Affinage

NR1H4

Bile acid receptor · UniProt Q96RI1

Length
486 aa
Mass
55.9 kDa
Annotated
2026-06-10
100 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR1H4/FXR is a bile acid-activated nuclear receptor that binds DNA as a heterodimer with RXR to transcriptionally program enterohepatic bile acid homeostasis and a broad range of metabolic, proliferative, and immune processes (PMID:9223286, PMID:11150726). The primary bile acid chenodeoxycholic acid binds and activates FXR, which then mediates feedback suppression of CYP7A1 and activates intestinal bile acid transport genes (PMID:11150726); ligand specificity for bile acids is an evolutionarily acquired property of the receptor's ligand-binding domain (PMID:17567710). As a direct transcription factor, FXR binds defined response elements to control physiologically diverse targets: it represses ASBT through an FXR→SHP→FTF cascade (PMID:15591588), activates renal AQP2 to support urine concentration (PMID:24464484), induces SOCS3 to inhibit STAT3 and restrain hepatocellular carcinoma (PMID:26416445), induces Rubicon to block autophagosome-lysosome fusion and thereby suppress autophagy and ciliogenesis (PMID:29771182, PMID:32001325), and directly drives ACE2 expression in gastrointestinal and respiratory tissues, controlling susceptibility to SARS-CoV-2 (PMID:36470304). FXR activity is tuned by post-translational modifications: SUMOylation limits agonist responsiveness in activated hepatic stellate cells (PMID:31932588), SIRT6-mediated deacetylation elevates its transcriptional activity to confer hepatoprotection (PMID:35526796), and O-GlcNAcylation modulates its repressive interaction with ChREBP at glycolytic genes (PMID:25628602). The co-factor BRD4 is required for FXR-dependent bile acid gene regulation and for recruitment of the corepressor SMRT at inflammatory loci (PMID:33290278). Beyond the liver, FXR governs intestinal Lgr5+ cancer stem cell proliferation (PMID:30794774), ILC3-mediated IL-17 production (PMID:36508655), and T cell metabolic fitness during starvation (PMID:33318189), and intestinal FXR antagonism by the bile acid GUDCA mediates metformin's metabolic benefits (PMID:30397356).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 High

    Established that FXR is a DNA-binding nuclear receptor acting as an RXR heterodimer with a ligand-dependent activation function, before its physiological ligand was known.

    Evidence Transactivation reporter assays, AF-2 mutagenesis, and DNA-binding/ligand-binding assays

    PMID:9223286

    Open questions at the time
    • Endogenous activating ligand not identified
    • Direct retinoid binding could not be detected
  2. 2000 High

    Identified FXR as the bile acid receptor, defining the feedback logic linking bile acid sensing to suppression of synthesis and control of transport.

    Evidence Ligand-binding and transactivation assays with CDCA, plus CYP7A1 and IBABP target gene analysis

    PMID:11150726

    Open questions at the time
    • Structural basis of bile acid binding not resolved in this work
    • In vivo physiological scope beyond CYP7A1/IBABP not addressed
  3. 2005 High

    Worked out the FXR→SHP→FTF repression cascade controlling the bile acid transporter ASBT, showing FXR acts through indirect transcriptional repression as well as direct activation.

    Evidence In vivo rabbit feeding, ASBT promoter luciferase assays in Caco-2 cells, and FTF binding element deletion

    PMID:15591588

    Open questions at the time
    • Generalizability of the SHP-FTF cascade to other transporters not established here
  4. 2007 High

    Defined the molecular basis for bile acid ligand specificity, showing it was acquired by a deletion in the FXRalpha LBD relative to the ancestral FXRbeta.

    Evidence Phylogenetic analysis and LBD domain swap/deletion mutagenesis with reporter assays

    PMID:17567710

    Open questions at the time
    • Does not resolve atomic-level ligand contacts
  5. 2009 High

    Extended FXR function beyond transcription of metabolic genes to control of endothelial cell motility through a signaling kinase axis.

    Evidence Time-lapse microscopy, siRNA knockdown, and a phosphodeficient FAK(Y397) mutant linking FXR to MMP-9 and paxillin

    PMID:19150878

    Open questions at the time
    • Whether FAK/MMP-9 regulation is direct transcriptional vs. indirect not fully resolved
    • In vivo vascular relevance not tested
  6. 2010 Low

    Surveyed post-translational control of FXR, proposing SUMOylation and phosphorylation distinguish transactivation from transrepression.

