ArticleJCI insight2020
BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination.
Article in JCI insight, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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Who cites it
18 citing papers in PubMed, 28 citations in OpenAlex.
- Decoding fibroblast activation: Transcriptional networks in hepatic stellate cells and across fibrotic organs (Review).International journal of molecular medicine · 2026Review
- CD38 Inhibition Enhances FXR Signaling in Male Rats With Diabetic Steatohepatitis Through SIRT1-Dependent Suppression of NLRP3.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Stomach at the crossroads: nuclear receptor signaling at the interface between what we are and what we eat.Physiological reviews · 2026Review
- Chemical Epigenetics: Small Molecules Targeting Chromatin Modifiers in Disease Modulation.Cell biochemistry and biophysics · 2026Review
- FXR and BET signaling orchestrate to protect β cells.bioRxiv : the preprint server for biology · 2026Article
- Comparative analysis of Microtus fortis and murine hosts reveals a correlation between BRD4 and hepatic inflammation during Schistosoma japonicum infection.Parasites & vectors · 2025Article
- BRD4: an effective target for organ fibrosis.Biomarker research · 2024Review
- Article
- Hammerhead-type FXR agonists induce an eRNAbioRxiv : the preprint server for biology · 2024Article
- Combined inhibition of bile salt synthesis and intestinal uptake reduces cholestatic liver damage and colonic bile salts in mice.JHEP reports : innovation in hepatology · 2024Article
- Association between diabetes mellitus and primary biliary cholangitis: a two-sample Mendelian randomization study.Frontiers in endocrinology · 2024Article
- Bromodomain Inhibition Reveals FGF15/19 As a Target of Epigenetic Regulation and Metabolic Control.Diabetes · 2022Article
- Inflammatory and fibrotic mechanisms in NAFLD-Implications for new treatment strategies.Journal of internal medicine · 2022Review
- Physiological Role of Bile Acids Modified by the Gut Microbiome.Microorganisms · 2021Review
- Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis.Advanced drug delivery reviews · 2021Review
- Targeting Farnesoid X receptor (FXR) for developing novel therapeutics against cancer.Molecular biomedicine · 2021Review
- The long and the small collide: LncRNAs and small heterodimer partner (SHP) in liver disease.Molecular and cellular endocrinology · 2021Review
- Obeticholic Acid Derivative, T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling Pathway.International journal of molecular sciences · 2021Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 2 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.