GGPPS deficiency aggravates CCl4-induced liver injury by inducing hepatocyte apoptosis

Wei-Bo Chen; Shan-Shan Lai; De-Cai Yu; Jia Liu; Shan Jiang; Dan-Dan Zhao; Yi-Tao Ding; Chao-Jun Li; Bin Xue

doi:10.1016/j.febslet.2015.03.015

GGPPS deficiency aggravates CCl4-induced liver injury by inducing hepatocyte apoptosis

FEBS Lett. 2015 Apr 28;589(10):1119-26. doi: 10.1016/j.febslet.2015.03.015. Epub 2015 Mar 24.

Authors

Wei-Bo Chen¹, Shan-Shan Lai², De-Cai Yu³, Jia Liu², Shan Jiang², Dan-Dan Zhao², Yi-Tao Ding⁴, Chao-Jun Li⁵, Bin Xue⁶

Affiliations

¹ Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China; Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
² Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China; MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Centre and the School of Medicine, Nanjing University, National Resource Centre for Mutant Mice, Nanjing 210093, China.
³ Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
⁴ Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China. Electronic address: yitao_ding1@163.com.
⁵ Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China; MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Centre and the School of Medicine, Nanjing University, National Resource Centre for Mutant Mice, Nanjing 210093, China. Electronic address: licj@nju.edu.cn.
⁶ Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China; MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Centre and the School of Medicine, Nanjing University, National Resource Centre for Mutant Mice, Nanjing 210093, China. Electronic address: xuebin@nju.edu.cn.

PMID: 25819439
DOI: 10.1016/j.febslet.2015.03.015

Abstract

GGPPS catalyses the expression of GGPP, a key protein in the mevalonate metabolic pathway. HMG-CoA reductase inhibitor statins can induce liver injury by inhibiting GGPP. However, the function of GGPPS in liver injury has not yet been revealed. In this study, we found that GGPPS increased in liver injury and that GGPPS deletion augmented liver injury and fibrosis. GGPPS inhibition induced hepatocyte apoptosis, inflammation and TGF-β1 secretion, which activated hepatic stellate cells. Our findings imply that GGPPS deletion induces hepatocyte apoptosis, which makes the liver vulnerable to hepatotoxicity.

Keywords: Geranylgeranyl diphosphate synthase; Hepatocyte apoptosis; Liver fibrosis; Liver injury.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carbon Tetrachloride Poisoning / enzymology*
Carbon Tetrachloride Poisoning / genetics
Carbon Tetrachloride Poisoning / pathology
Farnesyltranstransferase / genetics
Farnesyltranstransferase / metabolism*
Gene Deletion
Hepatocytes / enzymology*
Hepatocytes / pathology
Liver / enzymology*
Liver / pathology
Liver Cirrhosis / chemically induced
Liver Cirrhosis / enzymology*
Liver Cirrhosis / genetics
Liver Cirrhosis / pathology
Mice
Mice, Knockout
Polyisoprenyl Phosphates / biosynthesis
Transforming Growth Factor beta1 / genetics
Transforming Growth Factor beta1 / metabolism

Substances

Polyisoprenyl Phosphates
Tgfb1 protein, mouse
Transforming Growth Factor beta1
Farnesyltranstransferase
geranylgeranyl pyrophosphate