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 CCl 4 -induced acute liver injury model in wildtype and FXR-knockout mice and identified an essential role of FXR poly(ADP-ribosyl)ation in CCl 4 -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. © 2013, American Society for Microbiology.
CITATION STYLE
Wang, C., Zhang, F., Wang, L., Zhang, Y., Li, X., Huang, K., … Huang, K. (2013). Poly(ADP-Ribose) Polymerase 1 Promotes Oxidative-Stress-Induced Liver Cell Death via Suppressing Farnesoid X Receptor α. Molecular and Cellular Biology, 33(22), 4492–4503. https://doi.org/10.1128/mcb.00160-13
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