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Pin1 induction in the fibrotic liver and its roles in TGF-beta 1 expression and Smad2/3 phosphorylation

Pin1 induction in the fibrotic liver and its roles in TGF-beta 1 expression and Smad2/3 phosphorylation
Other Titles
3 phosphorylation
Liver fibrosis; Pin1; TGF-beta 1; Smad2/3
Issue Date
European Association for the Study of the Liver.
Journal of hepatology : the journal of the European Association for the Study of the Liver, v.60 no.6[2014년], pp. 1235-1241
Background & Aims: 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-beta 1 (TGF-beta 1) 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-beta 1 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- 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-beta 1 and alpha-smooth muscle actin (alpha-SMA) by DMN treatment. Pin1 knockdown suppressed TGF beta 1 gene expression in both LX-2 and MEF cells. Pin1-mediated TGF beta 1 gene transcription was controlled by extra-cellular signal-regulated kinase (ERK)- and phosphoinositide 3-kinase/Akt-mediated activator protein-1 (AP-1) activation. Moreover, TGF beta 1-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, TGF beta 1 expression, and TGF beta 1-mediated fibrogenesis signalling. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.
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