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Protein

Bile acid receptor

Gene

Nr1h4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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 in innate immune response (PubMed:11030617, 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 (PubMed:20091679, PubMed:20483916). 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) (PubMed:21383957, PubMed:25651182, PubMed:25545350). 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:21383957). In ileal enterocytes activates FABP6/IBABP (involved in cytosolic transport), SLC51A/OSTA and SLC51B/OSTB (involved in secretion of conjugated BAs to the portal blood), and repressor NR0B2/SHP thereby indirectly inhibiting SLC10A2/ASBT (involved in BA uptake) (By similarity). In the intestine activates FGF15 expression and secretion leading to hepatic CYP7A1 repression; the function also involves the coordinated induction of hepatic KLB/beta-klotho expression (PubMed:16213224, PubMed:26505219). Transcriptional activation of FABP6/IBAP and SCD1 but not of ABCB11 is isoform-specific (PubMed:12393883). 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 (By similarity). Modulates lipid homoestasis by activating liver NR0B2/SHP-mediated repression of SREBF1 isoform SREBP-1C (involved in de novo lipogenesis), expression of PLTP (involved in HDL formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1, APOC4, VLDLR and SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and inhibiting expression of MTTP (involved in VLDL assembly) (PubMed:12421815, PubMed:15146238). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance) (PubMed:11579204). Transrepresses APOA1 probably involving a monomeric competition with NR2A1 for binding to a DR1 element (PubMed:21804189). Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase) (PubMed:12891557, PubMed:15146238). 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 (PubMed:15564327, PubMed:16446356, PubMed:16557297, PubMed:16410358, 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 (PubMed:16473946, PubMed:21242261). Down-regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells (PubMed:19864602). Mediates transrepression 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 (By similarity). Involved in the TLR9-mediated protective mechanism in intestinal inflammation (PubMed:23372731). Plays a anti-inflammatory role in liver inflammation; proposed to inhibit proinflammatory (but not antiapoptotic) NF-kappa-B signaling (PubMed:18972444).By similarity2 Publications27 Publications
Isoform 2: Activates transcription of IBAP and SDC1.1 Publication
Isoform 4: Activates transcription of IBAP and SDC1.1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei377 – 3771AgonistBy similarity
Binding sitei385 – 3851AgonistBy similarity
Binding sitei463 – 4631AgonistBy similarity
Binding sitei485 – 4851AgonistBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi135 – 21076Nuclear receptorPROSITE-ProRule annotationAdd
BLAST
Zinc fingeri138 – 15821NR C4-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri174 – 19825NR C4-typePROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

GO - Biological processi

  • bile acid metabolic process Source: MGI
  • bile acid signaling pathway Source: BHF-UCL
  • cell-cell junction assembly Source: UniProtKB
  • cellular response to fatty acid Source: MGI
  • cellular response to lipopolysaccharide Source: UniProtKB
  • cellular response to organonitrogen compound Source: BHF-UCL
  • cellular triglyceride homeostasis Source: MGI
  • defense response to bacterium Source: UniProtKB
  • digestive tract development Source: Ensembl
  • fatty acid homeostasis Source: UniProtKB
  • glucose homeostasis Source: UniProtKB
  • histone H3-R17 methylation Source: MGI
  • inflammatory response Source: UniProtKB-KW
  • innate immune response Source: UniProtKB-KW
  • interleukin-17 secretion Source: MGI
  • intracellular bile acid receptor signaling pathway Source: MGI
  • intracellular receptor signaling pathway Source: BHF-UCL
  • negative regulation of apoptotic process Source: MGI
  • negative regulation of bile acid biosynthetic process Source: MGI
  • negative regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
  • negative regulation of inflammatory response Source: UniProtKB
  • negative regulation of interferon-gamma production Source: UniProtKB
  • negative regulation of interferon-gamma secretion Source: MGI
  • negative regulation of interleukin-1 production Source: UniProtKB
  • negative regulation of interleukin-2 production Source: UniProtKB
  • negative regulation of interleukin-6 production Source: UniProtKB
  • negative regulation of monocyte chemotactic protein-1 production Source: UniProtKB
  • negative regulation of NF-kappaB transcription factor activity Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  • negative regulation of tumor necrosis factor-mediated signaling pathway Source: UniProtKB
  • negative regulation of tumor necrosis factor production Source: UniProtKB
  • negative regulation of tumor necrosis factor secretion Source: MGI
  • nitrogen catabolite activation of transcription from RNA polymerase II promoter Source: BHF-UCL
  • Notch signaling pathway Source: MGI
  • positive regulation of adipose tissue development Source: UniProtKB
  • positive regulation of ammonia assimilation cycle Source: BHF-UCL
  • positive regulation of glucose import in response to insulin stimulus Source: UniProtKB
  • positive regulation of glutamate metabolic process Source: BHF-UCL
  • positive regulation of insulin receptor signaling pathway Source: UniProtKB
  • positive regulation of insulin secretion involved in cellular response to glucose stimulus Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  • regulation of carbohydrate metabolic process Source: Ensembl
  • regulation of cholesterol homeostasis Source: UniProtKB
  • regulation of insulin secretion involved in cellular response to glucose stimulus Source: MGI
  • regulation of low-density lipoprotein particle clearance Source: MGI
  • regulation of transcription from RNA polymerase II promoter Source: MGI
  • regulation of urea metabolic process Source: BHF-UCL
  • response to glucose Source: Ensembl
  • toll-like receptor 4 signaling pathway Source: MGI
  • toll-like receptor 9 signaling pathway Source: UniProtKB
  • transcription from RNA polymerase II promoter Source: GOC
  • triglyceride homeostasis Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Activator, Receptor, Repressor

