title: Silent information regulator 1 inhibition induces lipid metabolism disorders of hepatocytes and enhances hepatitis C virus replication.
abstract: OBJECTIVE
  Hepatic steatosis is an important histopathological feature of chronic hepatitis C virus (HCV) infection. Silent information regulator 1 (SIRT1) plays key role in regulation of hepatic lipid metabolism. We investigated the possible effect of HCV replication on lipid metabolism of hepatocytes and expression of SIRT1 using Huh-7.5 cells harboring HCV replicon.
  
  
  METHODS
  The level of reactive oxygen species (ROS) and malondialdehyde (MDA), the activity of superoxide dismutase (SOD), and the value of nicotinamide adenine dinucleotide (NAD(+) )/NADH was detected. The level of triacylglycerol (TG), total cholesterol (TC) and fatty acid β-oxidation rate was detected. The activity and expression levels of SIRT1 and expression of its downstream lipid-metabolism genes were measured.
  
  
  RESULTS
  In replicon cells, the level of ROS and MDA increased, SOD activity and the value of NAD(+) /NADH decreased, then the activity and expression level of mRNA and protein of SIRT1 reduced. Inhibition of SIRT1 decreased phosphorylation of forkhead box O1 (FoxO1), which not only upregulated SREBP-1c, FAS, ACC, SREBP-2, HMGR and HMGS genes and increased fatty acid synthesis; but also downregulated PPAR-α and CPT1A genes and decreased fatty acid β-oxidation. Interferon treatment restored aforementioned changes. SIRT1 activator improved lipid metabolism disorders by an increase in fatty acid β-oxidation and a decrease in TG and TC synthesis and inhibited HCV replication.
  
  
  CONCLUSIONS
  HCV replication decreasing NAD(+) /NADH ratio may downregulate the activity and the expression of SIRT1, then change the expression profile of lipid metabolism-related genes, thereby cause lipid metabolism disorders of hepatocytes and promote HCV replication. Treatment with SIRT1 activator ameliorates lipid metabolic disorders and inhibits HCV replication.
authors.affiliation: Department of Infectious Diseases, Second Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: Li-Jie
authors.initials: LJ
authors.lastname: Sun
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Li
authors.forename: Yong-Hua
authors.initials: YH
authors.lastname: Zhao
authors.forename: Jian-Wu
authors.initials: JW
authors.lastname: Yu
authors.forename: Peng
authors.initials: P
authors.lastname: Kang
authors.forename: Bing-Zhu
authors.initials: BZ
authors.lastname: Yan
keywords: hepatic lipid metabolism; hepatitis C viruses; silent information regulator 1