Affinage

NR1H4

Bile acid receptor · UniProt Q96RI1

Round 2 corrected
Length
486 aa
Mass
55.9 kDa
Annotated
2026-04-29
130 papers in source corpus 42 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR1H4 (FXR) is a bile acid-activated nuclear receptor that heterodimerizes with RXR to bind bile acid response elements and transcriptionally coordinate bile acid synthesis, transport, lipid and glucose metabolism, autophagy, intestinal barrier integrity, and innate immune responses (PMID:10334992, PMID:11030617, PMID:25383523, PMID:19864602). FXR represses bile acid biosynthesis through two major cascades: an intracellular FXR→SHP→LRH-1 pathway that silences CYP7A1, and an endocrine FXR→FGF19→FGFR4→JNK axis that suppresses hepatic CYP7A1 from the intestine (PMID:11030332, PMID:12815072). FXR transrepresses NF-κB-dependent inflammatory genes by stabilizing the corepressor NCoR on target promoters, and in the fed state it suppresses hepatic autophagy by competing with CREB–CRTC2 at autophagy gene promoters (PMID:19864602, PMID:25383523). FXR transcriptional activity is post-translationally tuned by CK2-dependent SUMOylation at K325/S327 (coupled to RNF4-mediated proteasomal turnover), by SIRT1/SIRT6-controlled deacetylation at K217 governing importin KPNA3-mediated nuclear import, by phosphorylation at T442 controlling CRM1-dependent nuclear export, and by BRD4-dependent coactivation (PMID:28201649, PMID:36873184, PMID:35526796, PMID:33290278).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1995 High

    Identification of NR1H4 as a ligand-modulated orphan nuclear receptor that heterodimerizes with RXR established it as a transcription factor responsive to isoprenoid metabolites, setting the stage for ligand deorphanization.

    Evidence Receptor cloning, farnesol activation assays, and RXR heterodimerization assays in mammalian cells

    PMID:7774010

    Open questions at the time
    • Physiological ligand unidentified
    • No in vivo target genes known
    • Tissue-specific roles undefined
  2. 1999 High

    Identification of bile acids as the endogenous FXR ligands and demonstration that FXR represses CYP7A1 while inducing IBABP transformed the receptor from an orphan into the central bile acid sensor governing enterohepatic circulation.

    Evidence Radioligand binding, reporter assays, and Northern blot for CYP7A1/IBABP across three independent labs

    PMID:10334992 PMID:10334993 PMID:10360171

    Open questions at the time
    • Molecular mechanism of CYP7A1 repression unknown
    • In vivo confirmation in knockout animals pending
  3. 2000 High

    The FXR→SHP→LRH-1 cascade and FXR-null mouse phenotype jointly defined the molecular pathway for bile acid feedback repression of CYP7A1 and established FXR as essential for bile acid and lipid homeostasis in vivo.

    Evidence Epistatic reporter/expression analysis of SHP-LRH-1 cascade; FXR knockout mice with elevated serum bile acids, cholesterol, and triglycerides

    PMID:11030331 PMID:11030332 PMID:11030617

    Open questions at the time
    • SHP-independent repression mechanisms unexplored
    • FXR roles beyond liver not yet characterized
  4. 2003 High

    Discovery that FXR induces intestinal FGF19, which signals through FGFR4–JNK to repress hepatic CYP7A1, revealed a second, endocrine axis for bile acid feedback that operates across the gut–liver axis.

    Evidence FXR agonist induction of FGF19 in hepatocytes, JNK inhibitor studies, CYP7A1 reporter assays

    PMID:12815072

    Open questions at the time
    • Relative contributions of SHP vs FGF19 axes in humans unclear
    • FGF19 regulation of non-bile-acid targets not defined
  5. 2006 High

    FXR was shown to regulate glucose metabolism through SHP-dependent repression of gluconeogenic genes and enhanced insulin sensitivity, and to be required for liver regeneration after partial hepatectomy, broadening its role beyond bile acid homeostasis.

    Evidence GW4064 treatment and adenoviral FXR overexpression in db/db mice; hyperinsulinemic clamp in FXR-null mice; partial hepatectomy in FXR-null mice

    PMID:16410358 PMID:16557297 PMID:16614213

    Open questions at the time
    • Direct FXR target genes for gluconeogenesis incompletely mapped
    • Whether regeneration defect is cell-autonomous or bile acid-mediated unclear
  6. 2009 High

    FXR was established as an anti-inflammatory transcription factor in innate immune cells, acting through NCoR stabilization on NF-κB-dependent promoters, and as a regulator of endothelial cell motility via FAK–paxillin–MMP-9 signaling.

    Evidence ChIP for NCoR on IL-1β promoter in macrophages; FXR-null colitis models; siRNA/phosphodeficient FAK mutant in endothelial cells

    PMID:19150878 PMID:19864602

    Open questions at the time
    • FXR target gene specificity in immune cells beyond NF-κB unclear
    • Physiological relevance of endothelial FXR signaling in vivo not confirmed
  7. 2014 High

    Genome-wide ChIP-seq revealed that FXR suppresses hepatic autophagy in the fed state by directly occupying autophagy gene promoters and disrupting CREB–CRTC2 coactivator complexes, linking nutrient sensing to autophagic flux.