    Evidence Review of PTM literature without original data described

    PMID:21130162

    Open questions at the time
    • Review without original experimental data
    • Specific modified residues and enzymes not defined here
  7. 2012 High

    Demonstrated FXR is a tumor suppressor in HCC by directly inducing SOCS3 to dampen STAT3 signaling.

    Evidence EMSA and ChIP showing FXR binding to an IR9 motif in the SOCS3 promoter, SOCS3 siRNA rescue, and xenograft model

    PMID:26416445

    Open questions at the time
    • Relevance to spontaneous (non-xenograft) HCC not established
    • Contribution relative to other FXR anti-tumor targets unclear
  8. 2014 High

    Established a renal role for FXR in water handling via direct transcriptional activation of AQP2.

    Evidence FXR KO mouse phenotyping, agonist treatment, AQP2 promoter reporter with FXRE identification, and collecting duct cell culture

    PMID:24464484

    Open questions at the time
    • Upstream physiological signals driving renal FXR activity not defined
  9. 2015 Medium

    Defined two metabolic regulatory layers: FXR transcribes Srebp-2/miR-33 while blocking SREBP-2 processing via INSIG-2A, and O-GlcNAcylation tunes FXR's repressive partnership with ChREBP at glycolytic genes.

    Evidence ChIP-seq FXRE identification with Scap-/- epistasis (Srebp-2/INSIG-2A); Co-IP, O-GlcNAcylation and reporter assays (ChREBP)

    PMID:25593129 PMID:25628602

    Open questions at the time
    • O-GlcNAc sites on FXR not mapped
    • Quantitative impact on systemic lipid/carbohydrate balance not established
  10. 2018 High

    Connected FXR to autophagy and ciliogenesis, showing FXR activation represses cilia formation by suppressing autophagy.

    Evidence Pharmacological activation and knockdown of FXR in cells, ppara-/- starvation kidney injury model, and autophagy inhibition experiments

    PMID:29771182

    Open questions at the time
    • Direct transcriptional target mediating autophagy suppression not yet identified in this study
  11. 2018 High

    Identified GUDCA as an intestinal FXR antagonist mediating metformin's metabolic benefits through a gut microbiome–FXR axis.

    Evidence Metagenomics/metabolomics, germ-free B. fragilis colonization, GUDCA FXR antagonism assays, and intestine-specific FXR mouse models

    PMID:30397356

    Open questions at the time
    • Downstream intestinal FXR targets driving the metabolic effect not fully mapped
    • Human translatability not established here
  12. 2019 High

    Showed FXR coordinates intestinal stem cell self-renewal with bile acid levels, restraining Lgr5+ cancer stem cell proliferation; and identified an FXR→Src→YAP renal anti-fibrotic pathway.

    Evidence Lgr5 lineage tracing, organoids, APC/high-fat cancer models (intestinal CSC); FXR KO, co-IP of Hippo kinases and Src phosphorylation immunoblotting (renal)

    PMID:30794774 PMID:31298930

    Open questions at the time
    • Whether Src/YAP regulation is direct transcriptional vs. signaling-level remains unresolved
    • Stem cell direct target genes not enumerated
  13. 2020 High

    Defined Rubicon and Perilipin-1 as direct FXR targets and SUMOylation as the mechanism of agonist resistance in activated stellate cells, linking FXR to autophagic flux and antifibrotic lipid droplet stability.

    Evidence FXR ChIP-seq, luciferase promoter assays, autophagic flux and Rubicon knockdown (Rubicon); SUMOylation assays, fibrosis mouse models and Perilipin-1 identification (HSC)

    PMID:31932588 PMID:32001325

    Open questions at the time
    • SUMO sites and responsible E3 ligase in activated HSCs not pinpointed
    • Interplay between autophagy suppression and stellate cell quiescence not integrated
  14. 2020 High

    Established FXR as a cell-intrinsic immune regulator, sensing starvation in T cells to limit their metabolic fitness, and identified BRD4 as a required FXR co-factor for bile acid gene regulation and SMRT/NF-κB control.

