Changes in the expression of cholesterol metabolism-associated genes in HCV-infected liver: A novel target for therapy?

Abstract

Abstract. Recent investigations indicate that hepatitis C virus (HCV) infection is closely associated with hepatocytic lipid metabolism and induces hepatic steatosis. However, the actual lipid metabolism in HCV-infected liver has not been extensively investigated in humans. In this study, we evaluated the expression of lipid metabolism-associated genes in patients with HCV infection by real-time PCR. Sterol regulatory element-binding protein (SREBP)-2 expression was unchanged and low density lipoprotein receptor expression was markedly reduced by 90% in HCV-infected liver. The expression of apolipoprotein B100, microsomal triglyceride transfer ptotein and ATP-binding cassette G5 was significantly increased. Up-regulation of cholesterol synthesis-associated genes, including HMG-CoA reductase, HMG-CoA synthase, farnesyldiphosphate synthase and squalene synthase, confirmed enhanced de novo cholesterol synthesis. The expression of cholesterol 7·-hydroxylase and farnesoid X receptor was enhanced, while bile salt export pump expression was unchanged. Fatty acid synthase expression was increased which was accompanied by increased expression of liver X receptor · and SREBP-1c. In summary, the regulation of lipid metabolism was impaired and cholesterol and fatty acid synthesis continued to increase without negative feedback in HCV-infected liver. These changes may be beneficial for HCV replication. IntroductionA close association between hepatitis C virus (HCV) infection and lipid metabolism was previously reported. For example, the low density lipoprotein receptor (LDLR) is a target for HCV entry into hepatocytes (1,2), therefore, ß-lipoproteins influence HCV proliferation. Serum HCV-Ag levels are negatively correlated with serum ß-lipoproteins (3) and LDLcholesterol levels are correlated with the outcome of HCV treatment with interferon (IFN) (4,5). HCV core protein induces hepatic lipid accumulation by activating sterol regulatory element-binding protein (SREBP)-1c (6,7). In addition, liver microsomal triglyceride transfer protein (MTP), a key enzyme for the assembly of very low density lipoprotein (VLDL), may be involved in HCV-related steatosis, and hepatic MTP expression and steatosis showed significant negative correlation in patients with chronic hepatitis C (8-11). Approximately 50% of patients with chronic hepatitis C have hepatic steatosis which enhances disease progression (12-14). Host metabolic factors as well as viral factors should be involved in the pathogenesis of hepatic steatosis. However, the actual lipid metabolism in HCV-infected liver has not been extensively INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 24: 825-828, 2009 825 Changes in the expression of cholesterol metabolism-associated genes in HCV-infected liver:A novel target for therapy?