    Evidence ChIP-seq in mouse liver, CREB–CRTC2 co-IP disruption, autophagy flux assays in FXR-null mice

    PMID:25383523 PMID:25383539

    Open questions at the time
    • Whether FXR directly represses autophagy in non-hepatic tissues not established
    • Structural basis for CREB–FXR competition unknown
  8. 2017 High

    Definition of the CK2→pS327→SUMO2-K325→RNF4 ubiquitin–proteasome axis revealed that SUMOylation is a dual-purpose post-translational switch that both licenses FXR transcriptional activity and programs its degradation.

    Evidence Site-directed mutagenesis (K325R, S327A/E), Co-IP of SUMO2/ubiquitin, RNF4 knockdown, ChIP

    PMID:28201649

    Open questions at the time
    • In vivo quantitative contribution of SUMOylation to FXR turnover unknown
    • Whether other E3 ligases cooperate with RNF4 not tested
  9. 2022 High

    Mapping of acetylation at K217 (controlling KPNA3-dependent nuclear import) and phosphorylation at T442 (controlling CRM1-dependent nuclear export), together with identification of CHIP as the cytosolic E3 ligase for FXR, defined a complete nucleocytoplasmic trafficking code that is disrupted in liver injury.

    Evidence Acetylation/phosphorylation site mutagenesis, importin/exportin binding assays, CHIP Co-IP, SIRT1 activator rescue in liver injury models

    PMID:36873184

    Open questions at the time
    • Kinase responsible for T442 phosphorylation not identified
    • Whether the same trafficking code operates in intestinal FXR is unknown
  10. 2022 High

    FXR was identified as a direct transcriptional regulator of ACE2 in gastrointestinal and respiratory epithelia, with FXR inhibition by UDCA reducing SARS-CoV-2 susceptibility, revealing an unexpected connection between bile acid signaling and viral entry.

    Evidence FXR agonist/antagonist treatment in human organoids, ex vivo perfused human lungs, mouse and hamster in vivo models, SARS-CoV-2 infection assays

    PMID:36470304

    Open questions at the time
    • Long-term consequences of FXR-mediated ACE2 suppression on cardiometabolic function unknown
    • Whether FXR regulates other viral receptors unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for FXR's competition with CREB at autophagy promoters, the kinase(s) governing T442 phosphorylation, the relative tissue-specific contributions of hepatic versus intestinal FXR to metabolic disease, and the full scope of FXR's immune-regulatory transcriptome.
  • No co-crystal structure of FXR with CREB–CRTC2 exists
  • No systematic comparison of hepatic vs intestinal FXR cistrome in humans
  • T442 kinase identity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 4 GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 7 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 8 R-HSA-74160 Gene expression (Transcription) 8 R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3 R-HSA-168256 Immune System 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-9612973 Autophagy 2 R-HSA-8953854 Metabolism of RNA 1
Partners
BRD4CHIPKPNA3NCOR1NR0B2RNF4RXRAXPO1
Complex memberships
FXR-RXR heterodimer