    Evidence T cell-specific FXR KO with metabolic flux analysis (T cells); liver-specific BRD4 knockdown with ChIP of FXR/SMRT/NF-κB (cofactor)

    PMID:33290278 PMID:33318189

    Open questions at the time
    • Direct FXR target genes controlling T cell metabolism not defined
    • Mechanism of BRD4 recruitment to FXR not resolved
  15. 2022 High

    Expanded FXR's regulatory reach to ACE2 transcription (controlling SARS-CoV-2 susceptibility), ILC3 maturation and IL-17 output, and SIRT6-mediated deacetylation as an activating modification conferring hepatoprotection.

    Evidence FXR ChIP and multi-model ACE2 studies (organoids, in vivo, ex vivo human organs); intestinal FXR activation with ILC profiling; SIRT6/FXR double-KO epistasis and deacetylation assays

    PMID:35526796 PMID:36470304 PMID:36508655

    Open questions at the time
    • FXR-acetylation residues targeted by SIRT6 not mapped
    • Mechanism by which FXR shapes ILC differentiation not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FXR's transcriptional outputs are integrated across tissues to produce coherent metabolic, immune, and proliferative programs, and the residue-level rules governing PTM-dependent switching, remain unresolved.
  • No unified map of PTM sites and their functional consequences
  • Tissue-specific cofactor and corepressor logic incompletely defined
  • Endogenous ligand-PTM crosstalk governing target selection unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 5 GO:0140299 molecular sensor activity 2
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1430728 Metabolism 4 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2
Partners
BRD4CHREBPRXRSHPSMRT

