title: Hepatitis C virus proteins induce lipogenesis and defective triglyceride secretion in transgenic mice.
abstract: Chronic hepatitis C virus (HCV) infection is associated with altered lipid metabolism and hepatocellular steatosis. Virus-induced steatosis is a cytopathic effect of HCV replication. The goal of this study was to examine the mechanisms underlying HCV-induced lipid metabolic defects in a transgenic mouse model expressing the full HCV protein repertoire at levels corresponding to natural human infection. In this model, expression of the HCV full-length open reading frame was associated with hepatocellular steatosis and reduced plasma triglyceride levels. Triglyceride secretion was impaired, whereas lipogenesis was activated. Increased lipogenic enzyme transcription was observed, resulting from maturational activation and nuclear translocation of sterol regulatory element-binding protein 1c (SREBP1c). However, endoplasmic reticulum (ER) stress markers were expressed at similar levels in both HCV transgenic mice and their wild type counterparts, suggesting that SREBP1c proteolytic cleavage in the presence of HCV proteins was independent of ER stress. In conclusion, transgenic mice expressing the HCV full-length polyprotein at low levels have decreased plasma triglyceride levels and develop hepatocellular steatosis in the same way as HCV-infected patients. In these mice, SREBP1c activation by one or several HCV proteins induces de novo triglyceride synthesis via the lipogenic pathway, in a manner independent of ER stress, whereas triglyceride secretion is simultaneously reduced.
authors.affiliation: INSERM U955, 94010 Créteil, France. herve.lerat@inserm.fr
authors.forename: Hervé
authors.initials: H
authors.lastname: Lerat
authors.forename: Hélène L
authors.initials: HL
authors.lastname: Kammoun
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hainault
authors.forename: Emilie
authors.initials: E
authors.lastname: Mérour
authors.forename: Martin R
authors.initials: MR
authors.lastname: Higgs
authors.forename: Céline
authors.initials: C
authors.lastname: Callens
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Lemon
authors.forename: Fabienne
authors.initials: F
authors.lastname: Foufelle
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pawlotsky
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005234:Fatty Liver / Q000097:blood / Q000209:etiology / Q000378:metabolism; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006526:Hepatitis C / Q000097:blood / Q000150:complications / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis / Q000502:physiology*; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D014764:Viral Proteins