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BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination
Hyunkyung Jung, … , Lin-Feng Chen, Jongsook Kim Kemper
Hyunkyung Jung, … , Lin-Feng Chen, Jongsook Kim Kemper
Published December 8, 2020
Citation Information: JCI Insight. 2021;6(1):e141640. https://doi.org/10.1172/jci.insight.141640.
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Research Article Hepatology Inflammation

BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination

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Abstract

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.

Authors

Hyunkyung Jung, Jinjing Chen, Xiangming Hu, Hao Sun, Shwu-Yuan Wu, Cheng-Ming Chiang, Byron Kemper, Lin-Feng Chen, Jongsook Kim Kemper

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Figure 2

BRD4 coactivates FXR for induction of Shp.

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BRD4 coactivates FXR for induction of Shp.
(A) Co-IP: C57BL/6 mice were ...
(A) Co-IP: C57BL/6 mice were treated with GW4064 or vehicle for 1 hour. The indicated proteins in anti-FXR immune complexes from liver whole-cell extracts or input levels detected by immunoblot. (B) Reporter assay: HepG2 cells were infected with Ad-FXR, transfected with reporter plasmids for Shp-luc and β-galactosidase, and treated with GW4064, JQ1, or Brd4 siRNA (siBrd4) as indicated. Luciferase activities normalized to β-galactosidase levels. (C and D) RT-qPCR: PMHs were treated with siBrd4, JQ1, or GW4064 as indicated, and levels of mRNA for Brd4, Shp, and Cyp7a1 in hepatocytes were determined by RT-qPCR. (E–F) C57BL/6 mice were treated daily with 30 mg/kg GW4064, 10 mg/kg OCA, or 50 mg/kg JQ1 for 7 days as indicated. (E) Experimental outline. (F) Levels of indicated mRNAs. (B–D and F) Mean ± SD. Statistical significance was determined by 1-way (B, r = 3 culture dishes) or 2-way ANOVA (C and D, r = 3 culture dishes; F, r = 6–8 mice), *P < 0.05, **P < 0.01, ***P < 0.001.
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