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 RIP14 (NR1H4/FXR) binds DNA as a heterodimer with RXR and can be activated by all-trans-retinoic acid and the synthetic retinoid TTNPB; mutagenesis of the ligand-dependent activation function (AF-2) demonstrated that TTNPB activates the RIP14 component of the RIP14-RXR heterodimer, while 9-cis-RA and LG1069 activate RXR. No direct binding of tRA or TTNPB to RIP14 was detected by multiple approaches, suggesting RIP14 responds to an as-yet-unidentified retinoid metabolite. Transactivation reporter assays, AF-2 domain mutagenesis, DNA-binding assays, ligand-binding assays (negative result for direct binding) Proceedings of the National Academy of Sciences of the United States of America High 9223286
2000 FXR functions as a bile acid receptor: chenodeoxycholic acid (CDCA), a primary bile acid, binds directly to and activates FXR. Activated FXR mediates feedback suppression of CYP7A1 (the rate-limiting enzyme in bile acid biosynthesis) and activates intestinal bile acid binding protein (IBABP) involved in enterohepatic circulation of bile acids. Ligand-binding assays, transactivation reporter assays, target gene expression analysis Trends in cardiovascular medicine High 11150726
2005 FXR-activating bile acid ligands repress rabbit ASBT (apical sodium-dependent bile acid transporter) expression via the regulatory cascade FXR→SHP→FTF (alpha-fetoprotein transcription factor). A cis-acting FTF binding site in the ASBT promoter is required for this repression; SHP inhibits FTF-dependent transactivation of the ASBT promoter. Non-FXR-activating bile acids (UDCA, ursocholic acid) do not repress ASBT. In vivo feeding experiments in rabbits, ASBT promoter cloning, luciferase reporter assays in Caco-2 cells, site-directed deletion of FTF binding element American journal of physiology. Gastrointestinal and liver physiology High 15591588
2007 The FXRalpha (NR1H4) ligand binding domain (LBD) acquired bile acid ligand specificity by deletion of a sequence present in the ancestral FXRbeta LBD. Deletion of the extra amino acids in skate FXRbeta and replacement with corresponding hFXRalpha sequence conferred responsiveness to ursodeoxycholic acid, GW4064, and fexaramine. All-trans retinoic acid was capable of transactivating both hFXRalpha and sFxr. Phylogenetic analysis, luciferase reporter assays, LBD domain deletion/replacement mutagenesis American journal of physiology. Regulatory, integrative and comparative physiology High 17567710
2009 FXR activation by the bile acid CDCA promotes endothelial cell motility and in vitro tube formation via a FXR→MMP-9→FAK(Y397 phosphorylation)→paxillin signaling axis. FAK phosphorylation at Y397 (but not Y576/577 or Y925) is required for CDCA-induced paxillin activation and downstream MMP-9 upregulation. FXR or MMP-9 siRNA knockdown abolished the motility increase. Time-lapse video microscopy, siRNA knockdown, site-specific phosphodeficient FAK mutant, immunoblotting Arteriosclerosis, thrombosis, and vascular biology High 19150878
2010 Multiple post-translational modifications regulate FXR transcriptional activity: SUMOylation and phosphorylation have been reported to distinguish between FXR-mediated transactivation and transrepression, with dysregulation of these modifications contributing to metabolic disease states. Review of PTM studies (biochemical analysis of SUMOylation and phosphorylation of FXR reported in the literature surveyed) Biochimica et biophysica acta Low 21130162
2012 FXR directly binds an IR9 DNA motif within the SOCS3 promoter region, inducing SOCS3 transcription. FXR-mediated SOCS3 induction inhibits STAT3 phosphorylation and HCC cell growth; siRNA knockdown of SOCS3 abrogated the anti-tumor effects of FXR activation. In vivo, GW4064 treatment decelerated HCC xenograft growth with up-regulated SOCS3 and p21 and inhibited STAT3 phosphorylation. Reporter assay, EMSA, chromatin immunoprecipitation (ChIP), siRNA knockdown, xenograft mouse model Oncotarget High 26416445