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 NR1H4 (then called FXR) was identified as an orphan nuclear receptor that forms a heterodimeric complex with retinoid X receptor (RXR) and is activated by farnesol and related metabolites, establishing it as a ligand-modulated transcription factor. Receptor isolation, ligand screening, heterodimerization assays Cell High 7774010
1997 RIP14 (NR1H4) can be activated by all-trans-retinoic acid and the synthetic retinoid TTNPB; it binds DNA as a heterodimer with RXR, and mutagenesis of the ligand-dependent activation function showed TTNPB activates the RIP14 component while 9-cis-RA and LG1069 activate the RXR component. Reporter gene activation assays, site-directed mutagenesis of AF-2 domain, DNA binding assays Proceedings of the National Academy of Sciences of the United States of America High 9223286
1999 Bile acids (chenodeoxycholic acid, lithocholic acid, deoxycholic acid) are physiological ligands for FXR/NR1H4; ligand-bound FXR repressed CYP7A1 transcription (rate-limiting enzyme in bile acid synthesis) and activated intestinal bile acid-binding protein (IBABP) expression, establishing FXR as a bile acid sensor that transcriptionally regulates bile acid biosynthesis and enterohepatic transport. Radioligand binding assays, reporter gene assays, Northern blot analysis of CYP7A1 and IBABP Science High 10334992 10334993 10360171
1999 Physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid, and deoxycholic acid activate FXR and promote coactivator (SRC-1 peptide) recruitment, demonstrating a nuclear bile acid signaling pathway. Transactivation assays, coactivator interaction assays (SRC-1 peptide recruitment) Science High 10334993
2000 FXR induces expression of SHP-1 (small heterodimer partner), which then represses CYP7A1 by inhibiting the activity of LRH-1 (liver receptor homolog-1); this FXR→SHP-1→LRH-1 regulatory cascade provides the molecular basis for bile acid feedback suppression of CYP7A1. Nonsteroidal FXR ligand treatment, reporter assays, mRNA expression analysis, epistasis with SHP-1 and LRH-1 Molecular cell High 11030331 11030332
2000 Targeted disruption of FXR/BAR in mice resulted in elevated serum bile acids, cholesterol, and triglycerides; increased hepatic cholesterol and triglycerides; reduced bile acid pools; and loss of bile acid-mediated regulation of CYP7A1 and IBABP, establishing FXR's in vivo role as an intracellular bile acid sensor critical for bile acid and lipid homeostasis. FXR knockout mice, serum lipid measurements, hepatic lipid measurements, gene expression analysis Cell High 11030617
2000 FXR (as an RXR heterodimer) activates ABC1 expression and represses CYP7A1; rexinoid treatment phenocopies these effects, establishing FXR-RXR as a key regulator of reverse cholesterol transport and bile acid synthesis downstream of bile acid sensing. Receptor-selective agonist treatment in mice, gene expression analysis, ABC1 and CYP7A1 reporter assays Science High 10968783
2002 Guggulsterone is a highly efficacious antagonist of FXR; its cholesterol-lowering activity depends on FXR, as guggulsterone failed to decrease hepatic cholesterol in FXR-null mice fed a high-cholesterol diet. FXR reporter assays, FXR knockout mice, high-cholesterol diet model Science High 11988537
2003 FXR directly regulates expression of FGF19 (FGF-15 in mice), a secreted growth factor; FGF19 signals through FGFR4 to strongly suppress CYP7A1 expression in hepatocytes via a c-Jun N-terminal kinase (JNK)-dependent pathway, defining a novel endocrine feedback loop for repression of bile acid biosynthesis. FXR agonist treatment, FGF19 expression in primary hepatocytes, FGFR4 signaling, JNK pathway inhibitor studies, CYP7A1 reporter assays Genes & development High 12815072
2003 FXR activates the human PPARα gene promoter via a defined FXR response element (αFXRE) in the PPARα promoter, as shown by gel shift analysis (FXR binding to αFXRE), cotransfection assays, and mutation analysis; this cross-talk is species-specific (not present in mice). Gel shift (EMSA), cotransfection with FXR/RXR, mutation analysis, reporter assays in HepG2 cells and primary hepatocytes Molecular endocrinology High 12554753
2005 FXR-activating ligands downregulate rabbit ASBT (apical sodium-dependent bile acid transporter) expression through the regulatory cascade FXR→SHP→FTF (alpha-fetoprotein transcription factor); a functional FTF binding site at -1166/-1158 of the rabbit ASBT promoter is required, and only FXR-activating ligands (not non-activating bile acids) repress ASBT. In vivo rabbit feeding experiments, promoter cloning and deletion analysis, Caco-2 cell transfection, mRNA quantification American journal of physiology. Gastrointestinal and liver physiology High 15591588