Keywords - Biological processi

Immunity, Inflammatory response, Innate immunity, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding, Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-MMU-159418. Recycling of bile acids and salts.
R-MMU-192105. Synthesis of bile acids and bile salts.
R-MMU-193368. Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol.
R-MMU-193807. Synthesis of bile acids and bile salts via 27-hydroxycholesterol.
R-MMU-211976. Endogenous sterols.
R-MMU-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
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:1352464. Nr1h4.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

Activation protects mice against cholestasis, development of chronical intestinal inflammation and fibrosis. May suppress intestinal tumorigenesis.

Disruption phenotypei

Elevated serum bile acid, cholesterol, and triglycerides, increased hepatic cholesterol and triglycerides, and a proatherogenic serum lipoprotein profile. Reduced bile acid pools and reduced fecal bile acid excretion.1 Publication

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi370 – 3701K → N: Increases affinity to CDCA and transcriptional activity in response to CDCA; when associated with I-388. 1 Publication
Mutagenesisi388 – 3881V → I: Increases affinity to CDCA and transcriptional activity in response to CDCA; when associated with N-370. 1 Publication

Keywords - Diseasei

Tumor suppressor

Chemistry

ChEMBLiCHEMBL5343.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 488488Bile acid receptorPRO_0000053539Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Cross-linki133 – 133Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) ProbableBy similarity
Modified residuei146 – 1461Phosphoserine; by PKC/PRKCABy similarity
Modified residuei165 – 1651Phosphoserine; by PKC/PRKCABy similarity
Modified residuei168 – 1681N6-acetyllysine; by EP300By similarity
Modified residuei221 – 2211N6-methyllysine; by SETD7By similarity
Modified residuei228 – 2281N6-acetyllysine; by EP300By similarity
Cross-linki291 – 291Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) ProbableBy similarity
Modified residuei458 – 4581Phosphothreonine; by PKC/PRKCZ ProbableBy similarity

Post-translational modificationi

Acetylated by EP300 (PubMed:18842595). Lys-228 as is the major acetylation site for EP300; the dynamicly regulated acetylation inhibits heterodimerization with RXRA and transactivation activity. Deacetylated by SIRT1 (By similarity). Elevated acetylation levels are found in metabolic disease states (mouse models of obesity and type II diabetes) (PubMed:19883617).By similarity2 Publications
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

MaxQBiQ60641.
PaxDbiQ60641.
PRIDEiQ60641.

PTM databases

iPTMnetiQ60641.
PhosphoSiteiQ60641.

Expressioni

Tissue specificityi

Expressed in liver and kidney. Expressed in pancreatic beta cells and macrophages. Expressed in the villus epithelium in adult ileum, with highest expression in the intervillus regions. Expression in colon is reduced by inflammation.4 Publications

Gene expression databases

BgeeiQ60641.
CleanExiMM_NR1H4.
ExpressionAtlasiQ60641. baseline and differential.
GenevisibleiQ60641. MM.

Interactioni

Subunit structurei

Binds DNA predominantly as a heterodimer with RXRA (PubMed:7760852). After activation by agonist binding interacts with coactivators. Interacts with PPARGC1A, SMARCA4 and EP300 (PubMed:14729567, PubMed:18842595, PubMed:19805516). Interacts with NCOA1, NCOA2, CARM1, SETD7, PRMT1, GPS2, SMARCA4 and MED1. 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 similarity). Interacts with NR5A2 (PubMed:20483916).By similarity5 Publications

GO - Molecular functioni

  • retinoid X receptor binding Source: MGI

Protein-protein interaction databases

BioGridi203043. 7 interactions.
DIPiDIP-443N.
STRINGi10090.ENSMUSP00000100933.

