An inverse agonist of estrogen-related receptor gamma regulates 2-arachidonoylglycerol synthesis by modulating diacylglycerol lipase expression in alcohol-intoxicated mice

Abstract

Chronic alcohol feeding increases the levels of 2-arachidonoylglycerol (2-AG) in the liver, which activates hepatic cannabinoid receptor type 1 (CB1R), leading to oxidative liver injury. 2-AG biosynthesis is catalyzed by diacylglycerol lipase (DAGL). However, the mechanisms regulating hepatic DAGL gene expression and 2-AG production are largely unknown. In this study, we show that CB1R-induced estrogen-related receptor gamma (ERR gamma) controls hepatic DAGL gene expression and 2-AG levels. Arachidonyl-2 '-chloroethylamide (ACEA), a synthetic CB1R agonist, significantly upregulated ERR gamma, DAGL alpha, and DAGL beta, and increased 2-AG levels in the liver (10 mg/kg) and hepatocytes (10 mu M) of wild-type (WT) mice. ERR gamma overexpression upregulated DAGL alpha and DAGL beta expressions and increased 2-AG levels, whereas ERR gamma knockdown abolished ACEA-induced DAGL alpha, DAGL beta, and 2-AG in vitro and in vivo. Promoter assays showed that ERR gamma positively regulated DAGL alpha and DAGL beta transcription by binding to the ERR response element in the DAGL alpha and DAGL beta promoters. Chronic alcohol feeding (27.5% of total calories) induced hepatic steatosis and upregulated ERR gamma, leading to increased DAGL alpha, DAGL beta, or 2-AG in WT mice, whereas these alcohol-induced effects did not occur in hepatocyte-specific CB1R knockout mice or in those treated with the ERR gamma inverse agonist GSK5182 (40 mg/kg in mice and 10 mu M in vitro). Taken together, these results indicate that suppression of alcohol-induced DAGL alpha and DAGL beta gene expressions and 2-AG levels by an ERR gamma-specific inverse agonist may be a novel and attractive therapeutic approach for the treatment of alcoholic liver disease.