title: Antifibrotic effects of luteolin on hepatic stellate cells and liver fibrosis by targeting AKT/mTOR/p70S6K and TGFβ/Smad signalling pathways.
abstract: OBJECTIVE
  Luteolin has been reported to exert antifibrogenic effects in CCl4 -induced hepatic fibrosis in mice. However, limited information is available on the cellular and molecular events responsible for this effect. This study focused on the action of luteolin on hepatic stellate cells (HSCs) and the relevant signalling molecules and pathways as well as the antifibrotic efficacy in multiple models of fibrosis.
  
  
  METHODS
  The in vitro effect of luteolin on rat HSCs and HSC-T6 cells was assessed using proliferation assays, invasion chamber, quantitative real-time PCR analysis and Western blotting. The in vivo effect of luteolin on progression of fibrosis was assessed in three experimental rat models induced by CCl4 , dimethylnitrosamine (DMN) and bile duct ligation (BDL).
  
  
  RESULTS
  Luteolin inhibited proliferation, migration, collagen synthesis as well as expression of fibrosis-related genes in the activated HSCs and HSC-T6 cells stimulated with or without transforming growth factor-β1(TGFβ1) or platelet-derived growth factor (PDGF). Luteolin induced HSC apoptosis associated with the increased caspase 3 activity and p53 expression, and induced G1 arrest with the decreased expression of bcl-2, Cyclin E and p-Cdk-2. Moreover, luteolin significantly inhibited PDGF and TGFβ1-simulated phosphorylation of AKT and Smad pathway. In vivo study showed that luteolin administration markedly alleviated hepatic fibrosis along with reduced elevations of alanine aminotransferase and aspartate aminotransferase. HSCs were found to undergo apoptosis and decreased expression of p-Smad2 and p-AKT in luteolin-treated animals.
  
  
  CONCLUSIONS
  This study demonstrates that luteolin prevents the progression of liver fibrosis through multiple mechanisms and indicates that luteolin has potential for effective treatment of liver fibrosis.
authors.affiliation: Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China; School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Xingxia
authors.initials: X
authors.lastname: Li
authors.forename: Weiheng
authors.initials: W
authors.lastname: Xu
authors.forename: Shaozhan
authors.initials: S
authors.lastname: Wang
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Hu
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xing
authors.initials: X
authors.lastname: Deng
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Junping
authors.initials: J
authors.lastname: Zhang
authors.forename: Cheng
authors.initials: C
authors.lastname: Guo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D003094:Collagen / Q000378:metabolism; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D047311:Luteolin / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D051899:Smad2 Protein; C497784:Smad2 protein, rat; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D003094:Collagen; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D047311:Luteolin
keywords: AKT; Smad; activation; hepatic fibrosis; hepatic stellate cells; luteolin