2006 FXR activation by GW4064 or constitutively active FXR adenovirus significantly lowered blood glucose in diabetic db/db mice by repressing hepatic gluconeogenic genes and increasing hepatic glycogen synthesis via enhanced insulin sensitivity; FXR-null mice showed glucose intolerance and insulin insensitivity, with blunted insulin signaling in skeletal muscle and liver. The FXR-SHP cascade mediates glucose metabolism. FXR agonist (GW4064) treatment, adenoviral FXR overexpression, FXR knockout mice, hyperinsulinemic euglycemic clamp, gene expression analysis Proceedings of the National Academy of Sciences / Journal of Clinical Investigation High 16410358 16557297
2006 Androsterone (a testosterone metabolite) directly binds the FXR ligand-binding domain (LBD) as shown by NMR spectroscopy, recruits SRC-1 coactivator peptide, and activates FXR; site-directed mutagenesis of hFXR-LBD identified Asn354 and Ser345 as critical for differential species sensitivity to CDCA and androsterone, respectively. Crystal structure-guided mutations (M265I, R331H) further dissected the binding mode. NMR spectroscopy of purified hFXR-LBD, site-directed mutagenesis, Gal4-LBD reporter assays, in vivo androsterone treatment of castrated mice Endocrinology High 16675527
2006 FXR-null mice have reduced expression of the major hepatic canalicular bile acid transport protein (BSEP); nuclear receptor-dependent bile acid signaling via FXR is required for normal liver regeneration after partial hepatectomy, as decreased bile acid levels inhibit liver regrowth and FXR absence prevents normal regeneration. FXR knockout mice, partial hepatectomy model, bile acid manipulation, gene expression analysis Science High 16614213
2007 FXRα (NR1H4) acquired ligand specificity for bile salts late in vertebrate evolution; deletion of an extra LBD sequence in a FXRβ homolog from skate (which normally responds weakly to bile salts) conferred responsiveness to GW4064 and ursodeoxycholic acid, demonstrating that the bile acid-binding specificity of FXRα is conferred by the structure of its LBD. Phylogenetic analysis, luciferase reporter assays, LBD deletion mutagenesis in heterologous cells American journal of physiology. Regulatory, integrative and comparative physiology Medium 17567710
2008 FXR directly induces GLUT4 transcription through a defined FXR response element (FXRE) in the GLUT4 promoter; EMSA and RXR knockdown showed FXR binds the GLUT4-FXRE as a monomer (RXR-independent); FXR activation does not interfere with insulin-induced GLUT4 translocation to the plasma membrane. 5'-deletion and site-mutation analysis of GLUT4 promoter, EMSA, RXR siRNA knockdown, in vivo CDCA treatment Cellular physiology and biochemistry High 18769028
2009 FXR activation by CDCA promotes endothelial cell motility and tube formation via FAK phosphorylation at Y397 (but not Y576/577 or Y925), which activates paxillin; FAK phosphorylation at Y397 is required for CDCA-induced MMP-9 upregulation; both FXR and MMP-9 siRNA blocked CDCA-induced motility, establishing a FXR→FAK(pY397)→paxillin→MMP-9 pathway for EC motility. Time-lapse video microscopy, siRNA knockdown of FXR/MMP-9/FAK, phosphodeficient FAK mutant, phospho-specific immunoblotting Arteriosclerosis, thrombosis, and vascular biology High 19150878
2009 FXR is expressed by cells of innate immunity (macrophages, dendritic cells); FXR activation stabilizes the nuclear corepressor NCoR on the NF-κB responsive element of the IL-1β promoter, thereby transrepressing NF-κB-dependent inflammatory genes (TNF-α, IL-1β, IL-6, COX-1, COX-2, iNOS); FXR-null mice show exacerbated colitis. FXR-null mice colitis models (TNBS, DSS), LPS-activated macrophage treatment, ChIP (NCoR on IL-1β promoter), gene expression analysis Journal of immunology High 19864602
2011 FXR activation by INT-747 (obeticholic acid) in vivo protects against DSS- and TNBS-induced colitis by downregulating pro-inflammatory cytokines and preserving epithelial barrier function; FXR-null mice show exacerbated colitis, establishing FXR as a regulator of intestinal inflammation and barrier integrity. FXR-null mice, DSS/TNBS colitis models, INT-747 treatment, epithelial permeability assay, cytokine ELISA, in vitro Caco-2/HT29 cells Gut High 21242261
2014 FXR suppresses hepatic autophagy in the fed state by binding to promoters of autophagy genes (including Atg7, Ulk1, Tfeb) and disrupting the functional CREB-CRTC2 coactivator complex; FXR and CREB compete for shared sites in autophagic gene promoters with opposite transcriptional outputs. FXR-knockout mice show partial defects in fed-state suppression of hepatic autophagy. ChIP-seq from mouse liver, pharmacological FXR activation/knockout, co-immunoprecipitation of CREB-CRTC2 complex disruption, autophagy flux assays Nature High 25383523 25383539
