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FLASH GENE
Symbol NR1H4 contributors: mct/npt/pgu - updated : 21-03-2018
HGNC name nuclear receptor subfamily 1, group H, member 4
HGNC id 7967
Corresponding disease
PFIC5 cholestasis, progressive familial intrahepatic, 5
Location 12q23.1      Physical location : 100.867.678 - 100.957.643
Synonym name
  • farnesoid-X activated receptor
  • bile acid receptor
  • RXR-interacting protein 14
  • farnesol receptor HRR-1
  • Synonym symbol(s) FXR, BAR, HRR-1, HRR1, RIP14, MGC163445, PFIC5
    DNA
    TYPE functioning gene
    STRUCTURE 90.09 kb     11 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked   status provisional
    Map cen - D12S1671 - D12S332 - NR1H4 - D12S1030 - D12S1572 - D12S1962 - D12S1607 - qter
    Authors GeneMap (98)
    Physical map
    LOC121456 12q23.1 similar to solute carrier family 9, member 7; nonselective sodium potassium/proton exchanger; sodium/hydrogen exchanger 7 TMPO 12q22-q23.1 thymopoietin LOC341457 12q23.1 similar to peptidyl-Pro cis trans isomerase SLC25A3 12q22-q23.1 solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3 LOC387877 FLJ31051 APAF1 12q23 apoptotic protease activating factor EB-1 12q23.1-q23.2 E2a-Pbx1-associated protein MGC39520 12q23.2 hypothetical protein MGC39520 LOC387878 12 similar to ribosomal protein S4, X-linked KIAA0701 12q23.1-q23.3 similar to ribosomal protein S4, X-linked DKFZp434M0331 12q23.3 hypothetical protein DKFZp434M0331 ACTR6 12q23.3 actin-related protein 6 FLJ33505 12q23.3 hypothetical protein FLJ33505 FLJ10074 12q23.3 hypothetical protein FLJ10074 SLC17A8 12q23.3 solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 8 NR1H4 12q21.3 nuclear receptor subfamily 1, group H, member 4 LOC283431 12q23.3 hypothetical protein LOC283431 PIGAP1 12q21 phosphatidylinositol glycan, class A, pseudogene 1 TMEM16D 12q23.3 transmembrane protein 16D (eight membrane-spanning domains) SLC5A8 12q23.3 solute carrier family 5 (iodide transporter), member 8 DRIM 12q23 down-regulated in metastasis ARL1 12q23.3 ADP-ribosylation factor-like 1 SPIC 12q23.3 likely ortholog of mouse Spi-C transcription factor (Spi-1/PU.1 related) MYBPC1 12q22-q23 myosin binding protein C, slow type CHPT1 12q11 choline phosphotransferase 1 SYCP3 12q24.2-q24.3 synaptonemal complex protein 3 MGC4170 12q23.3 synaptonemal complex protein 3 LOC387880 12 similar to 10 KD HEAT SHOCK PROTEIN, MITOCHONDRIAL (HSP10) (10 KD CHAPERONIN) (CPN10) FLJ11259 12q23.3 hypothetical protein FLJ11259 LOC390353 12 similar to ribosomal protein L9 CGI-116 12q23.3 CGI-116 protein Nup37 12q23.3 nucleoporin Nup37 FLJ20641 12q23.3 hypothetical protein FLJ20641 PMCH 12q23.1 pro-melanin-concentrating hormone IGF1 12q23.1 insulin-like growth factor 1 (somatomedin C)
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    11 - 2213 54.3 472 - 2017 28619996
    12 - 2492 - 476 - 2017 28619996
    11 - 2325 - 476 - 2017 28619996
    10 - 2172 - 425 - 2017 28619996
    9 - 1907 - 486 - 2017 28619996
    9 - 1895 - 482 - 2017 28619996
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinesmall intestine    Homo sapiens
     liver   highly Homo sapiens
    Endocrineadrenal gland     Homo sapiens
    Lymphoid/Immunelymph node     Homo sapiens
    Nervousbrain     Homo sapiens
    Reproductivemale systemtestis    Homo sapiens
    Urinarykidneytubule    Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose    Homo sapiens
    Muscularsmoothvessel  
    Muscularstriatumskeletal  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticplatelet Homo sapiens
    Lymphoid/Immune  Homo sapiens
    Nervousoligodendrocyte Homo sapiensFetal
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • receptor composed of a central bipartite (class II C4) zinc finger DNA binding domain
  • a N terminal modulator domain
  • a C terminal ligand binding domain of hormone receptor
  • mono polymer heteromer , dimer
    HOMOLOGY
    Homologene
    FAMILY
  • nuclear hormone receptor family
  • NR1 subfamily
  • CATEGORY regulatory , transcription factor , receptor nuclear
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome,euchromosome
    basic FUNCTION
  • plays an important role in the pathogenesis of cardiovascular diseases via regulating the metabolism and transport of cholesterol
  • role in the regulation of ALAS1 and, consequently, hepatic porphyrin and heme synthesis
  • inhibiting CYP7A1 synthesis when bound to bile acids
  • bile acid sensor regulating the expression of a number of genes the products of which control bile acid and cholesterol homeostasis
  • regulated 3beta-hydroxysteroid dehydrogenase type 2 (HSD3B2) expression in adrenocortical cells
  • plays a central role in maintaining lipid and glucose homeostasis
  • mediates important signaling functions of bile acids in diverse cell types including those residing in the vascular wall
  • regulates expression of liver cystathionase (CSE), hydrogen sulfide production and hepatic microcirculation
  • regulates adipocyte differentiation and function by regulating two counteracting pathways of adipocyte differentiation, the PPARG and WNT/CTNNB1 pathways
  • role for NR1H4 in the modulation of osteoblast/adipocyte balance: its activation stimulates RUNX2-mediated osteoblastic differentiation of bone marrow stromal cells (BMSC), whereas its inhibition leads to an adipocyte-like phenotype
  • contributes to the maintenance of cholesterol/bile acid homeostasis by regulating a variety of metabolic enzymes and transporters, and its activation also affects lipid and glucose metabolism, and can influence drug metabolism
  • nuclear bile acid receptor controlling bile acid, lipid, and glucose homeostasis
