title: Hepatitis C viral proteins perturb metabolic liver zonation.
abstract: OBJECTIVE
  The metabolic identity of a hepatocyte is determined by its position along the porto-centrilobular axis of a liver lobule. Altered patterns of metabolic liver zonation are associated with several pathologies. In hepatitis C, although only a minority of hepatocytes harbour the virus, the liver undergoes major systemic metabolic changes. We have investigated the HCV-driven mechanisms that allow the systemic loss of metabolic zonation.
  
  
  METHODS
  Transgenic mice with hepatocyte-targeted expression of all HCV proteins (FL-N/35 model) and needle biopsies from hepatitis C patients were studied with respect to patterns of lipid deposition in the context of metabolic zonation of the liver lobule.
  
  
  RESULTS
  We report that low levels of viral proteins are sufficient to drive striking alterations of hepatic metabolic zonation. In mice, a major lipogenic enzyme, fatty acid synthase, was redistributed from its normal periportal expression into the midzone of the lobule, coinciding with a highly specific midzone accumulation of lipids. Strikingly, alteration of zonation was not limited to lipogenic enzymes and appeared to be driven by systemic signalling via the Wnt/β-catenin pathway. Importantly, we show that similarly perturbed metabolic zonation appears to precede steatosis in early stages of human disease associated with HCV infection.
  
  
  CONCLUSIONS
  Our results rationalize systemic effects on liver metabolism, triggered by a minority of infected cells, thus opening new perspectives for the investigation of HCV-related pathologies.
authors.affiliation: CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Moreau
authors.affiliation: Département de Biopathologie Cellulaire et Tissulaire des Tumeurs, Hôpital Saint Eloi-Gui de Chauliac, Centre Hospitalier Universitaire, Montpellier, France; Université de Montpellier 1, Montpellier, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rivière
authors.affiliation: CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France.
authors.forename: Serena
authors.initials: S
authors.lastname: Vegna
authors.affiliation: Départment de Biochimie, CHU, Université Montpellier I, France.
authors.forename: Manar
authors.initials: M
authors.lastname: Aoun
authors.affiliation: CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France; University of Manchester, Manchester, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gard
authors.affiliation: Département de Biopathologie Cellulaire et Tissulaire des Tumeurs, Hôpital Saint Eloi-Gui de Chauliac, Centre Hospitalier Universitaire, Montpellier, France; Université de Montpellier 1, Montpellier, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Ramos
authors.affiliation: CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France; Service d'Oncologie Médicale, CHU St Eloi, Montpellier, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Assenat
authors.affiliation: CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France. Electronic address: ula.hibner@igmm.cnrs.fr.
authors.forename: Urszula
authors.initials: U
authors.lastname: Hibner
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D004279:DNA, Viral / Q000235:genetics; D004195:Disease Models, Animal; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D004279:DNA, Viral; D014764:Viral Proteins
keywords: HCV; Lipogenesis; Metabolic liver zonation; Wnt/β-catenin pathway