2014 FXR is expressed in renal tubules throughout the kidney. FXR directly binds and activates a response element in the AQP2 gene promoter, increasing AQP2 transcription in collecting duct cells. FXR knockout mice exhibit impaired urine concentrating ability and polyuria with reduced renal AQP2 expression; FXR agonist treatment increased urine osmolality and upregulated AQP2. FXR knockout mice phenotyping, FXR agonist/ligand treatment, AQP2 promoter luciferase reporter assay with FXR response element identification, primary inner medullary collecting duct cell culture Proceedings of the National Academy of Sciences of the United States of America High 24464484
2015 FXR activation by GW4064 in mice rapidly increases hepatic Srebp-2 mRNA, precursor SREBP-2 protein, and miR-33, yet does not increase nuclear SREBP-2 (nSREBP-2) or SREBP-2 target genes. FXR agonists induce INSIG-2A, which likely prevents processing of pSREBP-2 to nSREBP-2. FXR-dependent induction of both Srebp-2 and miR-33 requires transcription of the Srebp-2 gene (absent in Scap-/- mice). A ChIP-seq-identified FXR response element was found within intron 10 of Srebp-2. ChIP-seq (FXR response element identification), FXR agonist treatment in mice, Scap-/- epistasis, qPCR, immunoblotting Arteriosclerosis, thrombosis, and vascular biology High 25593129
2015 O-GlcNAcylation modifies FXR in response to glucose, and FXR directly interacts with ChREBP, acting as a repressor on the carbohydrate response element (ChoRE) of glycolytic genes. O-GlcNAcylation of FXR can modify its mutual affinity with ChREBP and their transcriptional activity. Co-immunoprecipitation, O-GlcNAcylation assays, reporter assays, interaction studies Frontiers in endocrinology Medium 25628602
2018 FXR activation represses cilia formation (ciliogenesis) by suppressing autophagy. Pharmacological activation of NR1H4/FXR in cells reduced cilia length/frequency, while knockdown of NR1H4 enhanced ciliogenesis by inducing autophagy. In vivo, NR1H4 agonist exacerbated starvation-induced kidney damage in ppara-/- mice by impairing the autophagy-ciliogenesis axis. Pharmacological activation and genetic knockdown of NR1H4 in cell lines, ppara-/- mouse model, autophagy inhibition experiments (pharmacological and genetic), ciliogenesis quantification Autophagy High 29771182
2019 FXR activation inhibits the nonreceptor tyrosine kinase Src (suppressing Tyr416 phosphorylation), which promotes YAP Ser127 phosphorylation and cytosolic retention, protecting against renal fibrosis. FXR agonist GW4064 increased interaction of hippo core kinases (MST1, LATS1, SAV1) and cytosolic accumulation of YAP in HK2 cells. FXR knockout mice showed increased expression of fibrosis, inflammatory, and YAP target genes in kidneys. FXR agonist treatment and FXR knockout mouse model, co-IP of hippo kinase complex, phosphorylation immunoblotting, siRNA (Src inhibitor PP2), unilateral ureteral obstruction model FASEB journal High 31298930
2020 FXR directly induces Rubicon (an inhibitor of autophagosome-lysosome fusion), identified as a direct FXR transcriptional target by FXR ChIP-seq and luciferase promoter studies in human cholestatic liver. FXR agonists (CDCA and OCA) inhibit autophagic flux at the autophagosome-to-lysosome fusion step in an FXR-dependent manner. Genetic inhibition of Rubicon reverses bile acid-induced impairment of autophagic flux. FXR ChIP-seq, luciferase promoter assays, autophagic flux assays, Rubicon genetic knockdown, FXR agonist/antagonist pharmacology in vitro Journal of hepatology High 32001325
2020 Activated hepatic stellate cells (HSCs) show limited response to FXR agonists due to enhanced FXR SUMOylation in activated HSCs. SUMOylation inhibitors rescue FXR signaling and increase the efficacy of FXR agonist OCA against HSC activation and fibrosis. FXR upregulates Perilipin-1 (a direct FXR target gene) to stabilize lipid droplets and prevent HSC activation. SUMOylation assays, FXR agonist treatment, luciferase reporter assays, CCl4/BDL/NASH mouse fibrosis models, Perilipin-1 target gene identification Nature communications High 31932588