2014 FXR is a molecular target for the metabolic benefits of vertical sleeve gastrectomy (VSG); VSG increases circulating bile acids, and in FXR-knockout mice, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced, establishing FXR as a key mediator of VSG metabolic effects. FXR knockout mice with VSG surgery, gut microbiota analysis, circulating bile acid measurement, glucose tolerance tests Nature High 24670636
2014 FXR directly regulates renal AQP2 (aquaporin 2) expression by binding to a FXR response element in the AQP2 gene promoter; FXR agonist treatment increased urine osmolality and upregulated AQP2, while FXR-knockout mice showed impaired urine concentrating ability and reduced AQP2 expression. FXR knockout mice, FXR agonist treatment, luciferase reporter assay with AQP2 promoter FXRE, primary inner medullary collecting duct cell culture Proceedings of the National Academy of Sciences High 24464484
2015 FXR directly binds an IR9 DNA motif within the SOCS3 promoter (by EMSA and ChIP) and enhances SOCS3 transcription; FXR-induced SOCS3 upregulates p21 and represses STAT3 phosphorylation, mediating anti-tumor effects in HCC; SOCS3 siRNA knockdown abolished FXR's anti-HCC effects. EMSA, ChIP assay, luciferase reporter assay, SOCS3 siRNA, HCC xenograft mouse model Oncotarget High 26416445
2015 Intestinal FXR inhibition (by Gly-MCA) improves obesity-related metabolic dysfunction; mechanistically, reduced intestinal FXR signaling decreases biosynthesis of intestinal ceramides, which directly compromise beige fat thermogenic function; intestine-specific FXR knockout mice were unresponsive to Gly-MCA benefits. Intestine-specific FXR knockout mice, Gly-MCA treatment, ceramide measurement, beige fat thermogenesis assays, FXR agonist blockade experiments Nature communications High 26670557
2015 FXR activation by GW4064 induces SREBP-2 mRNA and miR-33 expression via a defined FXR response element in intron 10 of the Srebp-2 gene; however, FXR simultaneously induces INSIG-2A, which prevents processing of pSREBP-2 to nuclear SREBP-2, uncoupling miR-33 induction from SREBP-2 target gene regulation. ChIP-seq (FXR response element in Srebp-2 intron 10), FXR agonist treatment in mice, Scap-knockout mice, INSIG-2A expression analysis, miR-33 target gene analysis Arteriosclerosis, thrombosis, and vascular biology High 25593129
2016 FXR activation suppresses renal fibrosis by inhibiting the transcriptional activity of the Smad3 gene promoter (luciferase reporter assay); FXR-mediated repression of fibrosis is alleviated by ectopic Smad3 overexpression, and FXR agonist protected against fibrosis in UUO mice while downregulating Smad3. Luciferase reporter assay (Smad3 promoter), Smad3 overexpression, FXR antagonist, FXR agonist in UUO mouse model Scientific reports Medium 27853248
2017 A CK2-RNF4 interplay coordinates non-canonical FXR SUMOylation and degradation: CK2 phosphorylates Ser-327 of FXR, enabling SUMO2 conjugation at Lys-325 (a pSuM motif) by Ubc9/PIAS1; Lys-325 SUMOylation promotes efficient ligand activation and transcriptional coactivation. Constitutive SUMOylation directs FXR ubiquitination by E3 ligase RNF4 and proteasomal degradation; RNF4 is required for maximal FXR-dependent gene regulation. Site-directed mutagenesis (K325R, S327A/E), Co-IP of SUMO2/ubiquitin, PIAS1/Ubc9 interaction, RNF4 knockdown, ChIP, CK2 inhibition Journal of molecular cell biology High 28201649
2019 FXR restricts abnormal Lgr5+ intestinal cancer stem cell growth; bile acids antagonizing intestinal FXR (T-βMCA, DCA) induce proliferation and DNA damage in Lgr5+ cells, while selective intestinal FXR activation curtails CRC progression; this implicates FXR in coordinating intestinal self-renewal with bile acid levels. Intestinal organoids, Lgr5+ cell sorting, FXR agonist/antagonist treatment, APC-mutant/high-fat-diet mouse model, DNA damage assays Cell High 30794774
2019 FXR activation inhibits Src kinase (Tyr416 phosphorylation), leading to increased Ser127 phosphorylation and cytosolic retention of YAP (via Hippo kinase complex stabilization), thereby protecting against renal fibrosis; FXR-knockout mice show increased fibrosis markers and nuclear YAP. FXR agonist (GW4064) in HK2 cells and UUO mice, FXR-KO mice, Src inhibitor (PP2), phospho-specific immunoblotting, Co-IP of Hippo kinases FASEB journal High 31298930
