HSC-specific knockdown of GGPPS alleviated CCl4-induced chronic liver fibrosis through mediating RhoA/Rock pathway

American Journal of Translational Research

Shan-Shan Lai¹  Zi-Han Yu²  Xiang Gao³  Xiao Fu⁴  Qi Cheng⁵  Huang-Xian Ju⁶  Dan-Dan Zhao⁷  De-Cai Yu⁸  Yu-Dong Qiu⁹  En-Ze Jiang^1,10  Qing Jiang^1,11  Wei Wang^1,12 

[1]Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China

[2]Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210093, China

[3]Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 210008, China

[4]Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China

[5]Jiangsu Key Laboratory of Molecular Medicine and School of Medicine, Nanjing University, Nanjing 210093, China

[6]Joint Research Center for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China

[7]Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing 210093, China

[8]MOE Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China

[9]National Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China

[10]Research Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China

[11]State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China

[12]State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine and School of Medicine, Nanjing University, Nanjing 210093, China

关键词: GGPPS;    hepatic stellate cell;    liver fibrosis;    TGF-β;    1;   

DOI  :  

学科分类：医学（综合）

来源: e-Century Publishing Corporation

【 摘 要 】

Hepatic stellate cells (HSCs) play a critical role in the pathogenesis and reversal of liver fibrosis. Targeting HSCs is of great significance in the treatment of hepatic fibrosis, and has attracted wide attention of scholars. Here we demonstrated that expression of geranylgeranyldiphosphate synthase (GGPPS) predominantly increased in HSCs in murine fibrotic liver. HSC-specific knockdown of GGPPS using vitamin A-coupled liposome carrying siRNA-ggpps decreased activation of HSCs and alleviated fiber accumulation in vivo. Furthermore, our in vitro studies showed that GGPPS was up-regulated during HSCs activation in TGF-β1-dependent manner. Inhibition of GGPPS suppressed TGF-β1 induced F-actin reorganization and HSCs activation in LX-2 cells. Further, we found that GGPPS regulated HSCs activation and liver fibrosis possibly by enhancing RhoA/Rock kinase signaling. So its concluded that GGPPS promotes liver fibrosis by activating HSCs, which may represent a potential target for anti-fibrosis therapies.

【 授权许可】

CC BY-NC