Elsevier

Laboratory Investigation

Volume 91, Issue 8, August 2011, Pages 1136-1145
Laboratory Investigation

Research Article
The nuclear receptor CAR modulates alcohol-induced liver injury

https://doi.org/10.1038/labinvest.2011.68Get rights and content
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Abstract

The constitutive androstane receptor (CAR) is a member of the nuclear receptor superfamily and a sensor and detoxifier of both xenobiotics and endobiotics. Recent studies also show that CAR participates in metabolism of glucose and lipid, and has an important role in fatty liver disease and diabetes. In this study, we investigate the roles of CAR in chronic and acute alcohol-induced liver injuries. The results showed that absence of CAR in rodents led to significantly increased susceptibility to chronic alcohol-induced liver injury, which was accompanied with elevated hepatocyte apoptosis and fat accumulation. However, pre-activation of CAR by a CAR agonist, TCPOBOP, strongly enhanced the hepatic toxicity by both chronic and acute alcohol infusion in wild-type, but not in CAR−/− mice. Gene expression analyses indicated that CAR pre-activation and alcohol infusion synergistically decreased the expression of enzymes that metabolize the alcohol in liver. These results support a role of CAR in modulating alcoholic liver injury and imply a risk of synergistic liver toxicity induced by alcohol and CAR activation.

Keywords

alcohol
alcohol dehydrogenase
aldehyde dehydrogenase
constitutive androstane receptor
liver injury

Cited by (0)

Xiaosong Chen and Zhipeng Meng: These authors contributed equally to this work.

The constitutive androstane receptor (CAR) is essential in xenobiotic detoxification. While CAR−/− mice are highly susceptible to alcohol-induced liver injury, pre-activation of CAR enhances the hepatic toxicity of alcohol in wild type but not CAR−/− mice. Drug-induced CAR activation thus enhances alcohol-induced liver injury by suppressing expression of enzymes that metabolize alcohol.