, Barbero-Becerra VJ, Uribe M, Chávez-Tapia NC. Mitochondrial Molecular Pathophysiology of Nonalcoholic Fatty Liver Disease: A Proteomics Approach. Int J Mol Sci 2016; 17:281. [PMID: 26999105 PMCID: PMC4813145 DOI: 10.3390/ijms17030281] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 02/19/2016] [Accepted: 02/19/2016] [Indexed: 12/14/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition that can progress to nonalcoholic steatohepatitis, cirrhosis and cancer. It is considered an emerging health problem due to malnourishment or a high-fat diet (HFD) intake, which is observed worldwide. It is well known that the hepatocytes’ apoptosis phenomenon is one of the most important features of NAFLD. Thus, this review focuses on revealing, through a proteomics approach, the complex network of protein interactions that promote fibrosis, liver cell stress, and apoptosis. According to different types of in vitro and murine models, it has been found that oxidative/nitrative protein stress leads to mitochondrial dysfunction, which plays a major role in stimulating NAFLD damage. Human studies have revealed the importance of novel biomarkers, such as retinol-binding protein 4, lumican, transgelin 2 and hemoglobin, which have a significant role in the disease. The post-genome era has brought proteomics technology, which allows the determination of molecular pathogenesis in NAFLD. This has led to the search for biomarkers which improve early diagnosis and optimal treatment and which may effectively prevent fatal consequences such as cirrhosis or cancer.
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Affiliation(s)
- Natalia Nuño-Lámbarri
- Traslational Research Unit, Médica Sur Clinic & Foundation, Mexico City 14050, Mexico.
| | | | - Misael Uribe
- Obesity and Digestive Diseases Unit, Médica Sur Clinic & Foundation, Mexico City 14050, Mexico.
| | - Norberto C Chávez-Tapia
- Traslational Research Unit, Médica Sur Clinic & Foundation, Mexico City 14050, Mexico.
- Obesity and Digestive Diseases Unit, Médica Sur Clinic & Foundation, Mexico City 14050, Mexico.
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Xu L, Wei Y, Dong D, Yin L, Qi Y, Han X, Xu Y, Zhao Y, Liu K, Peng J. iTRAQ-based proteomics for studying the effects of dioscin against nonalcoholic fatty liver disease in rats. RSC Adv 2014; 4:30704. [DOI: 10.1039/c4ra03948c] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2025] Open
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