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

Author:

Kozuka Chisayo12ORCID,Efthymiou Vissarion12,Sales Vicencia M.12,Zhou Liyuan1,Osataphan Soravis12,Yuchi Yixing12,Chimene-Weiss Jeremy1,Mulla Christopher12,Isganaitis Elvira12,Desmond Jessica1,Sanechika Suzuka1,Kusuyama Joji12,Goodyear Laurie12,Shi Xu23,Gerszten Robert E.24,Aguayo-Mazzucato Cristina12ORCID,Carapeto Priscila12,Teixeira Silvania DaSilva5,Sandoval Darleen5ORCID,Alonso-Curbelo Direna6,Wu Lei23,Qi Jun23,Patti Mary-Elizabeth12ORCID

Affiliation:

1. Section of Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Boston, MA

2. Harvard Medical School, Boston, MA

3. Dana-Farber Cancer Institute, Boston, MA

4. Cardiology Division, Beth Israel Deaconess Medical Center, Boston, MA

5. Department of Pediatrics, University of Colorado, Denver, CO

6. Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY

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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

Cited by 4 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3