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.
Highlights
Grant U19-AI40035. □S The on-line version of this article contains supplemental Table S1. 1 Both authors contributed to this work. 2 Supported by the INSERM Young Investigator Program, a grant from the Chronic hepatitis C virus (HCV) infection is associated with altered lipid metabolism, resulting in low serum cholesterol, triglyceride, and betalipoprotein levels [3, 4]
The sterol regulatory element-binding protein 1c (SREBP1c) isoform is predominant in the liver and enhances the transcription of genes involved in fatty acid synthesis
During the unfolded protein response (UPR), SREBP1c is matured by two successive cleavage steps, and its transcription factor domain relocates to the nucleus, where it up-regulates numerous genes involved in lipid synthesis and maturation
Summary
Animals—Animal housing was conducted in accordance with the Direction des Services Veterinaires, Ministere de l’Agriculture of France, with European Communities Council Directive 86/609/EEC and with the Federation of European Laboratory Animal Science Associations for the health monitoring recommendations. Agematched wild type male littermates were used as controls. The animals were housed in a temperature-controlled environment with a 12-h light/dark cycle and had free access to water and a regular diet (D04 from SAFE, Augy, France: 6.1% carbohydrate, 3.1% fat, and 15.8% protein). Assessment of Hepatic Triglyceride and Apolipoprotein Content—Frozen tissue sections were stained with Oil-Red-O dye to identify neutral lipids. As previously described [17], serum triglycerides and apolipoprotein B (apoB) were quantified immediately before and 4 h after intraperitoneal injection of 30 mg of Triton WR 1339 (Tyloxapol; Sigma) in 24 h fasted
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