Comprehensive Exploration of the Hepatitis C Virus-Associated Lipid Metabolism Alterations in the Hosts---A Joint Study Based on the Patients with Chronic Hepatitis C Infection and HCV Core Transgenic Mice

Hepatitis C virus (HCV) is a human pathogen responsible for acute and chronic liver disease, infecting an estimated 130-170 million individuals worldwide. Approximately 600,000 Taiwanese suffer from chronic HCV infection. In addition to cirrhosis and hepatocellular carcinoma, HCV induces several complex mechanisms that lead to steatosis, dyslipidemia, and insulin resistance. Therefore, in addition to merely being a simple viral infection, HCV is now viewed as causing metabolic alterations, particularly with regard to lipid metabolism, a process with which most of the HCV life cycle is closely associated. A number of puzzling clinical observations have emerged concerning HCV-related lipid metabolic alterations. (1) Most large-scale case-control studies have demonstrated that HCV infection leads to lower cholesterol, regardless of the HCV genotype, although the decrease of serum cholesterol concentration was reported to be most evident for genotype 3, intermediate for genotype 1, and not significant for genotype 2. Furthermore, another study noted that, among genotype 2 chronic hepatitis C (CHC) patients, HCV RNA levels proportionally parallel cholesterol levels. Therefore, it is unclear what accounts for the conflicting results for genotype-specific hypolipidemia in CHC patients. (2) Although HCV infection-induced lower serum C3 and C4 levels have been demonstrated both in vitro and in vivo, it is unclear whether the complements play any role in the lipid metabolism alterations observed in CHC patients. Lastly, (3) sustained virological response (SVR) in the CHC patients may lead to the reversal of hypocholesterolemia and decreased risk of de novo insulin resistance. Indeed, an abundance of circulating fatty acids secondary to an excess of cholesterol is now known to be an overt contributor to endothelium damage, whereas de novo insulin resistance is a confounder for cardiovascular disease. A longitudinal cohort study based in Taiwan showed a higher circulatory disease rate in CHC patients than in non-CHC patients; however, it is uncertain whether SVR secondary to anti-HCV therapy actually decreases the risk of cardiovascular events in CHC patients. Moreover, any differences in cardiovascular risk among various genotypes of HCV after SVR should be resolved. Efforts to define the role of various HCV gene products in lipid metabolic alterations have focused on the core protein, which dysregulates lipid and glucose metabolism in vitro. Several groups have generated transgenic mouse lines that constitutively over-expressed the HCV core; however, most humans acquire HCV infection via late-life horizontal transmission, which is different from animal models exposed to the HCV protein since the fetal stage. In our previous work, three conditional transgenic mice lines with low, intermediate, or high core (genotype 1b) expression under the control of the tetracycline transactivator were developed. The HCV core was not expressed until the mice were of weaning age, and their phenotypes varied from simple hepatic steatosis to steatohepatitis. Hypocholesterolemia, hypoadiponectinemia and abnormal liver function were demonstrated in the transgenic mice as they aged. These observations are similar to the pattern of metabolic alteration noted in humans with HCV infection. This proposal is designed to address the puzzling observations regarding HCV-related lipid metabolism alterations by analyzing the metabolic profiles and cardiovascular events of humans with HCV infection before and after anti-HCV therapy. Additionally, the serum HCV core and RNA levels of the patients will be correlated to their lipid metabolic alterations, as are those in HCV core-transgenic mice. In parallel, the basis of HCV core-transgenic mice with various phenotypes will be dissected to probe equivalent human cases. With the aid of genomic, proteomic and metabolomic approaches in both the human and animal studies, the current proposal holds promise to resolve the clinical controversies and may provide therapeutic interventions targeting host factors involved in metabolic alterations to control HCV-related complications.

Project ID:PC10301-0128
External Project ID:NSC102-2628-B182-021-MY3