TY - JOUR
T1 - Poly(ADP-ribose) polymerase 1 promotes oxidative-stress-induced liver cell death via suppressing farnesoid X receptor α
AU - Wang, Cheng
AU - Zhang, Fengxiao
AU - Wang, Lin
AU - Zhang, Yanqing
AU - Li, Xiangrao
AU - Huang, Kun
AU - Du, Meng
AU - Liu, Fangmei
AU - Huang, Shizheng
AU - Guan, Youfei
AU - Huang, Dan
AU - Huang, Kai
PY - 2013/11/15
Y1 - 2013/11/15
N2 - Farnesoid X receptor α (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.
AB - Farnesoid X receptor α (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.
UR - http://www.scopus.com/inward/record.url?scp=84887009619&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84887009619&partnerID=8YFLogxK
U2 - 10.1128/MCB.00160-13
DO - 10.1128/MCB.00160-13
M3 - Article
C2 - 24043304
AN - SCOPUS:84887009619
SN - 0270-7306
VL - 33
SP - 4492
EP - 4503
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 22
ER -