Bromodomain inhibition reveals FGF15/19 as a target of epigenetic regulation and metabolic control Journal Article
| Authors: | Kozuka, C.; Efthymiou, V.; Sales, V. M.; Zhou, L.; Osataphan, S.; Yuchi, Y.; Chimene-Weiss, J.; Mulla, C.; Isganaitis, E.; Desmond, J.; Sanechika, S.; Kusuyama, J.; Goodyear, L.; Shi, X.; Gerszten, R. E.; Aguayo-Mazzucato, C.; Carapeto, P.; DaSilva Teixeira, S.; Sandoval, D.; Alonso-Curbelo, D.; Wu, L.; Qi, J.; Patti, M. E. |
| Article Title: | Bromodomain inhibition reveals FGF15/19 as a target of epigenetic regulation and metabolic control |
| Abstract: | 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. |
| Keywords: | genetics; mouse; animal; metabolism; animals; mice; nuclear protein; transcription factor; transcription factors; nuclear proteins; hyperglycemia; epigenesis, genetic; glucose; genetic epigenesis; fibroblast growth factor; fibroblast growth factors |
| Journal Title: | Diabetes |
| Volume: | 71 |
| Issue: | 5 |
| ISSN: | 0012-1797 |
| Publisher: | American Diabetes Association |
| Date Published: | 2022-05-01 |
| Start Page: | 1023 |
| End Page: | 1033 |
| Language: | English |
| DOI: | 10.2337/db21-0574 |
| PUBMED: | 35100352 |
| PROVIDER: | scopus |
| PMCID: | PMC9044127 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2022 -- Source: Scopus |
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