HCV Core Protein affects Lipid Metabolism in a Genotype-Dependent Manner
Chronic HCV infection is the leading cause of steatosis (fatty liver disease) and hepatocellular carcinoma (HCC). The virus establishes a chronic infection in 70% of patients and infects approximately 71 million people worldwide. Genotypes (gt) 1 and 3 are the most prevalent, with gt3 HCV being associated with more severe disease. It is known that core protein plays a role in the development of steatosis, but the precise mechanism is not yet understood. In this study, we investigate the role of genotypes in core-mediated differential regulation of lipid metabolism. Prior studies described the lipid induction by HCV infection or ectopic expression of core derived from gt1a and 3a HCV qualitatively. The goal of this thesis is to define the gt1a and 3a HCV core-mediated lipid regulation in a quantitative manner. Using FACS analysis, and immunofluorescence analysis by using confocal microscope, we found that gt3a core protein induces larger lipid droplet formation, although the quantity of lipids remains similar to that induced by gt1a core protein. We then attempted to determine the difference in fatty liver-associated gene expression levels induced by gt1a and gt3a core proteins. To do this, we utilized microarray to analyze the gene expression in cells transfected with different HCV core proteins. The analysis showed that both gt1a and gt3a core upregulated SOCS3; this upregulation has been shown to influence the liver response to previously used antiviral therapies, as well as the induction of insulin resistance. Additionally, genes that were downregulated by gt1a and gt3a core are largely associated with insulin resistance, which plays a role in the development of diabetes. Interestingly, more genes appear to be downregulated by gt3a than gt1a core protein, which could suggest that gt3a core protein induces insulin resistance and steatosis in a different manner, or to a more severe degree. Overall, these results present a potential mechanism for the relationship between insulin resistance and lipid metabolism deregulation induced by gt1a and gt3a core proteins.