2020 Enhanced FXR SUMOylation in activated hepatic stellate cells (HSCs) limits their response to FXR agonists in liver fibrosis; SUMOylation inhibitors rescue FXR signaling and synergize with OCA against HSC activation. FXR upregulates Perilipin-1 to stabilize lipid droplets and prevent HSC activation. SUMOylation assays in HSCs, SUMOylation inhibitors, OCA treatment, CCl4/BDL/NASH mouse fibrosis models, Perilipin-1 ChIP and siRNA knockdown Nature communications High 31932588
2020 FXR functions as a T cell-intrinsic sensor of nutrient availability; T cell-specific FXR deletion prevented starvation-induced loss of lymphocytes and increased effector T cell fitness under low-glucose conditions by increasing glutamine and fatty acid contribution to respiration and enhancing cell survival. T cell-specific FXR knockout mice, infection models, metabolic flux analysis (glutamine and fatty acid use), glucose rescue experiments Proceedings of the National Academy of Sciences High 33318189
2020 FXR and GPBAR1 (TGR5) exert antagonistic effects on autophagy: FXR represses autophagy-related genes (Atgs) in the fed state, while GPBAR1 promotes autophagy via cAMP-CREB pathway; mechanistically, GPBAR1 agonism promotes CREB recruitment to the LC3 promoter CRE and reverses FXR-mediated repression of autophagy. Gpbar1-null mice, FXR-null mice, FXR antagonist, GPBAR1 agonist (BAR501), ChIP (CREB on LC3 promoter), autophagy flux assays in liver and WAT FASEB journal High 33368684
2020 PPARγ directly binds the PPAR-responsive element in the FXR gene promoter in a PPARγ agonist-dependent manner (ChIP assay), driving FXR expression during adipogenesis; FXR activation then induces SCD (stearoyl-CoA desaturase) by binding a FXRE in the SCD gene promoter, promoting lipogenesis in adipocytes. ChIP assay (PPARγ binding to FXR promoter), FXRE identification in SCD promoter, reporter assay, troglitazone/CDCA/guggulsterone treatment in 3T3-L1 cells Biochemical and biophysical research communications Medium 32446390
2021 Hepatic FXR protects against NAFLD primarily through two distinct intestinal and hepatic mechanisms: hepatic FXR controls lipogenic genes (repressing Scd1, Dgat2, Lpin1 independently of SHP and SREBP1c), while intestinal FXR controls lipid absorption via regulation of bile acids; tissue-specific FXR knockout mice dissected these two pathways. Tissue-specific FXR knockout mice (hepatic vs intestinal), comprehensive lipidomics, bile acid replenishment experiments, GSK2324 FXR agonist treatment Cell metabolism High 34270928
2022 FXR is a direct transcriptional regulator of ACE2 in gastrointestinal and respiratory tissues; FXR inhibition by UDCA or z-guggulsterone downregulates ACE2 expression in human lung, cholangiocyte, and intestinal organoids, in mouse and hamster tissues, and in ex situ perfused human lungs, reducing susceptibility to SARS-CoV-2 infection. FXR agonist/antagonist treatment in human organoids, ex vivo perfused human organs, mouse and hamster in vivo models, ACE2 reporter assays, SARS-CoV-2 infection assays Nature High 36470304
2022 SIRT6 deacetylates FXR at the protein level, thereby elevating FXR transcriptional activity and protecting against APAP-induced hepatotoxicity; FXR ablation abolished SIRT6 overexpression-mediated hepatoprotection, and pharmacological FXR activation rescued SIRT6-knockout mice from APAP injury. Hepatocyte-specific SIRT6 and FXR knockout mice, SIRT6 overexpression and pharmacological activation, deacetylation assays, APAP hepatotoxicity model Cellular and molecular gastroenterology and hepatology High 35526796
2022 Under liver injury conditions, FXR acetylation at K217 (near the nuclear localization signal) blocks recognition by importin KPNA3, preventing nuclear import; simultaneously, reduced phosphorylation at T442 (within nuclear export signal) promotes recognition by exportin CRM1, facilitating FXR nuclear export and cytosolic retention; cytosolic FXR is then degraded by the E3 ligase CHIP. SIRT1 activators reduce FXR acetylation, prevent cytosolic degradation, and synergize with FXR agonists against liver injury. Acetylation site mutagenesis (K217, T442), importin/exportin binding assays (KPNA3, CRM1), CHIP E3 ligase Co-IP, SIRT1 activator treatment, acute/chronic liver injury mouse models Acta pharmaceutica Sinica. B High 36873184
2020 BRD4 is a co-factor required for FXR-mediated regulation of bile acid homeostasis; liver-specific BRD4 downregulation disrupted bile acid homeostasis, and FXR-mediated regulation of SHP and CYP7A1 was BRD4-dependent. In cholestasis, OCA-activated FXR increased binding of FXR and co-repressor SMRT at inflammatory genes, decreased NF-κB binding, and repressed inflammatory genes in a BRD4-dependent manner. Liver-specific BRD4 knockdown, cholestatic mouse models, ChIP for FXR/SMRT/NF-κB at inflammatory gene promoters, JQ1 (BRD4 inhibitor) and OCA treatment JCI insight High 33290278

