Poly(ADP-ribose) polymerase 1 promotes oxidative-stress-induced liver cell death via suppressing farnesoid X receptor α

Cheng Wang, Fengxiao Zhang, Lin Wang, Yanqing Zhang, Xiangrao Li, Kun Huang, Meng Du, Fangmei Liu, Shizheng Huang, Youfei Guan, Dan Huang, Kai Huang

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)4492-4503
Number of pages12
JournalMolecular and cellular biology
Volume33
Issue number22
DOIs
StatePublished - Nov 15 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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