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 (ERRγ) as a novel transcriptional regulator of human fibrinogen gene expression. Overexpression of ERRγ 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 ERRγ, whereas knockdown of ERRγ attenuated fibrinogen expression. Deletion analyses of the fibrinogen γ (FGG) gene promoter and ChIP assays revealed binding sites of ERRγ on human fibrinogen γ gene promoter. Moreover, overexpression of ERRγ was sufficient to increase fibrinogen gene expression, whereas treatment with GSK5182, a selective inverse agonist of ERRγ led to its attenuation in cell culture. Finally, fibrinogen and ERRγ 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, ERRγ expression and fibrinogen gene transcription. GSK5182 may have therapeutic potential to treat hyperfibrinogenemia.
Highlights
Obesity is frequently associated with elevated risk for cardiovascular disease (CVD) [1]
Knowing that the endocannabinoid system is hyperactivated in the obesity stage[35] and due to our previous study, where we showed that CB1R induces expression of ERRγ and its effect on modulating hepatic bile acid metabolism by alcohol [30], we speculated that CB1R might involve in regulating fibrinogen expression in liver
We focused our studies about regulation of fibrinogen expression on the fibrinogen γ-chain gene, because findings from most animal and cell culture studies indicate that the fibrinogen γ-chain gene is expressed at higher levels than the α- and β-chains
Summary
Obesity is frequently associated with elevated risk for cardiovascular disease (CVD) [1]. We identified a novel mechanism of regulation of hepatic bile acid metabolism by alcohol via CB1R-mediated activation of ERRγ [30]. Together, these findings suggest that blocking the CB1R signaling pathway can restore hepatic metabolic homeostasis. We identified the nuclear receptor ERRγ as a transcriptional regulator of hepatic fibrinogen gene expression. Activation of hepatic CB1R signaling induced ERRγ-mediated transcription of the fibrinogen gene. Inhibition of the transcriptional activity of ERRγ by an inverse agonist may have the potential to ameliorate hyperfibrinogenemia
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
