Abstract
The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that defends against toxic agents. We have shown that PXR promotes chronic ethanol (EtOH)–induced steatosis. Therefore, we examined the role of PXR in binge EtOH-induced hepatotoxicity. Male wild-type (WT) and Pxr-null mice were orally administered three binge doses of EtOH (4.5 g/kg, every 12 hours) and were euthanized 4 hours after the final dose. Pxr-null mice displayed higher basal mRNA levels of hepatic lipogenic transcription factor sterol regulatory element binding protein 1c (Srebp-1c) and its target stearoyl-CoA desaturase 1 and the lipid peroxide–detoxifying aldo-keto reductase 1b7 (Akr1b7) and higher protein levels of EtOH-metabolizing alcohol dehydrogenase 1 (ADH1). In both genotypes, binge EtOH-induced triglyceride accumulation was associated with inhibition of fatty acid β-oxidation and upregulation of Srebp-1c–regulated lipogenic genes and hepatic CYP2E1 protein. Unexpectedly, gene expression of Cyp2b10, a constitutive androstane receptor target gene implicated in EtOH hepatotoxicity, was PXR-dependent upregulated by binge EtOH. In addition, in WT mice, binge EtOH-induced inhibition of hepatic Akr1b8 mRNA, and protein levels of aldehyde dehydrogenase 1A1 and antiapoptotic Bcl-2 but increased proapoptotic Bax protein expression, leading to increases in residual EtOH concentration and the cellular oxidative stress marker, malondialdehyde. In contrast, Pxr-null mice displayed increased Akr1b7 gene and ADH1 protein expression and hypertriglyceridemia after binge EtOH exposure. Taken together, this study demonstrates that PXR ablation prevents EtOH-induced upregulation of Cyp2b10 and that PXR potentiates binge EtOH-induced oxidative stress and inhibition of EtOH catabolism but protects against alcoholic hyperlipidemia.
Footnotes
- Received August 17, 2017.
- Accepted January 30, 2018.
This work was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant U54-AA019765] and the National Institutes of Health National Institute on Minority Health and Health Disparities [Grants 1U54-MD012392 and P20-MD000175]. This work was also supported in part by the Intramural Research Program of the National Institutes of Health National Cancer Institute.
- U.S. Government work not protected by U.S. copyright
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