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Bromodomain Inhibition Reveals FGF15/19 as a Target of Epigenetic Regulation and Metabolic Control

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posted on 2022-01-31, 21:53 authored by Chisayo Kozuka, Vissarion Efthymiou, Vicencia M. Sales, Liyuan Zhou, Soravis Osataphan, Yixing Yuchi, Jeremy Chimene-Weiss, Christopher Mulla, Elvira Isganaitis, Jessica Desmond, Suzuka Sanechika, Joji Kusuyama, Laurie Goodyear, Xu Shi, Robert E. Gerszten, Cristina Aguayo-Mazzucato, Priscila Carapeto, Silvania DaSilva Teixeira, Darleen Sandoval, Direna Alonso-Curbelo, Lei Wu, Jun Qi, Mary-Elizabeth Patti
Epigenetic regulation is an important factor in glucose metabolism, but underlying mechanisms remain largely unknown. Here we investigated epigenetic control of systemic metabolism by bromodomain-containing proteins (Brds), which are transcriptional regulators binding to acetylated histone, in both intestinal cells and mice treated with the bromodomain inhibitor JQ-1. In vivo treatment with JQ-1 resulted in hyperglycemia and severe glucose intolerance. Whole-body or tissue-specific insulin sensitivity was not altered by JQ-1; however, JQ-1 treatment reduced insulin secretion during both in vivo glucose tolerance testing and ex vivo incubation of isolated islets. JQ-1 also inhibited expression of fibroblast growth factor (FGF)15 in the ileum and decreased FGF receptor 4-related signaling in the liver. These adverse metabolic effects of Brd4 inhibition were fully reversed by in vivo overexpression of FGF19, with normalization of hyperglycemia. At a cellular level, we demonstrate Brd4 binds to the promoter region of FGF19 in human intestinal cells; Brd inhibition by JQ-1 reduces FGF19 promoter binding and downregulates FGF19 expression. Thus, we identify Brd4 as a novel transcriptional regulator of intestinal FGF15/19 in ileum and FGF signaling in the liver, and a contributor to the gut-liver axis and systemic glucose metabolism.

Funding

grant support from NIH DK106193 (to MEP), R01DK101043 (to RG), R01CA142106 and R01HD093540 (to JQ), and DK036836 (Joslin DRC).

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