Bromodomain inhibition reveals FGF15/19 as a target of epigenetic regulation and metabolic control

Epigenetic regulation is an important factor in glucose metabolism, but underlying mechanisms remain largely unknown. Here we demonstrated that bromodomain-containing proteins (Brds), transcriptional regulators binding to acetylated histone, are potent modulators of glucose metabolism via the gut-liver farnesoid X receptor (FXR)-fibroblast growth factor 15/19 (FGF15/19) pathway. In vivo inhibition of Brd4 by the inhibitor JQ1 in mice strongly inhibited ileal expression of FGF15, resulting in decreased FGFR4-related signaling, increased glucose production in the liver and hyperglycemia. Adverse metabolic effects of BRD4 inhibition were reversed by overexpression of FGF19, with improvement in hyperglycemia. At a cellular level, we demonstrate that BRD4 binds to the promoter region of FGF19 in human intestinal cells; BRD inhibition by JQ1 reduces binding to the FGF19 promoter and downregulates FGF19 expression. Thus, we identify Brd4 as a novel transcriptional regulator of intestinal FGF15/19 in ileum, and a contributor to hepatic and systemic glucose metabolism.