Orphan nuclear receptor ERR. is a key regulator of human fibrinogen gene expression

Abstract

Fibrinogen, 1 of 13 coagulation factors responsible for normal blood clotting, is synthesized by hepatocytes. Detailed roles of the orphan nuclear receptors regulating fibrinogen gene expression have not yet been fully elucidated. Here, we identified estrogen-related receptor gamma (ERR.) as a novel transcriptional regulator of human fibrinogen gene expression. Overexpression of ERR. specially increased fibrinogen expression in human hepatoma cell line. Cannabinoid receptor types 1(CB1R) agonist arachidonyl-2'-chloroethylamide (ACEA) up-regulated transcription of fibrinogen via induction of ERR., whereas knockdown of ERR. attenuated fibrinogen expression. Deletion analyses of the fibrinogen. (FGG) gene promoter and ChIP assays revealed binding sites of ERR. on human fibrinogen. gene promoter. Moreover, overexpression of ERR. was sufficient to increase fibrinogen gene expression, whereas treatment with GSK5182, a selective inverse agonist of ERR. led to its attenuation in cell culture. Finally, fibrinogen and ERR. gene expression were elevated in liver tissue of obese patients suggesting a conservation of this mechanism. Overall, this study elucidates a molecular mechanism linking CB1R signaling, ERR. expression and fibrinogen gene transcription. GSK5182 may have therapeutic potential to treat hyperfibrinogenemia.