{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T14:41:40Z","timestamp":1787668900812,"version":"build-2736575974"},"reference-count":50,"publisher":"American Society for Clinical Investigation","issue":"1","license":[{"start":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:00:00Z","timestamp":1610323200000},"content-version":"vor","delay-in-days":34,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000041","name":"the American Diabetes Association","doi-asserted-by":"crossref","award":["1-19-PDF-117"],"award-info":[{"award-number":["1-19-PDF-117"]}],"id":[{"id":"10.13039\/100000041","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health grant","doi-asserted-by":"crossref","award":["1R01CA251698-01"],"award-info":[{"award-number":["1R01CA251698-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004917","name":"CPRIT","doi-asserted-by":"crossref","award":["RP180349,RP190077"],"award-info":[{"award-number":["RP180349,RP190077"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000928","name":"Welch Foundation","doi-asserted-by":"crossref","award":["I-1805"],"award-info":[{"award-number":["I-1805"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Arnold O. Beckman Research Award","award":["RB18061"],"award-info":[{"award-number":["RB18061"]}]},{"name":"National Institutes of Health R01 grants","award":["DK062777,DK095842"],"award-info":[{"award-number":["DK062777,DK095842"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,11]]},"abstract":"<jats:p>\n                    Activation of farnesoid X receptor (FXR) by obeticholic acid (OCA) reduces hepatic inflammation and fibrosis in patients with primary biliary cholangitis (PBC), a life-threatening cholestatic liver failure. Inhibition of bromodomain-containing protein 4 (BRD4) also has antiinflammatory, antifibrotic effects in mice. We determined the role of BRD4 in FXR function in bile acid (BA) regulation and examined whether the known beneficial effects of OCA are enhanced by inhibiting BRD4 in cholestatic mice. Liver-specific downregulation of BRD4 disrupted BA homeostasis in mice, and FXR-mediated regulation of BA-related genes, including small heterodimer partner and cholesterol 7 alpha-hydroxylase, was BRD4 dependent. In cholestatic mice, JQ1 or OCA treatment ameliorated hepatotoxicity, inflammation, and fibrosis, but surprisingly, was antagonistic in combination. Mechanistically, OCA increased binding of FXR, and the corepressor silencing mediator of retinoid and thyroid hormone receptor (SMRT) decreased NF-\u03baB binding at inflammatory genes and repressed the genes in a BRD4-dependent manner. In patients with PBC, hepatic expression of\n                    <jats:italic>FXR<\/jats:italic>\n                    and\n                    <jats:italic>BRD4<\/jats:italic>\n                    was significantly reduced. In conclusion, BRD4 is a potentially novel cofactor of FXR for maintaining BA homeostasis and hepatoprotection. Although BRD4 promotes hepatic inflammation and fibrosis in cholestasis, paradoxically, BRD4 is required for the antiinflammatory, antifibrotic actions of OCA-activated FXR. Cotreatment with OCA and JQ1, individually beneficial, may be antagonistic in treatment of liver disease patients with inflammation and fibrosis complications.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.141640","type":"journal-article","created":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T12:20:38Z","timestamp":1607430038000},"source":"Crossref","is-referenced-by-count":25,"title":["BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination"],"prefix":"10.1172","volume":"6","author":[{"given":"Hyunkyung","family":"Jung","sequence":"first","affiliation":[{"name":"Department of Molecular and Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangming","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0556-8212","authenticated-orcid":true,"given":"Hao","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shwu-Yuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Harold C. 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