Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Bile acid receptor

Gene

Nr1h4

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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. 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. 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). 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). 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). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression. The function also involves the coordinated induction of hepatic KLB/beta-klotho expression. 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. Modulates lipid homeostasis 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). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element. Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase). 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). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance. Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier. Down-regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells. 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. Involved in the TLR9-mediated protective mechanism in intestinal inflammation. Plays an anti-inflammatory role in liver inflammation; proposed to inhibit proinflammatory (but not antiapoptotic) NF-kappa-B signaling.By similarity2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei358Agonist1 Publication1
Binding sitei366Agonist1 Publication1
Binding sitei444Agonist1 Publication1
Binding sitei466Agonist1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi121 – 196Nuclear receptorPROSITE-ProRule annotationAdd BLAST76
Zinc fingeri124 – 144NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri160 – 184NR C4-typePROSITE-ProRule annotationAdd BLAST25

GO - Molecular functioni

  • bile acid binding Source: RGD
  • bile acid receptor activity Source: UniProtKB
  • DNA binding Source: RGD
  • peptide binding Source: RGD
  • protein heterodimerization activity Source: RGD
  • RNA polymerase II proximal promoter sequence-specific DNA binding Source: NTNU_SB
  • steroid hormone receptor activity Source: InterPro
  • thyroid hormone receptor activity Source: InterPro
  • transcriptional activator activity, RNA polymerase II proximal promoter sequence-specific DNA binding Source: NTNU_SB
  • zinc ion binding Source: InterPro

GO - Biological processi

  • bile acid metabolic process Source: RGD
  • digestive tract development Source: RGD
  • inflammatory response Source: UniProtKB-KW
  • innate immune response Source: UniProtKB-KW
  • negative regulation of transcription by RNA polymerase II Source: RGD
  • positive regulation of transcription by RNA polymerase II Source: NTNU_SB
  • regulation of carbohydrate metabolic process Source: RGD
  • response to glucose Source: RGD
  • response to lipopolysaccharide Source: RGD

Keywordsi

Molecular functionActivator, DNA-binding, Receptor, Repressor
Biological processImmunity, Inflammatory response, Innate immunity, Transcription, Transcription regulation
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-RNO-159418 Recycling of bile acids and salts
R-RNO-192105 Synthesis of bile acids and bile salts
R-RNO-193368 Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
R-RNO-193807 Synthesis of bile acids and bile salts via 27-hydroxycholesterol
R-RNO-211976 Endogenous sterols
R-RNO-383280 Nuclear Receptor transcription pathway

Names & Taxonomyi

Protein namesi
Recommended name:
Bile acid receptor
Alternative name(s):
Farnesoid X-activated receptor
Farnesol receptor HRR-1
Nuclear receptor subfamily 1 group H member 4
Retinoid X receptor-interacting protein 14
Short name:
RXR-interacting protein 14
Gene namesi
Name:Nr1h4
Synonyms:Bar, Fxr, Rip14
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 7

Organism-specific databases

RGDi628831 Nr1h4

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000535401 – 469Bile acid receptorAdd BLAST469

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki119Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)By similarity
Modified residuei132Phosphoserine; by PKC/PRKCABy similarity1
Modified residuei151Phosphoserine; by PKC/PRKCABy similarity1
Modified residuei154N6-acetyllysine; by EP300By similarity1
Modified residuei203N6-methyllysine; by SETD7By similarity1
Modified residuei210N6-acetyllysine; by EP300By similarity1
Cross-linki272Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)By similarity
Modified residuei439Phosphothreonine; by PKC/PRKCZBy similarity1

Post-translational modificationi

Acetylated by EP300. Lys-210 as is the major acetylation site for EP300; the dynamicly regulated acetylation inhibits heterodimerization with RXRA and transactivation activity. Deacetylated by SIRT1.By similarity
Methylation may increase transactivation of target genes.By similarity
Phosphorylation by PKC/PRKCA increases transactivation activity by promoting association with PPARGC1A.By similarity
Sumoylated upon ligand binding.By similarity

Keywords - PTMi

Acetylation, Isopeptide bond, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ62735
PRIDEiQ62735

PTM databases

PhosphoSitePlusiQ62735

Expressioni

Inductioni

Heterodimer of NR1H4 and RXR activated by farnesol.1 Publication

Gene expression databases

BgeeiENSRNOG00000007197
ExpressionAtlasiQ62735 baseline and differential
GenevisibleiQ62735 RN

Interactioni

Subunit structurei

Binds DNA predominantly as a heterodimer with RXRA. After activation by agonist binding interacts with coactivators. Interacts with NCOA1, NCOA2, PPARGC1A, CARM1, SETD7, PRMT1, GPS2, SMARCA4 and MED1, EP300 and SMARCD1. Interacts with XRCC5 and XRCC6; decreasing NR1H4/FXR transactivation activity towards ABCB11/BSEP. Interacts with PAGR1 AND NCOA6; indicative for an association with an MLL2/MLL3 complex (ASCOM).By similarity2 Publications

