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

• Main Authors: Aguayo-Mazzucato, C. (Author), Alonso-Curbelo, D. (Author), Carapeto, P. (Author), Chimene-Weiss, J. (Author), Desmond, J. (Author), Efthymiou, V. (Author), Gerszten, R.E (Author), Goodyear, L. (Author), Isganaitis, E. (Author), Kozuka, C. (Author), Kusuyama, J. (Author), Mulla, C. (Author), Osataphan, S. (Author), Patti, M.-E (Author), Qi, J. (Author), Sales, V.M (Author), Sandoval, D. (Author), Sanechika, S. (Author), Shi, X. (Author), Teixeira, S.D (Author), Wu, L. (Author), Yuchi, Y. (Author), Zhou, L. (Author)
• Format: Article
• Language: English
• Published: NLM (Medline) 2022
• Subjects: animal; Animals; Epigenesis, Genetic; fibroblast growth factor; Fibroblast Growth Factors; genetic epigenesis; genetics; glucose; Glucose; hyperglycemia; Hyperglycemia; metabolism; Mice; mouse; nuclear protein; Nuclear Proteins; transcription factor; Transcription Factors
• Online Access: View Fulltext in Publisher
• ISBN: 1939327X (ISSN)
• DOI: 10.2337/db21-0574

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. © 2022 by the American Diabetes Association.