title: Poly(ADP-ribose) polymerase 1 promotes oxidative-stress-induced liver cell death via suppressing farnesoid X receptor α.
abstract: 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 wild-type 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.
authors.affiliation: Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Fengxiao
authors.initials: F
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiangrao
authors.initials: X
authors.lastname: Li
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.forename: Meng
authors.initials: M
authors.lastname: Du
authors.forename: Fangmei
authors.initials: F
authors.lastname: Liu
authors.forename: Shizheng
authors.initials: S
authors.lastname: Huang
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
mesh_terms: D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D006861:Hydrogen Peroxide; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C499320:PARP1 protein, human; C499321:Parp1 protein, mouse
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