2020 FXR functions as a T cell-intrinsic sensor mediating starvation-induced lymphocyte loss. T cell-specific deletion of FXR prevented starvation-induced loss of lymphocytes and increased effector T cell fitness in nutrient-limiting conditions. FXR deficiency increased contribution of glutamine and fatty acids toward respiration and enhanced cell survival under low-glucose conditions. T cell-specific FXR knockout, infection models with imposed feeding reduction, metabolic flux analysis (glutamine/fatty acid contribution to respiration), lymphocyte counting Proceedings of the National Academy of Sciences of the United States of America High 33318189
2022 FXR is a direct transcriptional regulator of ACE2 expression in gastrointestinal and respiratory tissues. FXR inhibition (by z-guggulsterone or UDCA) downregulates ACE2 in human lung, cholangiocyte, and intestinal organoids and in mouse/hamster tissues. Reduced FXR signaling decreases susceptibility to SARS-CoV-2 infection in vitro and in vivo. FXR ChIP (direct transcriptional regulation of ACE2), human organoids, mouse and hamster in vivo models, ex situ perfused human lungs and livers, nasal epithelium expression studies, SARS-CoV-2 infection assays Nature High 36470304
2022 FXR is expressed in innate lymphoid cells (ILCs) and acts as an intrinsic regulator of ILC biology. Intestinal FXR activation blocked inflammation-driven increases in ILCs (particularly ILC3s) and suppressed induction of Il17a and Il17f in ILC3s. A population of ILC precursor-like cells was increased with FXR activation, implicating FXR in ILC maturation/differentiation. Intestine-selective FXR activation, ILC population analysis by flow cytometry, cytokine expression measurement, IBD mouse models Proceedings of the National Academy of Sciences of the United States of America High 36508655
2022 SIRT6 deacetylates FXR, elevating its transcriptional activity. SIRT6-mediated deacetylation of FXR is required for the hepatoprotective effects of SIRT6 against APAP-induced hepatotoxicity; FXR ablation blunted SIRT6-overexpression-mediated protective effects, while pharmacological FXR activation rescued APAP-induced injury in SIRT6 KO mice. Hepatocyte-specific SIRT6 KO mice, FXR KO mice, SIRT6 overexpression/pharmacological activation, RNA-seq, deacetylation assays, epistasis (FXR ablation in SIRT6 OE context) Cellular and molecular gastroenterology and hepatology High 35526796
2020 BRD4 is a co-factor of FXR required for FXR-mediated bile acid gene regulation. Liver-specific downregulation of BRD4 disrupted bile acid homeostasis, and FXR-mediated regulation of BA-related genes (including SHP and CYP7A1) was BRD4-dependent. Mechanistically, OCA-activated FXR increased binding of the corepressor SMRT and decreased NF-κB binding at inflammatory genes in a BRD4-dependent manner. Liver-specific BRD4 knockdown, ChIP analysis of FXR/SMRT/NF-κB binding, FXR agonist treatment, cholestatic mouse models, gene expression analysis JCI insight High 33290278
2019 FXR regulates intestinal cancer stem cell (Lgr5+) proliferation. Bile acids that antagonize intestinal FXR (T-βMCA and DCA) induce proliferation and DNA damage in Lgr5+ cells, while selective intestinal FXR activation restricts abnormal Lgr5+ cell growth and curtails colorectal cancer progression. FXR coordinates intestinal self-renewal with bile acid levels. Lgr5-CreERT2 lineage tracing, intestinal organoids, mouse adenoma-to-adenocarcinoma model (APC mutation + high-fat diet), selective intestinal FXR activation/antagonism, DNA damage quantification Cell High 30794774
2018 Metformin acts in part through a B. fragilis–GUDCA–intestinal FXR axis to improve metabolic dysfunction. GUDCA was identified as an intestinal FXR antagonist; colonization with B. fragilis abolished metformin's metabolic benefits on glucose intolerance. Metformin decreases gut B. fragilis leading to increased GUDCA which inhibits intestinal FXR signaling. Metagenomic and metabolomic analysis, germ-free mouse colonization, GUDCA FXR antagonism assays, intestinal FXR-specific mouse models Nature medicine High 30397356