  • transrepresses the expression of genes involved in glycolysis in human hepatocytes
  • positively regulates likely bone metabolism through both arms of the bone remodeling pathways, bone formation and resorption
  • control steroid production, and also participates in steroid catabolism in the liver and interferes with the steroid signaling pathways in target tissues via crosstalk with steroid receptors
  • plays a critical role in the regulation of urine volume, and its activation increases urinary concentrating capacity mainly via up-regulating its target gene AQP2 expression in the collecting ducts
  • regulates bile acid, lipid and glucose metabolism
  • important role of NR1H4 in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses
  • bile acids and NR1H4 play pivotal roles in sepsis via controlling the NLRP3 inflammasome
  • is dispensable for oligodendroglial differentiation
  • NR1H4 and GPBAR1 may play an important role in modulation of age-related kidney disease
  • NR1H3, NR1H4 initiate formation of coated platelets
  • NR1H4 and DDIT3 have critical functions in hepatic lipid metabolism
  • bile acids have emerged as important for renal pathophysiology by activating NR1H4 and GPBAR1 and transcription factors relevant for lipid, cholesterol and carbohydrate metabolism, as well as genes involved in inflammation and renal fibrosis (
  • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
    a component
  • heterodimerizing with RXRs(retinoic X receptors)
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with DCN (activation in vascular smooth muscle cells)
  • interacting with AGTR2 (upregulates AGTR2 expression at a transcriptional level and play a role in the NR1H4-mediated inhibition of ERK activation via upregulation of PTPN6)
  • interacting with PTK2 (pivotal role for PTK2 in the process of NR1H4-induced and MMP9-dependent endothelial cell motility and vascular tube formation)
  • co-localized with NR0B1 in the nucleus and acted as a negative regulator of NR1H4 through a physical interaction with NR1H4
  • NR0B1 acts as a novel co-repressor of NR1H4 in the liver
  • activation of NR1H4 induced hepatic CES1, and reduced the levels of hepatic and plasma triglyceride (TG) as well as plasma cholesterol in a CES1-dependent manner
  • CDX2 transcription factor as a positive regulator of NR1H4 expression in the enterocytes
  • NR1H4 controls the liver derived tumor suppressor HRG
  • KDM1A is a novel histone-modifying enzyme in the orchestrated regulation mediated by NR1H4 and small heterodimer partner that reduces hepatic Bile acids (BAs) levels and protects the liver against BA toxicity
  • NR1H4 controls DDIT3 expression in steatohepatitis
  • cell & other
  • binding bile acids
  • REGULATION
    activated by retinoids,farnesol metabolites
    by bile acids such as chenodeoxycholic acid, or synthetic ligands such as GW4064
    Other phosphorylated by PRKCA (phosphorylation induced by PKCalpha directly modulates the ability of agonists to activate NR1H4)
    ASSOCIATED DISORDERS
    corresponding disease(s) PFIC5
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    in the liver in PFIC1 with severe cholestasis
    constitutional     --low  
    GPBAR1 and NR1H4 expression levels are decreased in the aging kidney and that caloric restriction prevents these age-related decreases
    constitutional     --over  
    of NR1H4, NR0B2, SLC10A1 and ABCB11 was significantly up-regulated in the non-alcoholic steatohepatitis (NASH) in comparison with simple steatosis (SS) patients
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    digestive  
    NR1H4 agonists may increase gallbladder fluid secretion through transcriptional activation of VIPR1, which may contribute to the regulation of bile secretion by bile salts and to a protective effect of NR1H4 pharmacological agonists in gallstone disease
    diabete  
    emerging role of NR1H4 agonists as therapeutic treatment of diabetes and certain liver diseases
    cardiovascularatheroma 
    NR1H4-NR0B2 way may be a novel therapeutic target for vascular inflammation, remodeling, and atherosclerotic plaque stability
    cardiovascular  
    in smooth muscle cells may serve as a novel molecular target for modulating AGTR2 signalling in the vasculature
    diabete  
    activation of both NR1H4 and GPBAR1 may represent an effective therapy for diabetes
    digestiveliversteatosis
    activation of both NR1H4 and GPBAR1 may represent an effective therapy for managing hepatic steatosis
    miscelleaneousurinary 
    NR1H4 and GPBAR1 agonists play an important role in preventing progression of kidney disease, atherosclerosis, and vascular calcification
    neurologyacquired 
    NR1H4 agonists, such as GW4064, represent a potential therapeutic approach for multiple sclerosis (MS) which specifically targets peripheral immune cells including macrophages but not brain-resident cells, such as oligodendrocytes, astrocytes or microglia
    immunologyinfectious 
    may represent a therapeutic strategy for cholestasis-associated sepsis
    miscelleaneousvascularischemic injury
    is a potential target for the prevention of atherothrombotic disease
    cancerdigestiveliver
    NR1H4-SOCS3 signaling may serve as a new potential target for the prevention/treatment of hepatocellular carcinoma
    ANIMAL & CELL MODELS
  • mice lacking expression of Fxr in the intestine were resistant to high-fat diet (HFD)-induced obesity, insulin resistance, and nonalcoholic fatty liver disease, thus confirming that intestinal Fxr is involved in the potentiation of metabolic disease