Abstract
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 antiinflammatory, antifibrotic 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 small heterodimer partner and cholesterol 7 alpha-hydroxylase, 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 silencing mediator of retinoid and thyroid hormone receptor (SMRT) decreased NF-κB binding at inflammatory genes and repressed the genes in a BRD4-dependent manner. In patients with PBC, hepatic expression of FXR and BRD4 was significantly reduced. In conclusion, BRD4 is a potentially novel cofactor of FXR for maintaining BA homeostasis and hepatoprotection. Although BRD4 promotes hepatic inflammation and fibrosis in cholestasis, paradoxically, BRD4 is required for the antiinflammatory, antifibrotic actions of OCA-activated FXR. Cotreatment with OCA and JQ1, individually beneficial, may be antagonistic in treatment of liver disease patients with inflammation and fibrosis complications.
Highlights
Bile acids (BAs) aid in digestion of lipid nutrients and function as signaling molecules that profoundly influence metabolism and energy balance [1, 2]
Since bromodomain-containing protein 4 (BRD4) is known to interact with P300 and binds to acetylated histones [21, 25, 33], we have examined whether BRD4 has a role in the farnesoid X receptor (FXR) induction of small heterodimer partner (Shp) in the regulation of BA levels in mice
These results suggest that liver-specific downregulation of BRD4 disrupts BA homeostasis in mice
Summary
Bile acids (BAs) aid in digestion of lipid nutrients and function as signaling molecules that profoundly influence metabolism and energy balance [1, 2]. Farnesoid X receptor (FXR/NR1H4) plays a central role in maintaining normal BA levels and protecting against cholestatic liver injury by transcriptional regulation of genes involved in BA synthesis, transport, and metabolism [5,6,7]. An FXR agonist, obeticholic acid (OCA), was recently approved by the FDA for treatment of patients with PBC who did not respond adequately to ursodeoxycholic acid (UDCA), the only drug approved previously [3, 4, 19]. In patients with NASH in recent phase 3 studies, OCA reduced liver fibrosis but was not approved on an accelerated basis by the FDA, and additional safety and clinical efficacy data were requested. Despite its exciting therapeutic potential, the molecular mechanisms of the antiinflammatory, antifibrotic actions of OCA remain unclear
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