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Chemical Biology


Activation of Protein Serine/Threonine Phosphatase PP2Ca Efficiently Prevents Liver Fibrosis
Published: Monday, December 06, 2010
Author: Lirui Wang et al.

by Lirui Wang, Xu Wang, Jing Chen, Zhengyi Yang, Liang Yu, Lihong Hu, Xu Shen

Background

Over-activation of TGFß signaling pathway and uncontrolled cell proliferation of hepatic stellate cells (HSCs) play pivotal roles in liver fibrogenesis, while the protein serine/threonine phosphatase PP2Ca was reported to negatively regulate TGFß signaling pathway and cell cycle. Our study aimed to investigate the role of PP2Ca in liver fibrogenesis.

Methodology/Principal Findings

The effects of PP2Ca 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 PP2Ca by overexpression or the new discovered small molecular activator NPLC0393 terminated TGFß-Smad3 and TGFß-p38 signaling pathways, induced cell cycle arrest in HSCs and decreased a-smooth muscle actin (a-SMA) expression, collagen deposition and hepatic hydroxyproline (HYP) level in CCl4- and BDL-induced mice.

Conclusions/Significance

Our findings suggested that PP2Ca 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.

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