About 2-3% of the world population is infected with hepatitis C virus (HCV). Majority of HCV infections lead to chronic hepatitis. Hepatic steatosis (fatty liver) is recognized as a common histologic feature of chronic hepatitis C and occurs at an average rate of 50%. At molecular level, we and others have observed that HCV gene expression leads to alteration of cellular lipid metabolism. These changes manifest in elevated expression of genes involved in cholesterol/fatty acid biosynthetic pathways. In the current application, we propose investigate the role of HCV-induced oxidative stress in the activation of transcription factors, which include sterol regulatory element binding proteins (SREBP), liver X receptor, (LXR), PPAR1 and PCG-12. Attempts will be made to identify individual HCV gene product(s) playing a key role in steatosis. We further propose to investigate the mechanisms by which HCV gene expression impairs the lipidation of apolipoprotein B-100 (apoB). ApoB represents the major structural component of VLDL. Our recent studies identified the possible ternary complex composed of HCV NS5a protein, apoB and microsomal triglyceride transfer protein (MTP). Whether these protein-protein interactions lead to intervention of apoB lipidation will be investigated. Other possible mechanisms leading to the block in the secretion of apoB will be investigated. The results of these studies will provide unique insight into the ability of HCV gene expression in affecting lipid homeostasis and likely guide the design of future antiviral strategies in the treatment of liver disease associated with HCV infection. ? ? ?
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