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Names & Taxonomy

Uniprot ID:: Q96RI1
Entry Name:: NR1H4_HUMAN
Status:: reviewed
Protein Names:: Bile acid receptor (Farnesoid X-activated receptor) (Farnesol receptor HRR-1) (Nuclear receptor subfamily 1 group H member 4) (Retinoid X receptor-interacting protein 14) (RXR-interacting protein 14)
Gene Names:: NR1H4 BAR FXR HRR1 RIP14
Gene Names Primary:: NR1H4
Organism:: Homo sapiens (Human)

Structure

Length:: 486
Sequence:: MVMQFQGLENPIQISPHCSCTPSGFFMEMMSMKPAKGVLTEQVAGPLGQNLEVEPYSQYSNVQFPQVQPQISSSSYYSNLGFYPQQPEEWYSPGIYELRRMPAETLYQGETEVAEMPVTKKPRMGASAGRIKGDELCVVCGDRASGYHYNALTCEGCKGFFRRSITKNAVYKCKNGGNCVMDMYMRRKCQECRLRKCKEMGMLAECMYTGLLTEIQCKSKRLRKNVKQHADQTVNEDSEGRDLRQVTSTTKSCREKTELTPDQQTLLHFIMDSYNKQRMPQEITNKILKEEFSAEENFLILTEMATNHVQVLVEFTKKLPGFQTLDHEDQIALLKGSAVEAMFLRSAEIFNKKLPSGHSDLLEERIRNSGISDEYITPMFSFYKSIGELKMTQEEYALLTAIVILSPDRQYIKDREAVEKLQEPLLDVLQKLCKIHQPENPQHFACLLGRLTELRTFNHHHAEMLMSWRVNDHKFTPLLCEIWDVQ
Proteomes:: UP000005640

