{"doi":"10.2337/db21-0574","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.","journal":"Diabetes","year":2022,"id":280384,"datarank":0.5478877093778629,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.18820341845810717,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.18820341845810717,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":10,"citers_with_citation_signal":8,"citers_with_endowment":8,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9616,"is_data_producer":true,"deposit_databanks":{"figshare":["10.2337/figshare.19064309"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":954827,"name":"Vissarion Efthymiou","orcid":"0000-0003-4327-7977","position":1,"is_corresponding":false},{"id":955324,"name":"Vicência Sales","orcid":null,"position":2,"is_corresponding":false},{"id":954828,"name":"Liyuan Zhou","orcid":"0000-0002-8636-9217","position":3,"is_corresponding":false},{"id":746389,"name":"Soravis Osataphan","orcid":"0000-0002-6503-4418","position":4,"is_corresponding":false},{"id":310372,"name":"Yixing Yuchi","orcid":"0000-0002-9439-0913","position":5,"is_corresponding":false},{"id":954829,"name":"Jeremy Chimene-Weiss","orcid":"0000-0003-3345-7720","position":6,"is_corresponding":false},{"id":667449,"name":"Christopher M. 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