title: [Simvastatin inhibits activation of hepatic stellate cells and promotes activation of adenosine monophosphate-activated protein kinase].
abstract: OBJECTIVE
  To investigate the underlying molecular mechanism of the cholesterol-blocking drug, simvastatin, in treating nonalcoholic fatty liver fibrosis.
  
  
  METHODS
  A rat model of nonalcoholic fatty liver fibrosis was established by feeding Wistar rats a fat-rich diet. After treatment with simvastatin (4 mg/kg/day), liver histological specimens were stained with hematoxylin-eosin and Masson's trichrome for microscopic analysis. Expression of adenosine monophosphate-activated protein kinase-alpha (AMPKa) was evaluated by reverse transcription-polymerase chain reaction (RT-PCR; for mRNA) and Western blotting (protein). The levels of serum total cholesterol (TC), triglycerides (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and tumor necrosis factor-alpha (TNFa) were measured by standard biochemical assays. The human hepatic stellate cell line, LX-2 (quiescent or activated), was treated with transforming growth factor-beta 1 (TGF-b1) alone, simvastatin alone, or TGF-b1 + simvastatin. RT-PCR and Western blotting were used to determine changes in AMPKa mRNA and protein expression, respectively.
  
  
  RESULTS
  In the rat model of nonalcoholic fatty liver fibrosis, the extent of pathological changes in hepatic tissues correlated with severity of disease progression. The levels of serum TC, TG, ALT, AST and TNFa were increased significantly in model rats (vs. healthy controls; all, P less than 0.01). AMPKa mRNA expression and activity was significantly decreased in model rats (vs. healthy controls; P less than 0.01 and P less than 0.05, respectively). Simvastatin, treatment significantly improved all of these parameters in model rats (vs. untreated model rats; all, P less than 0.05). In vitro simvastatin treatment of human HSCs significantly increased AMPKa activity (quiescent LX-2: 0.93+/-0.10 vs. 0.72+/-0.09, activated LX-2: 0.72+/-0.10 vs. 0.54+/-0.10, q=7.00, 6.00; all, P less than 0.01), decreased a-smooth muscle actin expression (mRNA: 0.30+/-0.02 vs. 0.36+/-0.02, protein: 0.30+/-0.03 vs. 0.38+/-0.02, q=11.245, 11.216; all, P less than 0.01), and decreased collagen I expression (mRNA: 0.30+/-0.03 vs. 0.37+/-0.03, protein: 0.25+/-0.03 vs. 0.33+/-0.03, q=8.791, 11.163; all, P less than 0.01).
  
  
  CONCLUSIONS
  Simvastatin may improve nonalcoholic fatty liver fibrosis by inducing AMPK phosphorylation.
authors.affiliation: Department of Infectious Diseases, the Third Hospital of Hebei Medical University, Shijiazhuang 050051, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.forename: Lei
authors.initials: L
authors.lastname: Yan
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Cai-yan
authors.initials: CY
authors.lastname: Zhao
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019821:Simvastatin; D000263:Adenylate Kinase