Unknown

Dataset Information

0

Poly(ADP-ribosyl)ated PXR is a critical regulator of acetaminophen-induced hepatotoxicity.


ABSTRACT: Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure and remains a critical problem in medicine. PARP1-dependent poly(ADPribosyl)ation is a key mediator of cellular stress responses and functions in multiple physiological and pathological processes. However, whether it is involved in the process of APAP metabolism remains elusive. In this study, we find that PARP1 is activated in mouse livers after APAP overdose. Pharmacological or genetic manipulations of PARP1 are sufficient to suppress the APAP-induced hepatic toxicity and injury, as well as reduced APAP metabolism. Mechanistically, we identify pregnane X receptor (PXR) as a substrate of PARP1-mediated poly(ADP-ribosyl)ation. The poly(ADP-ribosyl)ation of PXR in ligand-binding domain activates PXR competitively and solidly, facilitates its recruitment to target gene CYP3A11 promoter, and promotes CYP3A11 gene transcription, thus resulting in increases of APAP pro-toxic metabolism. Additionally, PXR silence antagonizes the effects of PARP1 on APAP-induced hepatotoxicity. These results identifies poly(ADP-ribosyl)ation of PXR by PARP1 as a key step in APAP-induced liver injury. We propose that inhibition of PARP1-dependent poly(ADP-ribosyl)ation might represent a novel approach for the treatment of drug-induced hepatotoxicity.

SUBMITTER: Wang C 

PROVIDER: S-EPMC6062506 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

altmetric image

Publications

Poly(ADP-ribosyl)ated PXR is a critical regulator of acetaminophen-induced hepatotoxicity.

Wang Cheng C   Xu Wenjing W   Zhang Yanqing Y   Huang Dan D   Huang Kai K  

Cell death & disease 20180726 8


Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure and remains a critical problem in medicine. PARP1-dependent poly(ADPribosyl)ation is a key mediator of cellular stress responses and functions in multiple physiological and pathological processes. However, whether it is involved in the process of APAP metabolism remains elusive. In this study, we find that PARP1 is activated in mouse livers after APAP overdose. Pharmacological or genetic manipulations of PARP1 are su  ...[more]

Similar Datasets

| S-EPMC1138899 | biostudies-other
| S-EPMC6459841 | biostudies-literature
| S-EPMC4291492 | biostudies-literature
| S-EPMC3477232 | biostudies-literature
| S-EPMC1217374 | biostudies-other
2014-02-20 | E-GEOD-55136 | biostudies-arrayexpress
2022-12-21 | GSE200499 | GEO
| S-EPMC4670112 | biostudies-literature
| S-EPMC7127722 | biostudies-literature
| S-EPMC9772176 | biostudies-literature