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Combined Analysis of Metabolomes, Proteomes, and Transcriptomes of Hepatitis C Virus-Infected Cells and Liver to Identify Pathways Associated With Disease Development.

Authors
  • Lupberger, Joachim1
  • Croonenborghs, Tom2
  • Roca Suarez, Armando Andres3
  • Van Renne, Nicolaas3
  • Jühling, Frank3
  • Oudot, Marine A3
  • Virzì, Alessia3
  • Bandiera, Simonetta3
  • Jamey, Carole4
  • Meszaros, Gergö5
  • Brumaru, Daniel4
  • Mukherji, Atish3
  • Durand, Sarah C3
  • Heydmann, Laura3
  • Verrier, Eloi R3
  • El Saghire, Hussein3
  • Hamdane, Nourdine3
  • Bartenschlager, Ralf6
  • Fereshetian, Shaunt7
  • Ramberger, Evelyn8
  • And 16 more
  • 1 Institut National de la Santé et de la Recherche Médicale, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), Strasbourg, France; Université de Strasbourg, Strasbourg, France. Electronic address: [email protected] , (France)
  • 2 Department of Neurology, Harvard Medical School, Boston, Massachusetts; Cell Circuits Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts.
  • 3 Institut National de la Santé et de la Recherche Médicale, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), Strasbourg, France; Université de Strasbourg, Strasbourg, France. , (France)
  • 4 Université de Strasbourg, Strasbourg, France; Laboratoire de Biochimie et de Biologie Moléculaire, Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. , (France)
  • 5 Université de Strasbourg, Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, Illkirch, France. , (France)
  • 6 Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany; Division of Virus-Associated Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany. , (Germany)
  • 7 The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
  • 8 Proteomics Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Society, Berlin, Germany; Berlin Institute of Health, Berlin, Germany. , (Germany)
  • 9 The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts; Department of Biological Sciences, Columbia University, New York, New York.
  • 10 The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts; Proteomics Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Society, Berlin, Germany; Berlin Institute of Health, Berlin, Germany. , (Germany)
  • 11 Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. , (Japan)
  • 12 Université de Strasbourg, Strasbourg, France; Laboratoire de Biochimie et de Biologie Moléculaire, Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, Illkirch, France. , (France)
  • 13 Massachusetts General Hospital, Boston, Massachusetts.
  • 14 Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
  • 15 Cell Circuits Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Stanford Center for Biomedical Informatics Research, Department of Medicine and Biomedical Data Science, Stanford University, Stanford, California.
  • 16 Department of Neurology, Harvard Medical School, Boston, Massachusetts; Cell Circuits Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: [email protected]
  • 17 Institut National de la Santé et de la Recherche Médicale, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), Strasbourg, France; Université de Strasbourg, Strasbourg, France; Pôle Hépato-digestif, Institut Hopitalo-Universitaire, Strasbourg, France. Electronic address: [email protected] , (France)
Type
Published Article
Journal
Gastroenterology
Publication Date
Aug 01, 2019
Volume
157
Issue
2
Identifiers
DOI: 10.1053/j.gastro.2019.04.003
PMID: 30978357
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The mechanisms of hepatitis C virus (HCV) infection, liver disease progression, and hepatocarcinogenesis are only partially understood. We performed genomic, proteomic, and metabolomic analyses of HCV-infected cells and chimeric mice to learn more about these processes. Huh7.5.1dif (hepatocyte-like cells) were infected with culture-derived HCV and used in RNA sequencing, proteomic, metabolomic, and integrative genomic analyses. uPA/SCID (urokinase-type plasminogen activator/severe combined immunodeficiency) mice were injected with serum from HCV-infected patients; 8 weeks later, liver tissues were collected and analyzed by RNA sequencing and proteomics. Using differential expression, gene set enrichment analyses, and protein interaction mapping, we identified pathways that changed in response to HCV infection. We validated our findings in studies of liver tissues from 216 patients with HCV infection and early-stage cirrhosis and paired biopsy specimens from 99 patients with hepatocellular carcinoma, including 17 patients with histologic features of steatohepatitis. Cirrhotic liver tissues from patients with HCV infection were classified into 2 groups based on relative peroxisome function; outcomes assessed included Child-Pugh class, development of hepatocellular carcinoma, survival, and steatohepatitis. Hepatocellular carcinomas were classified according to steatohepatitis; the outcome was relative peroxisomal function. We quantified 21,950 messenger RNAs (mRNAs) and 8297 proteins in HCV-infected cells. Upon HCV infection of hepatocyte-like cells and chimeric mice, we observed significant changes in levels of mRNAs and proteins involved in metabolism and hepatocarcinogenesis. HCV infection of hepatocyte-like cells significantly increased levels of the mRNAs, but not proteins, that regulate the innate immune response; we believe this was due to the inhibition of translation in these cells. HCV infection of hepatocyte-like cells increased glucose consumption and metabolism and the STAT3 signaling pathway and reduced peroxisome function. Peroxisomes mediate β-oxidation of very long-chain fatty acids; we found intracellular accumulation of very long-chain fatty acids in HCV-infected cells, which is also observed in patients with fatty liver disease. Cells in livers from HCV-infected mice had significant reductions in levels of the mRNAs and proteins associated with peroxisome function, indicating perturbation of peroxisomes. We found that defects in peroxisome function were associated with outcomes and features of HCV-associated cirrhosis, fatty liver disease, and hepatocellular carcinoma in patients. We performed combined transcriptome, proteome, and metabolome analyses of liver tissues from HCV-infected hepatocyte-like cells and HCV-infected mice. We found that HCV infection increases glucose metabolism and the STAT3 signaling pathway and thereby reduces peroxisome function; alterations in the expression levels of peroxisome genes were associated with outcomes of patients with liver diseases. These findings provide insights into liver disease pathogenesis and might be used to identify new therapeutic targets. Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.

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