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bioRxiv · 10.1101/2019.12.11.872887

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

Kozuka, C.·Sales, V.·Osataphan, S.·Yuchi, Y.·Chimene-Weiss, J.·Mulla, C.·Isganaitis, E.·Desmond, J.·Sanechika, S.·Kusuyama, J.·Goodyear, L.·Shi, X.·Gerszten, R. E.·Wu, L.·Qi, J.·Patti, M. E.
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Abstract

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.

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Kozuka, C., Sales, V., Osataphan, S., Yuchi, Y., Chimene-Weiss, J., Mulla, C., Isganaitis, E., Desmond, J., Sanechika, S., Kusuyama, J., Goodyear, L., Shi, X., Gerszten, R. E., Wu, L., Qi, J., Patti, M. E.. 2019-12-12. Bromodomain inhibition reveals FGF15/19 as a target of epigenetic regulation and metabolic control. https://doi.org/10.1101/2019.12.11.872887

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