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Identification of a nuclear receptor for bile acids. Science (New York, N.Y.) 2233 10334992
1999 Bile acids: natural ligands for an orphan nuclear receptor. Science (New York, N.Y.) 1872 10334993
2000 A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Molecular cell 1610 11030332
2000 Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 1493 11030617
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1999 Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Molecular cell 1334 10360171
2000 Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Molecular cell 1231 11030331
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2000 Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science (New York, N.Y.) 1103 10968783
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1995 Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 997 7774010
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nature medicine 791 30397356
2006 Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proceedings of the National Academy of Sciences of the United States of America 780 16410358
2014 FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 760 24670636
2006 Farnesoid X receptor is essential for normal glucose homeostasis. The Journal of clinical investigation 726 16557297
2011 Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 710 21242261
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes & development 567 12815072
2009 The bile acid receptor FXR is a modulator of intestinal innate immunity. Journal of immunology (Baltimore, Md. : 1950) 530 19864602
2006 Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science (New York, N.Y.) 520 16614213
2006 LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annual review of physiology 490 16460270
2015 Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nature communications 460 26670557
2014 Nutrient-sensing nuclear receptors coordinate autophagy. Nature 431 25383539
2016 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 423 26871637
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. Journal of hepatology 407 25920087
2002 A natural product that lowers cholesterol as an antagonist ligand for FXR. Science (New York, N.Y.) 397 11988537
2003 Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Molecular endocrinology (Baltimore, Md.) 387 12554753
2021 FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption. Cell metabolism 370 34270928
2019 FXR Regulates Intestinal Cancer Stem Cell Proliferation. Cell 369 30794774
2015 Bile acid nuclear receptor FXR and digestive system diseases. Acta pharmaceutica Sinica. B 353 26579439
2014 Transcriptional regulation of autophagy by an FXR-CREB axis. Nature 352 25383523
2008 FXR: a metabolic regulator and cell protector. Cell research 346 18825165
2015 Bile Acids as Hormones: The FXR-FGF15/19 Pathway. Digestive diseases (Basel, Switzerland) 342 26045265
2020 Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism. Cell metabolism 338 33338411
2006 FXR, a multipurpose nuclear receptor. Trends in biochemical sciences 288 16908160
2002 BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis. Journal of lipid research 280 11792716
2010 Deciphering the nuclear bile acid receptor FXR paradigm. Nuclear receptor signaling 231 21383957
2022 FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature 230 36470304
2017 FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity. Journal of the American Society of Nephrology : JASN 188 29089371
2021 Farnesoid X receptor (FXR): Structures and ligands. Computational and structural biotechnology journal 181 33995909
2017 Nutrient-sensing nuclear receptors PPARα and FXR control liver energy balance. The Journal of clinical investigation 159 28287408
2018 Update on FXR Biology: Promising Therapeutic Target? International journal of molecular sciences 151 30013008
2020 Bile Acids and FXR: Novel Targets for Liver Diseases. Frontiers in medicine 149 33015098
2020 SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis. Nature communications 124 31932588
2023 FXR agonists in NASH treatment. Journal of hepatology 120 37562746
2022 Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis. International journal of molecular sciences 119 35682726
2019 Bile Acid-Activated Receptors: A Review on FXR and Other Nuclear Receptors. Handbook of experimental pharmacology 111 31230143
2006 Effects of FXR in foam-cell formation and atherosclerosis development. Biochimica et biophysica acta 107 17110163
2000 FXR, a bile acid receptor and biological sensor. Trends in cardiovascular medicine 101 11150726
2021 Gut microbiota depletion exacerbates cholestatic liver injury via loss of FXR signalling. Nature metabolism 97 34552267
2016 Fatty liver diseases, bile acids, and FXR. Acta pharmaceutica Sinica. B 96 27709009
2002 A comparison of ALPHAScreen, TR-FRET, and TRF as assay methods for FXR nuclear receptors. Journal of biomolecular screening 96 11897050
2015 Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling. American journal of physiology. Gastrointestinal and liver physiology 94 26608185
2012 Anti-inflammatory and metabolic actions of FXR: insights into molecular mechanisms. Biochimica et biophysica acta 92 22820415
2010 A role of the bile salt receptor FXR in atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology 92 20631352
2005 Role of FXR in regulating bile acid homeostasis and relevance for human diseases. Current drug targets. Immune, endocrine and metabolic disorders 92 16178789
2019 Targeting FXR in Cholestasis. Handbook of experimental pharmacology 91 31201556
2015 Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior. Frontiers in behavioral neuroscience 89 25870546
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
2017 Bile acids and colon cancer: Is FXR the solution of the conundrum? Molecular aspects of medicine 76 28400119
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 76 24464484
2006 The nuclear hormone receptor farnesoid X receptor (FXR) is activated by androsterone. Endocrinology 76 16675527
2006 Nuclear bile acid receptor FXR as pharmacological target: are we there yet? FEBS letters 75 16904670
2013 FXR silencing in human colon cancer by DNA methylation and KRAS signaling. American journal of physiology. Gastrointestinal and liver physiology 73 24177031
2005 FXR-activating ligands inhibit rabbit ASBT expression via FXR-SHP-FTF cascade. American journal of physiology. Gastrointestinal and liver physiology 73 15591588
2014 FXR and liver carcinogenesis. Acta pharmacologica Sinica 72 25500874
2015 Splenic dendritic cell involvement in FXR-mediated amelioration of DSS colitis. Biochimica et biophysica acta 69 26554605
