Hsu C.-S.Liu W.-L.Li Q.Lowey B.Hertz L.Chao Y.-C.Liang T.J.DING-SHINN CHENJIA-HORNG KAO2021-09-042021-09-0420200929-6646https://www.scopus.com/inward/record.uri?eid=2-s2.0-85083015145&doi=10.1016%2fj.jfma.2020.03.018&partnerID=40&md5=29a78bc892da2082cb034b3382bdc307https://scholars.lib.ntu.edu.tw/handle/123456789/581742Background: Patients with different hepatitis C virus (HCV) genotype infections are associated with varying metabolic disorders. Although alteration of lipid metabolism has been confirmed as a virus-induced metabolic derangement in chronic hepatitis C patients, the impact of various HCV genotypes on hepatic cholesterol metabolism remains elusive. In this study, we thus investigated the HCV genotype-specific lipogenic and cholesterol metabolism profiles in an in vitro cell culture system. Methods: We first conducted HCV cell culture system (HCVcc) assays by infecting Huh7.5.1 cells with multiple infection-competent HCV strains, including the genotype 2a JFH1 and JFH1-based intergenotypic recombinants 1b and 3a. We then examined the expression levels of various lipid and cholesterol-related genes. Results: The data showed that infection with individual HCV genotypes exerted unique gene expression regulatory effects on lipoproteins and cholesterol metabolism genes. Of note, all HCV strains suppressed cholesterol biosynthesis in hepatocytes through downregulating the expression of HMG-CoA reductase (HMGCR) and farnesyl-diphosphate farnesyltransferase 1 (FDFT1) – two essential enzymes for cholesterol biosynthesis. These HCV-mediated inhibitory effects could be reversed by treatment with sofosbuvir, a pangenotypic NS5B inhibitor. In addition, overexpression of HCV genotype 1b, 2a or 3a core protein significantly suppressed HMGCR mRNA transcription and translation, thus diminished cellular cholesterol biosynthesis. Nonetheless, the core protein had no effect on FDFT1 expression. Conclusion: Although HCV infection regulates host lipid metabolism in a genotype-specific manner, its inhibition on hepatocellular cholesterogenic gene expression and total cholesterol biosynthesis is a common effect among HCV genotype 1b, 2a and 3a. ? 2020 Formosan Medical AssociationGenotype; Human; Lipid metabolism; Metabolic diseases; Sofosbuvir[SDGs]SDG33 hydroxy 3 methylglutaryl coenzyme A; 3 hydroxy 3 methylglutaryl coenzyme A synthase 1; 3 hydroxy 3 methylglutaryl coenzyme A synthase 2; cholesterol; core protein; farnesyl diphosphate farnesyltransferase 1; hydroxymethylglutaryl coenzyme A reductase; hydroxymethylglutaryl coenzyme A synthase; lipid; lipoprotein; messenger RNA; nonstructural protein 3; sofosbuvir; squalene synthase; sterol regulatory element binding protein 1; sterol regulatory element binding protein 2; unclassified drug; cholesterol; HMGCR protein, human; hydroxymethylglutaryl coenzyme A reductase; squalene synthase; Article; cholesterol blood level; cholesterol liver level; cholesterol metabolism; cholesterol synthesis; controlled study; down regulation; gene expression level; gene expression profiling; gene expression regulation; gene overexpression; hepatitis C; Hepatitis C virus subtype 1b; Hepatitis C virus subtype 2a; Hepatitis C virus subtype 3a; Huh-7.5.1 cell line; human; human cell; in vitro study; lipogenesis; liver cell; metabolic disorder; metabolic regulation; mixed infection; mRNA expression level; nonhuman; regulatory mechanism; RNA transcription; RNA translation; signal transduction; virus recombinant; virus strain; biosynthesis; cell line; chronic hepatitis C; genetics; genotype; Hepacivirus; lipid metabolism; liver cell; metabolism; virology; Cell Line; Cholesterol; Farnesyl-Diphosphate Farnesyltransferase; Gene Expression Regulation; Genotype; Hepacivirus; Hepatitis C, Chronic; Hepatocytes; Humans; Hydroxymethylglutaryl CoA Reductases; Lipid Metabolismjournal article10.1016/j.jfma.2020.03.018322841642-s2.0-85083015145