title: Activation of protein serine/threonine phosphatase PP2Cα efficiently prevents liver fibrosis.
abstract: BACKGROUND
  Over-activation of TGFβ signaling pathway and uncontrolled cell proliferation of hepatic stellate cells (HSCs) play pivotal roles in liver fibrogenesis, while the protein serine/threonine phosphatase PP2Cα was reported to negatively regulate TGFβ signaling pathway and cell cycle. Our study aimed to investigate the role of PP2Cα in liver fibrogenesis.
  
  
  RESULTS
  The effects of PP2Cα activation on liver fibrosis were investigated in human HSCs and primary rat HSCs in vitro using western blotting, real-time PCR, nuclear translocation, cell viability and cell cycle analyses. The antifibrogenic effects in carbon tetrachloride (CCl(4))- and bile duct ligation (BDL)-induced mice in vivo were assessed using biochemical, histological and immunohistochemical analyses. The results demonstrated that activation of PP2Cα by overexpression or the new discovered small molecular activator NPLC0393 terminated TGFβ-Smad3 and TGFβ-p38 signaling pathways, induced cell cycle arrest in HSCs and decreased α-smooth muscle actin (α-SMA) expression, collagen deposition and hepatic hydroxyproline (HYP) level in CCl(4)- and BDL-induced mice.
  
  
  CONCLUSIONS
  Our findings suggested that PP2Cα activation might be an attractive new strategy for treating liver fibrosis while the small molecular activator NPLC0393 might represent a lead compound for antifibrogenic drug development. Moreover, our study might provide the first evidence for the role of PP2C family members in the fibrotic disease.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Lirui
authors.initials: L
authors.lastname: Wang
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Zhengyi
authors.initials: Z
authors.lastname: Yang
authors.forename: Liang
authors.initials: L
authors.lastname: Yu
authors.forename: Lihong
authors.initials: L
authors.lastname: Hu
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle; D004789:Enzyme Activation; D005355:Fibrosis; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000473:pathology*; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012503:Saponins / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000199:Actins; C559056:NPLC 0393; D012503:Saponins; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C