GO - Molecular functioni

  • protein heterodimerization activity Source: RGD

Protein-protein interaction databases

IntActiQ62735, 1 interactor
STRINGi10116.ENSRNOP00000009910

Structurei

Secondary structure

1469
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi244 – 257Combined sources14
Helixi264 – 268Combined sources5
Turni269 – 271Combined sources3
Helixi277 – 300Combined sources24
Helixi305 – 307Combined sources3
Helixi310 – 333Combined sources24
Helixi343 – 349Combined sources7
Beta strandi350 – 353Combined sources4
Helixi356 – 371Combined sources16
Helixi376 – 387Combined sources12
Helixi398 – 419Combined sources22
Helixi426 – 448Combined sources23
Helixi460 – 465Combined sources6

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1OSVX-ray2.50A/B241-469[»]
1OT7X-ray2.90A/B240-468[»]
ProteinModelPortaliQ62735
SMRiQ62735
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ62735

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini245 – 469NR LBDPROSITE-ProRule annotationAdd BLAST225

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni325 – 333Agonist binding1 Publication9

Sequence similaritiesi

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri124 – 144NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri160 – 184NR C4-typePROSITE-ProRule annotationAdd BLAST25

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG3575 Eukaryota
ENOG410XRZC LUCA
GeneTreeiENSGT00870000136372
HOGENOMiHOG000220843
HOVERGENiHBG108655
InParanoidiQ62735
KOiK08537

Family and domain databases

Gene3Di3.30.50.10, 1 hit
InterProiView protein in InterPro
IPR035500 NHR_like_dom_sf
IPR000536 Nucl_hrmn_rcpt_lig-bd
IPR001723 Nuclear_hrmn_rcpt
IPR001728 ThyrH_rcpt
IPR001628 Znf_hrmn_rcpt
IPR013088 Znf_NHR/GATA
PfamiView protein in Pfam
PF00104 Hormone_recep, 1 hit
PF00105 zf-C4, 1 hit
PRINTSiPR00398 STRDHORMONER
PR00047 STROIDFINGER
PR00546 THYROIDHORMR
SMARTiView protein in SMART
SM00430 HOLI, 1 hit
SM00399 ZnF_C4, 1 hit
SUPFAMiSSF48508 SSF48508, 1 hit
PROSITEiView protein in PROSITE
PS51843 NR_LBD, 1 hit
PS00031 NUCLEAR_REC_DBD_1, 1 hit
PS51030 NUCLEAR_REC_DBD_2, 1 hit

Sequencei

Sequence statusi: Complete.

Q62735-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MNLIGPSHLQ ATDEFALSEN LFGVLTEHAA GPLGQNLDLE SYSPYNNVQF
60 70 80 90 100
PQVQPQISSS SYYSNLGFYP QQPEDWYSPG LYELRRMPTE SVYQGETEVS
110 120 130 140 150
EMPVTKKPRM AASSAGRIKG DELCVVCGDR ASGYHYNALT CEGCKGFFRR
160 170 180 190 200
SITKNAVYKC KNGGNCVMDM YMRRKCQDCR LRKCREMGML AECLLTEIQC
210 220 230 240 250
KSKRLRKNVK QHADQTVNED SEGRDLRQVT STTKLCREKT ELTVDQQTLL
260 270 280 290 300
DYIMDSYSKQ RMPQEITNKI LKEEFSAEEN FLILTEMATS HVQILVEFTK
310 320 330 340 350
RLPGFQTLDH EDQIALLKGS AVEAMFLRSA EIFNKKLPAG HADLLEERIR
360 370 380 390 400
KSGISDEYIT PMFSFYKSVG ELKMTQEEYA LLTAIVILSP DRQYIKDREA
410 420 430 440 450
VEKLQEPLLD VLQKLCKIYQ PENPQHFACL LGRLTELRTF NHHHAEMLMS
460
WRVNDHKFTP LLCEIWDVQ
Length:469
Mass (Da):53,935
Last modified:November 1, 1996 - v1
Checksum:i2BEAF5847D9E403C
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U18374 mRNA Translation: AAC52205.1
PIRiA56918
RefSeqiNP_068513.1, NM_021745.1
UniGeneiRn.42943

Genome annotation databases

EnsembliENSRNOT00000009910; ENSRNOP00000009910; ENSRNOG00000007197
GeneIDi60351
KEGGirno:60351
UCSCiRGD:628831 rat

Similar proteinsi

Entry informationi

Entry nameiNR1H4_RAT
AccessioniPrimary (citable) accession number: Q62735
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 27, 2002
Last sequence update: November 1, 1996
Last modified: May 23, 2018
This is version 147 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Cookie policy

We would like to use anonymized google analytics cookies to gather statistics on how uniprot.org is used in aggregate. Learn more

UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health