Pregnane X receptor promotes ethanol-induced hepatosteatosis in mice.

5 years ago

Pregnane X receptor promotes ethanol-induced hepatosteatosis in mice.

Maxwell A Gyamfi, Sora Choi, Prince Neequaye, Frank J Gonzalez, Samuel W French

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 (ALD). However, the molecular mechanism of PXR-mediated activation of ethanol (EtOH)-induced steatosis is unclear. Here, using male wild type (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) upregulated 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 TNFα (3.0-fold), while the expression of peroxisome proliferator-activated receptor α 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.

Publisher URL: http://doi.org/10.1074/jbc.M117.815217

DOI: 10.1074/jbc.M117.815217