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nature medicine 808 30397356
2006 LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annual review of physiology 492 16460270
2015 New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. Journal of hepatology 410 25920087
2019 FXR Regulates Intestinal Cancer Stem Cell Proliferation. Cell 379 30794774
2015 Bile acid nuclear receptor FXR and digestive system diseases. Acta pharmaceutica Sinica. B 364 26579439
2020 Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism. Cell metabolism 355 33338411
2008 FXR: a metabolic regulator and cell protector. Cell research 348 18825165
2015 Bile Acids as Hormones: The FXR-FGF15/19 Pathway. Digestive diseases (Basel, Switzerland) 345 26045265
2012 FXR signaling in the enterohepatic system. Molecular and cellular endocrinology 307 22609541
2006 FXR, a multipurpose nuclear receptor. Trends in biochemical sciences 290 16908160
2022 FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature 235 36470304
2010 Deciphering the nuclear bile acid receptor FXR paradigm. Nuclear receptor signaling 234 21383957
2017 FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity. Journal of the American Society of Nephrology : JASN 191 29089371
2021 Farnesoid X receptor (FXR): Structures and ligands. Computational and structural biotechnology journal 187 33995909
2007 FXR signaling in metabolic disease. FEBS letters 178 18023284
2017 Nutrient-sensing nuclear receptors PPARα and FXR control liver energy balance. The Journal of clinical investigation 166 28287408
2020 Bile Acids and FXR: Novel Targets for Liver Diseases. Frontiers in medicine 153 33015098
2018 Update on FXR Biology: Promising Therapeutic Target? International journal of molecular sciences 151 30013008
2011 FXR and PXR: potential therapeutic targets in cholestasis. The Journal of steroid biochemistry and molecular biology 131 21801835
2022 Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis. International journal of molecular sciences 130 35682726
2023 FXR agonists in NASH treatment. Journal of hepatology 129 37562746
2010 Bile acids and their nuclear receptor FXR: Relevance for hepatobiliary and gastrointestinal disease. Biochimica et biophysica acta 129 20399894
2020 SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis. Nature communications 128 31932588
2021 FXR in liver physiology: Multiple faces to regulate liver metabolism. Biochimica et biophysica acta. Molecular basis of disease 122 33771667
2019 Bile Acid-Activated Receptors: A Review on FXR and Other Nuclear Receptors. Handbook of experimental pharmacology 115 31230143
2021 Gut microbiota depletion exacerbates cholestatic liver injury via loss of FXR signalling. Nature metabolism 103 34552267
2000 FXR, a bile acid receptor and biological sensor. Trends in cardiovascular medicine 103 11150726
2016 Fatty liver diseases, bile acids, and FXR. Acta pharmaceutica Sinica. B 97 27709009
2010 A role of the bile salt receptor FXR in atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology 94 20631352
2010 Regulation of FXR transcriptional activity in health and disease: Emerging roles of FXR cofactors and post-translational modifications. Biochimica et biophysica acta 94 21130162
2005 Role of FXR in regulating bile acid homeostasis and relevance for human diseases. Current drug targets. Immune, endocrine and metabolic disorders 93 16178789
2019 Targeting FXR in Cholestasis. Handbook of experimental pharmacology 92 31201556
2012 Anti-inflammatory and metabolic actions of FXR: insights into molecular mechanisms. Biochimica et biophysica acta 92 22820415
2014 Tissue-specific actions of FXR in metabolism and cancer. Biochimica et biophysica acta 89 25139561
1997 Activation of the orphan receptor RIP14 by retinoids. Proceedings of the National Academy of Sciences of the United States of America 80 9223286
2023 FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid. Medicinal research reviews 79 37899676
2014 Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice. Proceedings of the National Academy of Sciences of the United States of America 79 24464484
2017 Bile acids and colon cancer: Is FXR the solution of the conundrum? Molecular aspects of medicine 76 28400119
2014 FXR and liver carcinogenesis. Acta pharmacologica Sinica 75 25500874
2013 FXR silencing in human colon cancer by DNA methylation and KRAS signaling. American journal of physiology. Gastrointestinal and liver physiology 74 24177031
2010 FXR an emerging therapeutic target for the treatment of atherosclerosis. Journal of cellular and molecular medicine 74 20041971
2005 FXR-activating ligands inhibit rabbit ASBT expression via FXR-SHP-FTF cascade. American journal of physiology. Gastrointestinal and liver physiology 74 15591588
2017 Nuclear receptor FXR, bile acids and liver damage: Introducing the progressive familial intrahepatic cholestasis with FXR mutations. Biochimica et biophysica acta. Molecular basis of disease 73 28965883
2022 FXR: structures, biology, and drug development for NASH and fibrosis diseases. Acta pharmacologica Sinica 72 35217809
2018 FXR modulators for enterohepatic and metabolic diseases. Expert opinion on therapeutic patents 70 30259754
2023 Akkermansia muciniphila and Bifidobacterium bifidum Prevent NAFLD by Regulating FXR Expression and Gut Microbiota. Journal of clinical and translational hepatology 69 37408808
2019 Nonsteroidal FXR Ligands: Current Status and Clinical Applications. Handbook of experimental pharmacology 68 31197565
2022 Recent advances on FXR-targeting therapeutics. Molecular and cellular endocrinology 67 35605722
2017 Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression. Biochimica et biophysica acta. Molecular basis of disease 64 28916388
2021 The Pathophysiology of Farnesoid X Receptor (FXR) in the GI Tract: Inflammation, Barrier Function and Innate Immunity. Cells 63 34831429
2020 FXR-dependent Rubicon induction impairs autophagy in models of human cholestasis. Journal of hepatology 61 32001325
2021 Targeting Farnesoid X receptor (FXR) for developing novel therapeutics against cancer. Molecular biomedicine 60 35006466
2018 Simultaneous inhibition of FXR and TGR5 exacerbates atherosclerotic formation. Journal of lipid research 55 29976576