Subcellular location

Subcellular Location:: Nucleus

Function

Function:: Ligand-activated transcription factor. Receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential role in BA homeostasis through the regulation of genes involved in BA synthesis, conjugation and enterohepatic circulation. Also regulates lipid and glucose homeostasis and is involved innate immune response (PubMed:10334992, PubMed:10334993, PubMed:21383957, PubMed:22820415). The FXR-RXR heterodimer binds predominantly to farnesoid X receptor response elements (FXREs) containing two inverted repeats of the consensus sequence 5'-AGGTCA-3' in which the monomers are spaced by 1 nucleotide (IR-1) but also to tandem repeat DR1 sites with lower affinity, and can be activated by either FXR or RXR-specific ligands. It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1 bound to coregulatory nuclear responsive element (NRE) halfsites located in close proximity to FXREs modulate transcriptional activity (By similarity). In the liver activates transcription of the corepressor NR0B2 thereby indirectly inhibiting CYP7A1 and CYP8B1 (involved in BA synthesis) implicating at least in part histone demethylase KDM1A resulting in epigenomic repression, and SLC10A1/NTCP (involved in hepatic uptake of conjugated BAs). Activates transcription of the repressor MAFG (involved in regulation of BA synthesis) (By similarity). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:12754200, PubMed:15471871, PubMed:17895379). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:10514450, PubMed:15239098, PubMed:16269519). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression (PubMed:12815072, PubMed:19085950). The function also involves the coordinated induction of hepatic KLB/beta-klotho expression (By similarity). Regulates transcription of liver UGT2B4 and SULT2A1 involved in BA detoxification; binding to the UGT2B4 promoter seems to imply a monomeric transactivation independent of RXRA (PubMed:12806625, PubMed:16946559). Modulates lipid homoestasis by activating liver NR0B2/SHP-mediated repression of SREBF1 (involved in de novo lipogenesis), expression of PLTP (involved in HDL formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1, APOC4, PPARA (involved in beta-oxidation of fatty acids), VLDLR and SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and inhibiting expression of MTTP (involved in VLDL assembly (PubMed:12660231, PubMed:12554753, PubMed:15337761). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance) (PubMed:11579204). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element (PubMed:11927623, PubMed:21804189). Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase) (PubMed:12891557). Involved in glucose homeostasis by modulating hepatic gluconeogenesis through activation of NR0B2/SHP-mediated repression of respective genes. Modulates glycogen synthesis (inducing phosphorylation of glycogen synthase kinase-3) (By similarity). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance (PubMed:20447400). Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier (By similarity). Down-regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells (PubMed:21242261). Mediates trans-repression of TLR4-induced cytokine expression; the function seems to require its sumoylation and prevents N-CoR nuclear receptor corepressor clearance from target genes such as IL1B and NOS2 (PubMed:19864602). Involved in the TLR9-mediated protective mechanism in intestinal inflammation. Plays a anti-inflammatory role in liver inflammation; proposed to inhibit proinflammatory (but not antiapoptotic) NF-kappa-B signaling) (By similarity).
Cross Reference Drug Bank:: DB06777
Gene Ontology Go:: nuclear euchromatin
nucleoplasm
bile acid binding
bile acid receptor activity
chenodeoxycholic acid binding
ligand-dependent nuclear receptor binding
peptide binding
RNA polymerase II distal enhancer sequence-specific DNA binding
RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding
sequence-specific DNA binding
steroid hormone receptor activity
thyroid hormone receptor activity
transcription coactivator activity
transcription corepressor activity
transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding
transcription factor activity, sequence-specific DNA binding
transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding
transcriptional activator activity, RNA polymerase II transcription factor binding
zinc ion binding
bile acid and bile salt transport
bile acid metabolic process
bile acid signaling pathway
cellular response to fatty acid
cellular response to organonitrogen compound
cellular triglyceride homeostasis
digestive tract development
gene expression
histone H3-R17 methylation
inflammatory response
innate immune response
interleukin-17 secretion
intracellular bile acid receptor signaling pathway
intracellular receptor signaling pathway
negative regulation of apoptotic process
negative regulation of bile acid biosynthetic process
negative regulation of I-kappaB kinase/NF-kappaB signaling
negative regulation of interferon-gamma secretion
negative regulation of transcription from RNA polymerase II promoter
negative regulation of tumor necrosis factor secretion
nitrogen catabolite activation of transcription from RNA polymerase II promoter
Notch signaling pathway
positive regulation of ammonia assimilation cycle
positive regulation of glutamate metabolic process
positive regulation of transcription from RNA polymerase II promoter
regulation of bile acid biosynthetic process
regulation of carbohydrate metabolic process
regulation of cholesterol metabolic process
regulation of insulin secretion involved in cellular response to glucose stimulus
regulation of low-density lipoprotein particle clearance
regulation of urea metabolic process
response to glucose
response to lipopolysaccharide
signal transduction
small molecule metabolic process
toll-like receptor 4 signaling pathway
transcription initiation from RNA polymerase II promoter
Gene Ontology Biological Process:: bile acid and bile salt transport
bile acid metabolic process
bile acid signaling pathway
cellular response to fatty acid
cellular response to organonitrogen compound
cellular triglyceride homeostasis
digestive tract development
gene expression
histone H3-R17 methylation
inflammatory response
innate immune response
interleukin-17 secretion
intracellular bile acid receptor signaling pathway
intracellular receptor signaling pathway
negative regulation of apoptotic process
negative regulation of bile acid biosynthetic process
negative regulation of I-kappaB kinase/NF-kappaB signaling
negative regulation of interferon-gamma secretion
negative regulation of transcription from RNA polymerase II promoter
negative regulation of tumor necrosis factor secretion
nitrogen catabolite activation of transcription from RNA polymerase II promoter
Notch signaling pathway
positive regulation of ammonia assimilation cycle
positive regulation of glutamate metabolic process
positive regulation of transcription from RNA polymerase II promoter
regulation of bile acid biosynthetic process
regulation of carbohydrate metabolic process
regulation of cholesterol metabolic process
regulation of insulin secretion involved in cellular response to glucose stimulus
regulation of low-density lipoprotein particle clearance
regulation of urea metabolic process
response to glucose
response to lipopolysaccharide
signal transduction
small molecule metabolic process
toll-like receptor 4 signaling pathway
transcription initiation from RNA polymerase II promoter
Gene Ontology Molecular Function:: bile acid binding
bile acid receptor activity
chenodeoxycholic acid binding
ligand-dependent nuclear receptor binding
peptide binding
RNA polymerase II distal enhancer sequence-specific DNA binding
RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding
sequence-specific DNA binding
steroid hormone receptor activity
thyroid hormone receptor activity
transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding
transcriptional activator activity, RNA polymerase II transcription factor binding
transcription coactivator activity
transcription corepressor activity
transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding
transcription factor activity, sequence-specific DNA binding
zinc ion binding
Gene Ontology Cellular Component:: nuclear euchromatin
nucleoplasm
Keywords:: 3D-structure
Acetylation
Activator
Alternative promoter usage
Alternative splicing
Complete proteome
DNA-binding
Immunity
Inflammatory response
Innate immunity
Isopeptide bond
Metal-binding
Methylation
Nucleus
Phosphoprotein
Receptor
Reference proteome
Repressor
Transcription
Transcription regulation
Ubl conjugation
Zinc
Zinc-finger
Interacts With:: P03372; Q15788; P78527; Q8WTS6

Names & Taxonomy

Structure

Subcellular location

Function

Publication