BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination.

Activation of Farnesoid-X-Receptor (FXR) by obeticholic acid (OCA) reduces hepatic inflammation and fibrosis in patients with primary biliary cholangitis (PBC), a life-threatening cholestatic liver failure. Inhibition of bromodomain-containing protein-4 (BRD4) also has anti-inflammatory, anti-fibrotic effects in mice. We determined the role of BRD4 in FXR function in bile acid (BA) regulation and examined whether the known beneficial effects of OCA are enhanced by inhibiting BRD4 in cholestatic mice. Liver-specific downregulation of BRD4 disrupted BA homeostasis in mice, and FXR-mediated regulation of BA-related genes, including Shp and Cyp7a1, was BRD4-dependent. In cholestatic mice, JQ1 or OCA treatment ameliorated hepatotoxicity, inflammation, and fibrosis, but surprisingly, was antagonistic in combination. Mechanistically, OCA increased binding of FXR and the corepressor SMRT, decreased NF-κB binding at inflammatory genes, and repressed the genes in a BRD4-dependent manner. In PBC patients, hepatic expression of FXR and BRD4 was significantly reduced. In conclusion, BRD4 is a novel cofactor of FXR for maintaining BA homeostasis and hepatoprotection. While BRD4 promotes hepatic inflammation and fibrosis in cholestasis, paradoxically, BRD4 is required for the anti-inflammatory, anti-fibrotic actions of OCA-activated FXR. Co-treatment with OCA and JQ1, individually beneficial, may be antagonistic in treatment of liver disease patients with inflammation and fibrosis complications.