Orphan Nuclear Receptor Err Gamma Is A Transcriptional Regulator Of Cb1 Receptor-Mediated Tfr2 Gene Expression In Hepatocytes

Orphan nuclear receptor estrogen-related receptor gamma (ERR gamma) is an important transcription factor modulating gene transcription involved in endocrine control of liver metabolism. Transferrin receptor 2 (TFR2), a carrier protein for transferrin, is involved in hepatic iron overload in alcoholic liver disease (ALD). However, TFR2 gene transcriptional regulation in hepatocytes remains largely unknown. In this study, we described a detailed molecular mechanism of hepatic TFR2 gene expression involving ERR gamma in response to an endocannabinoid 2-arachidonoylglycerol (2-AG). Treatment with 2-AG and arachidonyl-2'-chloroethylamide, a selective cannabinoid receptor type 1 (CB1) receptor agonist, increased ERR gamma and TFR2 expression in hepatocytes. Overexpression of ERR gamma was sufficient to induce TFR2 expression in both human and mouse hepatocytes. In addition, ERR gamma knockdown significantly decreased 2-AG or alcohol-mediated TFR2 gene expression in cultured hepatocytes and mouse livers. Finally, deletion and mutation analysis of the TFR2 gene promoter demonstrated that ERR gamma directly modulated TFR2 gene transcription via binding to an ERR-response element. This was further confirmed by chromatin immunoprecipitation assay. Taken together, these results reveal a previously unrecognized role of ERR gamma in the transcriptional regulation of TFR2 gene expression in response to alcohol.