Unknown

Dataset Information

0

Pregnane X receptor promotes ethanol-induced hepatosteatosis in mice.


ABSTRACT: The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that modulates the metabolic response to drugs and toxic agents. Both PXR activation and deficiency promote hepatic triglyceride accumulation, a hallmark feature of alcoholic liver disease. However, the molecular mechanism of PXR-mediated activation of ethanol (EtOH)-induced steatosis is unclear. Here, using male wildtype (WT) and Pxr-null mice, we examined PXR-mediated regulation of chronic EtOH-induced hepatic lipid accumulation and hepatotoxicity. EtOH ingestion for 8 weeks significantly (1.8-fold) up-regulated Pxr mRNA levels in WT mice. The EtOH exposure also increased mRNAs encoding hepatic constitutive androstane receptor (3-fold) and its target, Cyp2b10 (220-fold), in a PXR-dependent manner. Furthermore, WT mice had higher serum EtOH levels and developed hepatic steatosis characterized by micro- and macrovesicular lipid accumulation. Consistent with the development of steatosis, lipogenic gene induction was significantly increased in WT mice, including sterol regulatory element-binding protein 1c target gene fatty-acid synthase (3.0-fold), early growth response-1 (3.2-fold), and TNF? (3.0-fold), whereas the expression of peroxisome proliferator-activated receptor ? target genes was suppressed. Of note, PXR deficiency suppressed these changes and steatosis. Protein levels, but not mRNAs levels, of EtOH-metabolizing enzymes, including alcohol dehydrogenase 1, aldehyde dehydrogenase 1A1, and catalase, as well as the microsomal triglyceride transfer protein, involved in regulating lipid output were higher in Pxr-null than in WT mice. These findings establish that PXR signaling contributes to ALD development and suggest that PXR antagonists may provide a new approach for ALD therapy.

SUBMITTER: Choi S 

PROVIDER: S-EPMC5766906 | BioStudies | 2018-01-01T00:00:00Z

SECONDARY ACCESSION(S): NM007988

REPOSITORIES: biostudies

Similar Datasets

2016-01-01 | S-EPMC5742869 | BioStudies
2013-01-01 | S-EPMC3859835 | BioStudies
2019-01-01 | S-EPMC6602874 | BioStudies
2019-01-01 | S-EPMC6462244 | BioStudies
1000-01-01 | S-EPMC5680911 | BioStudies
2016-01-01 | S-EPMC5133173 | BioStudies
2018-01-01 | S-EPMC6168334 | BioStudies
2018-01-01 | S-EPMC6028296 | BioStudies
2012-01-01 | S-EPMC3288318 | BioStudies
1000-01-01 | S-EPMC4479337 | BioStudies