title: Pin1 induction in the fibrotic liver and its roles in TGF-β1 expression and Smad2/3 phosphorylation.
abstract: OBJECTIVE
  Therapeutic management of liver fibrosis remains an unsolved clinical problem. Hepatic accumulation of extracellular matrix, mainly collagen, is mediated by the production of transforming growth factor-β1 (TGF-β1) in stellate cells. Pin1, a peptidyl-prolyl isomerase, plays an important pathophysiological role in several diseases, including neurodegeneration and cancer. Herein, we determined whether Pin1 regulates liver fibrogenesis and examined its mechanism of action by focusing on TGF-β1 signalling and hepatic stellate cell (HSC) activation.
  
  
  METHODS
  Pin1 expression was assessed by immunohistochemistry, Western blot or real-time-polymerase chain reaction (RT-PCR) analyses of human and mouse fibrotic liver samples. The role of Pin1 during HSC activation was estimated using Pin1-null mouse embryonic fibroblast (MEF) cells and Pin1-overexpressing LX-2 human hepatic stellate cells.
  
  
  RESULTS
  Pin1 expression was elevated in human and mouse fibrotic liver tissues, and Pin1 inhibition improved dimethylnitrosamine (DMN)-induced liver fibrosis in mice. Pin1 inhibition reduced the mRNA or protein expression of TGF-β1 and α-smooth muscle actin (α-SMA) by DMN treatment. Pin1 knockdown suppressed TGFβ1 gene expression in both LX-2 and MEF cells. Pin1-mediated TGFβ1 gene transcription was controlled by extracellular signal-regulated kinase (ERK)- and phosphoinositide 3-kinase/Akt-mediated activator protein-1 (AP-1) activation. Moreover, TGFβ1-stimulated Smad2/3 phosphorylation and plasminogen activator inhibitor-1 expression were inhibited by Pin1 knockdown.
  
  
  CONCLUSIONS
  Pin1 induction during liver fibrosis is involved in hepatic stellate cell activation, TGFβ1 expression, and TGFβ1-mediated fibrogenesis signalling.
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Jin Won
authors: JW
authors: Yang
authors: College of Pharmacy, Chosun University, Gwangju 501-759, Republic of Korea.
authors: Tran Thi
authors: TT
authors: Hien
authors: Department of Pathology, College of Medicine, Chosun University, Gwangju 501-759, Republic of Korea.
authors: Sung Chul
authors: SC
authors: Lim
authors: Department of Internal Medicine, Han Yang University, Seoul 133-791, Republic of Korea.
authors: Dae Won
authors: DW
authors: Jun
authors: College of Pharmacy, Chosun University, Gwangju 501-759, Republic of Korea.
authors: Hong Seok
authors: HS
authors: Choi
authors: Department of Oral & Maxillofacial Pathology, College of Dentistry, Daejeon Dental Hospital, Wonkwang University, Daejeon 302-120, Republic of Korea.
authors: Jung-Hoon
authors: JH
authors: Yoon
authors: Medical Research Center for Globalization of Herbal Formulation, College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 712-715, Republic of Korea.
authors: Il Je
authors: IJ
authors: Cho
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: kwkang@snu.ac.kr.
authors: Keon Wook
authors: KW
authors: Kang
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones / Q000494:pharmacology; D019696:Peptidylprolyl Isomerase / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; C005134:juglone
keywords: Liver fibrosis; Pin1; Smad2/3; TGF-β1