Activation of Protein Serine/Threonine Phosphatase PP2Cα Efficiently Prevents Liver Fibrosis

Background: Over-activation of TGF beta signaling pathway and uncontrolled cell proliferation of hepatic stellate cells (HSCs) play pivotal roles in liver fibrogenesis, while the protein serine/threonine phosphatase PP2C alpha was reported to negatively regulate TGF beta signaling pathway and cell cycle. Our study aimed to investigate the role of PP2C alpha in liver fibrogenesis. Methodology/Principal Findings: The effects of PP2C alpha 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 (CCl4)-and bile duct ligation (BDL)-induced mice in vivo were assessed using biochemical, histological and immunohistochemical analyses. The results demonstrated that activation of PP2C alpha by overexpression or the new discovered small molecular activator NPLC0393 terminated TGF beta-Smad3 and TGF beta-p38 signaling pathways, induced cell cycle arrest in HSCs and decreased alpha-smooth muscle actin (alpha-SMA) expression, collagen deposition and hepatic hydroxyproline (HYP) level in CCl4- and BDL-induced mice. Conclusions/Significance: Our findings suggested that PP2C alpha 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.