2023 FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid. Medicinal research reviews 68 37899676
2018 FXR modulators for enterohepatic and metabolic diseases. Expert opinion on therapeutic patents 68 30259754
2022 Recent advances on FXR-targeting therapeutics. Molecular and cellular endocrinology 67 35605722
2019 Nonsteroidal FXR Ligands: Current Status and Clinical Applications. Handbook of experimental pharmacology 66 31197565
2022 FXR: structures, biology, and drug development for NASH and fibrosis diseases. Acta pharmacologica Sinica 64 35217809
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 60 34831429
2021 Targeting Farnesoid X receptor (FXR) for developing novel therapeutics against cancer. Molecular biomedicine 58 35006466
2016 Activation of FXR protects against renal fibrosis via suppressing Smad3 expression. Scientific reports 58 27853248
2018 Simultaneous inhibition of FXR and TGR5 exacerbates atherosclerotic formation. Journal of lipid research 55 29976576
2008 Farnesoid X receptor induces GLUT4 expression through FXR response element in the GLUT4 promoter. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 52 18769028
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 51 31298930
2015 FXR induces SOCS3 and suppresses hepatocellular carcinoma. Oncotarget 48 26416445
2022 Immunomodulatory functions of FXR. Molecular and cellular endocrinology 47 35472625
2010 Nuclear bile acid receptor FXR in the hepatic regeneration. Biochimica et biophysica acta 46 21167938
2014 Targeting FXR in cholestasis: hype or hope. Expert opinion on therapeutic targets 44 25200104
2014 Beyond bile acids: targeting Farnesoid X Receptor (FXR) with natural and synthetic ligands. Current topics in medicinal chemistry 44 25388537
2022 Probiotic-derived nanoparticles inhibit ALD through intestinal miR194 suppression and subsequent FXR activation. Hepatology (Baltimore, Md.) 41 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 38 29883717
2012 Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders. Current topics in medicinal chemistry 38 22242859
2016 Bile Acids, FXR, and Metabolic Effects of Bariatric Surgery. Journal of obesity 37 27006824
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 36 33318189
2023 Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway. European journal of pharmacology 35 37263401
2024 Regulation of bile acids and their receptor FXR in metabolic diseases. Frontiers in nutrition 34 39726876
2021 Novel FXR agonist nelumal A suppresses colitis and inflammation-related colorectal carcinogenesis. Scientific reports 34 33436792
2017 Farnesoid-X Receptor (FXR) as a Promising Pharmaceutical Target in Atherosclerosis. Current medicinal chemistry 34 28120707
2015 Role of FXR in β-cells of lean and obese mice. Endocrinology 34 25599407
2009 FXR promotes endothelial cell motility through coordinated regulation of FAK and MMP-9. Arteriosclerosis, thrombosis, and vascular biology 33 19150878
2015 O-GlcNAcylation Links ChREBP and FXR to Glucose-Sensing. Frontiers in endocrinology 31 25628602
2015 Steroidal scaffolds as FXR and GPBAR1 ligands: from chemistry to therapeutical application. Future medicinal chemistry 31 26132522
2012 The significance of the nuclear farnesoid X receptor (FXR) in β cell function. Islets 30 23073079
2021 Post-Translational Modifications of FXR; Implications for Cholestasis and Obesity-Related Disorders. Frontiers in endocrinology 28 34646233
2022 SIRT1 activation synergizes with FXR agonism in hepatoprotection via governing nucleocytoplasmic shuttling and degradation of FXR. Acta pharmaceutica Sinica. B 27 36873184
2021 MECHANISMS IN ENDOCRINOLOGY: FXR signalling: a novel target in metabolic diseases. European journal of endocrinology 27 33630750
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 Promotion of lipogenesis by PPARγ-activated FXR expression in adipocytes. Biochemical and biophysical research communications 25 32446390
2020 Design and Structural Optimization of Dual FXR/PPARδ Activators. Journal of medicinal chemistry 25 32687365
2017 A novel intestinal-restricted FXR agonist. Bioorganic & medicinal chemistry letters 25 28629595
2022 Hepatic SIRT6 Modulates Transcriptional Activities of FXR to Alleviate Acetaminophen-induced Hepatotoxicity. Cellular and molecular gastroenterology and hepatology 24 35526796
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
2020 BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination. JCI insight 23 33290278
2012 Farnesoid X Receptor (FXR) from normal to malignant state. Histology and histopathology 23 22648540
2020 Yangonin inhibits ethanol-induced hepatocyte senescence via miR-194/FXR axis. European journal of pharmacology 22 33068587
2017 The bile acid receptor FXR attenuates acinar cell autophagy in chronic pancreatitis. Cell death discovery 22 28660075
2025 Bile acids affect intestinal barrier function through FXR and TGR5. Frontiers in medicine 21 40692955
2021 The bile acid activated receptors GPBAR1 and FXR exert antagonistic effects on autophagy. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 33368684
2020 Bile acid treatment and FXR agonism lower postprandial lipemia in mice. American journal of physiology. Gastrointestinal and liver physiology 21 32003602
2020 20S-Protopanaxatriol Ameliorates Hepatic Fibrosis, Potentially Involving FXR-Mediated Inflammatory Signaling Cascades. Journal of agricultural and food chemistry 21 32662640
2005 FXR, a therapeutic target for bile acid and lipid disorders. Mini reviews in medicinal chemistry 21 16101408
2023 Role of FXR in Renal Physiology and Kidney Diseases. International journal of molecular sciences 20 36768731
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 20 29908754
2017 A CK2-RNF4 interplay coordinates non-canonical SUMOylation and degradation of nuclear receptor FXR. Journal of molecular cell biology 20 28201649
2016 Transcriptional coordination of hepatic autophagy by nutrient-sensing nuclear receptor PPARα and FXR. Annals of pediatric endocrinology & metabolism 20 28164071
2012 NR1H4 analysis in patients with progressive familial intrahepatic cholestasis, drug-induced cholestasis or intrahepatic cholestasis of pregnancy unrelated to ATP8B1, ABCB11 and ABCB4 mutations. Clinics and research in hepatology and gastroenterology 20 23142591
2023 Probiotic Pediococcus pentosaceus Li05 Improves Cholestasis through the FXR-SHP and FXR-FGF15 Pathways. Nutrients 19 38068723
2022 Chlorogenic Acid Inhibits Lipid Deposition by Regulating the Enterohepatic FXR-FGF15 Pathway. BioMed research international 19 35257010
2024 Bruceine A alleviates alcoholic liver disease by inhibiting AIM2 inflammasome activation via activating FXR. Phytomedicine : international journal of phytotherapy and phytopharmacology 18 38763006