Poly(ADP-Ribose) Polymerase 1 Promotes Oxidative-Stress-Induced Liver Cell Death via Suppressing Farnesoid X Receptor α

被引：33

作者：

Wang, Cheng ^{[1
,2
]}

Zhang, Fengxiao ^{[1
,2
]}

Wang, Lin ^{[3
]}

Zhang, Yanqing ^{[1
]}

Li, Xiangrao ^{[1
]}

Huang, Kun ^{[1
]}

Du, Meng ^{[1
]}

Liu, Fangmei ^{[1
]}

Huang, Shizheng ^{[4
]}

Guan, Youfei ^{[4
]}

Huang, Dan ^{[1
,2
]}

Huang, Kai ^{[2
]}

机构：

[1] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dept Cardiovasc Dis, Wuhan 430074, Hubei, Peoples R China

[2] Huazhong Univ Sci & Technol, Union Hosp, Clin Ctr Human Genom Res, Wuhan 430074, Hubei, Peoples R China

[3] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Med Res Ctr, Wuhan 430074, Hubei, Peoples R China

[4] Peking Univ, Minist Educ, Hlth Sci Ctr, Dept Physiol & Pathophysiol,Key Lab Cardiovasc Sc, Beijing 100871, Peoples R China

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2013年 / 33卷 / 22期

基金：

中国国家自然科学基金;

关键词：

FXR; PARP-1; IDENTIFICATION; ACETYLATION; RECRUITMENT; EXPRESSION;

D O I：

10.1128/MCB.00160-13

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Farnesoid X receptor alpha (FXR) is highly expressed in the liver and regulates the expression of various genes involved in liver repair. In this study, we demonstrated that activated poly(ADP-ribose) polymerase 1 (PARP1) promoted hepatic cell death by inhibiting the expression of FXR-dependent hepatoprotective genes. PARP1 could bind to and poly(ADP-ribosyl) ate FXR. Poly( ADP-ribosyl)ation dissociated FXR from the FXR response element (FXRE), present in the promoters of target genes, and suppressed FXR-mediated gene transcription. Moreover, treatment with a FXR agonist attenuated poly(ADP-ribosyl) ation of FXR and promoted FXR-dependent gene expression. We further established the CCl4-induced acute liver injury model in wildtype and FXR-knockout mice and identified an essential role of FXR poly(ADP-ribosyl) ation in CCl4-induced liver injury. Thus, our results identified poly(ADP-ribosyl) ation of FXR by PARP1 as a key step in oxidative-stress-induced hepatic cell death. The molecular association between PARP1 and FXR provides new insight into the mechanism, suggesting that inhibition of PARP1 could prevent liver injury.

引用

页码：4492 / 4503

页数：12

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