title: Hepatitis C virus core protein induces hepatic metabolism disorders through down-regulation of the SIRT1-AMPK signaling pathway.
abstract: BACKGROUND
  Steatosis and insulin resistance induced by hepatitis C virus (HCV) infection are, at least in part, critical factors for the progression of chronic hepatitis C (CHC) and can influence the outcome of antiviral treatment. Silent information regulator 1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK) play a key role in the regulation of hepatic glucose and lipid metabolism. The aim of this study was to investigate the possible effect of HCV core protein on energy, glucose, and lipid metabolism of hepatocytes and expression of SIRT1 and AMPK.
  
  
  METHODS
  HCV core protein expression plasmid was transfected into HepG2 cells. The level of reactive oxygen species (ROS) and values of NAD(+)/NADH and ATP/ADP were detected. Intracellular levels of triacylglycerol (TG), cholesterol, glucose uptake by hepatocytes, and glucose production were measured. The expression levels of mRNA and protein of SIRT1 and AMPK were detected. The mRNA levels of SIRT1 and AMPK downstream glucose and lipid metabolism genes were measured.
  
  
  RESULTS
  In HepG2 cells expressing HCV core protein, the level of ROS increased, the value of NAD(+)/NADH decreased, the activity and expression levels of mRNA and protein of SIRT1 and AMPK decreased, glucose uptake and its regulator gene GLUT2 mRNA levels decreased, glucose production and its regulator genes PEPCK and G6Pase mRNA levels increased, intracellular TG and cholesterol contents and their regulator gene (SREBP-1c, FAS, ACC, HMGR, and HMGS) mRNA levels increased, the glycolytic gene GK and fatty acid oxidation genes PPARα and CPT1A mRNA levels decreased.
  
  
  CONCLUSIONS
  HCV core protein induces alterations in cellular redox state (decrease in the NAD(+)/NADH ratio), which could influence the activity of SIRT1 and secondarily AMPK, then change the expression profile of glucose and lipid metabolism-related genes, thereby causing metabolism disorders of hepatocytes.
authors.affiliation: Department of Infectious Diseases, Second Affiliated Hospital, Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin 150086, China.
authors.forename: Jian-Wu
authors.initials: JW
authors.lastname: Yu
authors.forename: Li-Jie
authors.initials: LJ
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Yong-Hua
authors.initials: YH
authors.lastname: Zhao
authors.forename: Peng
authors.initials: P
authors.lastname: Kang
authors.forename: Bing-Zhu
authors.initials: BZ
authors.lastname: Yan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D015536:Down-Regulation; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism*; D010957:Plasmids; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism; D014758:Viral Core Proteins / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014280:Triglycerides; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D002784:Cholesterol; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D005947:Glucose