2022 FXR mediates ILC-intrinsic responses to intestinal inflammation. Proceedings of the National Academy of Sciences of the United States of America 54 36508655
2019 Src-mediated crosstalk between FXR and YAP protects against renal fibrosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 53 31298930
2022 Immunomodulatory functions of FXR. Molecular and cellular endocrinology 51 35472625
2022 A new perspective on NAFLD: Focusing on the crosstalk between peroxisome proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR). Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 51 35988420
2021 Fxr signaling and microbial metabolism of bile salts in the zebrafish intestine. Science advances 51 34301599
2008 FXR, a target for different diseases. Histology and histopathology 50 18283647
2015 FXR induces SOCS3 and suppresses hepatocellular carcinoma. Oncotarget 48 26416445
2014 Targeting FXR in cholestasis: hype or hope. Expert opinion on therapeutic targets 48 25200104
2012 Association of genetic variation in the NR1H4 gene, encoding the nuclear bile acid receptor FXR, with inflammatory bowel disease. BMC research notes 47 22929053
2010 Nuclear bile acid receptor FXR in the hepatic regeneration. Biochimica et biophysica acta 47 21167938
2024 Regulation of bile acids and their receptor FXR in metabolic diseases. Frontiers in nutrition 46 39726876
2006 FXR: a target for cholestatic syndromes? Expert opinion on therapeutic targets 46 16706681
2022 Probiotic-derived nanoparticles inhibit ALD through intestinal miR194 suppression and subsequent FXR activation. Hepatology (Baltimore, Md.) 42 35689610
2007 The farnesoid X receptor FXRalpha/NR1H4 acquired ligand specificity for bile salts late in vertebrate evolution. American journal of physiology. Regulatory, integrative and comparative physiology 40 17567710
2018 Interaction of glucocorticoids with FXR/FGF19/FGF21-mediated ileum-liver crosstalk. Biochimica et biophysica acta. Molecular basis of disease 39 29883717
2012 Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders. Current topics in medicinal chemistry 38 22242859
2020 FXR mediates T cell-intrinsic responses to reduced feeding during infection. Proceedings of the National Academy of Sciences of the United States of America 37 33318189
2016 Bile Acids, FXR, and Metabolic Effects of Bariatric Surgery. Journal of obesity 37 27006824
2023 Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway. European journal of pharmacology 36 37263401
2017 Farnesoid-X Receptor (FXR) as a Promising Pharmaceutical Target in Atherosclerosis. Current medicinal chemistry 35 28120707
2021 Novel FXR agonist nelumal A suppresses colitis and inflammation-related colorectal carcinogenesis. Scientific reports 34 33436792
2019 Chemistry and Pharmacology of GPBAR1 and FXR Selective Agonists, Dual Agonists, and Antagonists. Handbook of experimental pharmacology 33 31201554
2009 FXR promotes endothelial cell motility through coordinated regulation of FAK and MMP-9. Arteriosclerosis, thrombosis, and vascular biology 33 19150878
2025 Bile acids affect intestinal barrier function through FXR and TGR5. Frontiers in medicine 32 40692955
2015 O-GlcNAcylation Links ChREBP and FXR to Glucose-Sensing. Frontiers in endocrinology 31 25628602
2018 Ciliogenesis is reciprocally regulated by PPARA and NR1H4/FXR through controlling autophagy in vitro and in vivo. Autophagy 30 29771182
2012 The significance of the nuclear farnesoid X receptor (FXR) in β cell function. Islets 30 23073079
2021 MECHANISMS IN ENDOCRINOLOGY: FXR signalling: a novel target in metabolic diseases. European journal of endocrinology 28 33630750
2021 Post-Translational Modifications of FXR; Implications for Cholestasis and Obesity-Related Disorders. Frontiers in endocrinology 28 34646233
2013 Genetic variation in NR1H4 encoding the bile acid receptor FXR determines fasting glucose and free fatty acid levels in humans. The Journal of clinical endocrinology and metabolism 28 23640969
2022 Farnesoid X receptor (FXR) agonists induce hepatocellular apoptosis and impair hepatic functions via FXR/SHP pathway. Archives of toxicology 27 35267068
2020 BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination. JCI insight 27 33290278
2017 A novel intestinal-restricted FXR agonist. Bioorganic & medicinal chemistry letters 27 28629595
2023 FXR and NASH: an avenue for tissue-specific regulation. Hepatology communications 26 37058105
2015 The nuclear receptor FXR uncouples the actions of miR-33 from SREBP-2. Arteriosclerosis, thrombosis, and vascular biology 26 25593129
2014 Medicinal chemistry and pharmacological effects of Farnesoid X Receptor (FXR) antagonists. Current topics in medicinal chemistry 26 25388533
2020 Design and Structural Optimization of Dual FXR/PPARδ Activators. Journal of medicinal chemistry 25 32687365
2022 Hepatic SIRT6 Modulates Transcriptional Activities of FXR to Alleviate Acetaminophen-induced Hepatotoxicity. Cellular and molecular gastroenterology and hepatology 24 35526796
2020 Bile acid treatment and FXR agonism lower postprandial lipemia in mice. American journal of physiology. Gastrointestinal and liver physiology 24 32003602
2022 Dihydroartemisinin promoted FXR expression independent of YAP1 in hepatocellular carcinoma. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 35616366
2012 Farnesoid X Receptor (FXR) from normal to malignant state. Histology and histopathology 23 22648540
2023 Role of FXR in Renal Physiology and Kidney Diseases. International journal of molecular sciences 22 36768731
2022 Pleiotropic roles of FXR in liver and colorectal cancers. Molecular and cellular endocrinology 22 34995680
2017 The bile acid receptor FXR attenuates acinar cell autophagy in chronic pancreatitis. Cell death discovery 22 28660075
2024 Bruceine A alleviates alcoholic liver disease by inhibiting AIM2 inflammasome activation via activating FXR. Phytomedicine : international journal of phytotherapy and phytopharmacology 21 38763006
2018 Bile acids and FXR in functional gastrointestinal disorders. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 21 29908754
2005 FXR, a therapeutic target for bile acid and lipid disorders. Mini reviews in medicinal chemistry 21 16101408

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