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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
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
  • NR1H4-mediated upregulation of CISH may play an important role in the homeostasis of cytokine signal networks and be beneficial to control cytokine-associated inflammatory diseases
  • 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
  • NR1H4 plays a central role in maintaining bile acid (BA) homeostasis by transcriptional control of numerous enterohepatic genes, including intestinal FGF19, a hormone that strongly represses hepatic BA synthesis
  • 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
  • Src-mediated NR1H4 phosphorylation is a potential biomarker for Bile-acid-related enterohepatic diseases
  • 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
    digestive  
    Src-mediated NR1H4 phosphorylation is a potential therapeutic target for Bile-acid-related enterohepatic diseases
    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