TY - JOUR
T1 - BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination
AU - Jung, Hyunkyung
AU - Chen, Jinjing
AU - Hu, Xiangming
AU - Sun, Hao
AU - Wu, Shwu Yuan
AU - Chiang, Cheng Ming
AU - Kemper, Byron
AU - Chen, Lin Feng
AU - Kemper, Jongsook Kim
N1 - Funding Information:
We thank the Liver Tissue Cell Distribution System, University of Minnesota (NIH contract HHSN276201200017C), for providing liver specimens of PBC patients. We also thank Peter Tontonoz (University of California, Los Angeles) for providing the (NF-κB site)3-tk-luciferase plasmid. This study was supported by an American Diabetes Association postdoctoral fellowship (1-19-PDF-117) to JC; NIH (1R01CA251698-01), Cancer Prevention and Research Institute of Texas (RP180349 and RP190077), and Welch Foundation (I-1805) grants to CMC; an Arnold O. Beckman Research Award (RB18061) to LFC; and NIH R01 grants (DK062777 and DK095842) to JKK.
Funding Information:
We thank the Liver Tissue Cell Distribution System, University of Minnesota (NIH contract HHSN276201200017C), for providing liver specimens of PBC patients. We also thank Peter Tontonoz (University of California, Los Angeles) for providing the (NF-?B site)3-tk-luciferase plasmid. This study was supported by an American Diabetes Association postdoctoral fellowship (1-19-PDF-117) to JC; NIH (1R01CA251698-01), Cancer Prevention and Research Institute of Texas (RP180349 and RP190077), and Welch Foundation (I-1805) grants to CMC; an Arnold O. Beckman Research Award (RB18061) to LFC; and NIH R01 grants (DK062777 and DK095842) to JKK.
Publisher Copyright:
© 2021, Jung et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2021/1/11
Y1 - 2021/1/11
N2 - 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-κB binding at inflammatory genes and repressed the genes in a BRD4-dependent manner. In patients with PBC, hepatic expression of FXR and BRD4 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.
AB - 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-κB binding at inflammatory genes and repressed the genes in a BRD4-dependent manner. In patients with PBC, hepatic expression of FXR and BRD4 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.
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U2 - 10.1172/jci.insight.141640
DO - 10.1172/jci.insight.141640
M3 - Article
C2 - 33290278
AN - SCOPUS:85099293460
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 1
M1 - e141640
ER -