Pregnane X receptor promotes ethanol-induced hepatosteatosis in mice

This is the authors' abstract. We don't add key points for this paper.

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 EtOHinduced 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.