Hepatitis C virus proteins induce lipogenesis and defective triglyceride secretion in transgenic mice

Hervé Lerat, Hélène L Kammoun, Isabelle Hainault, Emilie Mérour, Martin R Higgs, Céline Callens, Stanley M Lemon, Fabienne Foufelle, Jean-Michel Pawlotsky

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72 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)33466-74
Number of pages9
JournalJournal of Biological Chemistry
Issue number48
Publication statusPublished - 27 Nov 2009


  • Animals
  • Blotting, Western
  • Disease Models, Animal
  • Endoplasmic Reticulum
  • Fatty Liver
  • Hepacivirus
  • Hepatitis C
  • Humans
  • Lipogenesis
  • Liver
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sterol Regulatory Element Binding Protein 1
  • Triglycerides
  • Viral Proteins


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