Chemistry

BindingDBiQ60641.

Structurei

3D structure databases

ProteinModelPortaliQ60641.
SMRiQ60641. Positions 129-487.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni258 – 476219Ligand-bindingBy similarityAdd
BLAST
Regioni344 – 3529Agonist bindingBy similarity

Sequence similaritiesi

Contains 1 nuclear receptor DNA-binding domain.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri138 – 15821NR C4-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri174 – 19825NR C4-typePROSITE-ProRule annotationAdd
BLAST

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG3575. Eukaryota.
ENOG410XRZC. LUCA.
GeneTreeiENSGT00840000129681.
HOGENOMiHOG000220843.
HOVERGENiHBG108655.
InParanoidiQ60641.
KOiK08537.
OMAiMKPAKGV.
OrthoDBiEOG7DC25S.
TreeFamiTF316304.

Family and domain databases

Gene3Di1.10.565.10. 2 hits.
3.30.50.10. 1 hit.
InterProiIPR000536. Nucl_hrmn_rcpt_lig-bd.
IPR001723. Nuclear_hrmn_rcpt.
IPR001728. ThyrH_rcpt.
IPR001628. Znf_hrmn_rcpt.
IPR013088. Znf_NHR/GATA.
[Graphical view]
PfamiPF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]
PRINTSiPR00398. STRDHORMONER.
PR00047. STROIDFINGER.
PR00546. THYROIDHORMR.
SMARTiSM00430. HOLI. 1 hit.
SM00399. ZnF_C4. 1 hit.
[Graphical view]
SUPFAMiSSF48508. SSF48508. 1 hit.
PROSITEiPS00031. NUCLEAR_REC_DBD_1. 1 hit.
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
[Graphical view]

Sequences (4)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative promoter usage and alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q60641-1) [UniParc]FASTAAdd to basket

Also known as: FXRbeta1, FXRalpha3, FXRalpha2(+)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MVMQFQGLEN PIQISLHHSH RLSGFVPEGM SVKPAKGMLT EHAAGPLGQN
60 70 80 90 100
LDLESYSPYN NVPFPQVQPQ ISSSSYYSNL GFYPQQPEDW YSPGIYELRR
110 120 130 140 150
MPAETGYQGE TEVSEMPVTK KPRMAAASAG RIKGDELCVV CGDRASGYHY
160 170 180 190 200
NALTCEGCKG FFRRSITKNA VYKCKNGGNC VMDMYMRRKC QECRLRKCKE
210 220 230 240 250
MGMLAECMYT GLLTEIQCKS KRLRKNVKQH ADQTANEDDS EGRDLRQVTS
260 270 280 290 300
TTKFCREKTE LTADQQTLLD YIMDSYNKQR MPQEITNKIL KEEFSAEENF
310 320 330 340 350
LILTEMATSH VQILVEFTKK LPGFQTLDHE DQIALLKGSA VEAMFLRSAE
360 370 380 390 400
IFNKKLPAGH ADLLEERIRK SGISDEYITP MFSFYKSVGE LKMTQEEYAL
410 420 430 440 450
LTAIVILSPD RQYIKDREAV EKLQEPLLDV LQKLCKMYQP ENPQHFACLL
460 470 480
GRLTELRTFN HHHAEMLMSW RVNDHKFTPL LCEIWDVQ
Note: Produced by alternative promoter usage.
Length:488
Mass (Da):55,994
Last modified:July 27, 2011 - v3
Checksum:i3E59B7146F8ECC86
GO
Isoform 2 (identifier: Q60641-2) [UniParc]FASTAAdd to basket

Also known as: FXRbeta2, FXFRalpha4, FXRalpha2(-)

The sequence of this isoform differs from the canonical sequence as follows:
     208-211: Missing.

Note: Produced by alternative splicing of isoform 1.
Show »
Length:484
Mass (Da):55,542
Checksum:i06B56494305A438A
GO
Isoform 3 (identifier: Q60641-3) [UniParc]FASTAAdd to basket

Also known as: FXRalpha1, FXRalpha1(+)

The sequence of this isoform differs from the canonical sequence as follows:
     1-36: MVMQFQGLENPIQISLHHSHRLSGFVPEGMSVKPAK → MNLIGHSHLQATDEFSLSESLF

Note: Produced by alternative promoter usage.
Show »
Length:474
Mass (Da):54,439
Checksum:i8629C4BAD8DC75B0
GO
Isoform 4 (identifier: Q60641-4) [UniParc]FASTAAdd to basket

Also known as: FXRalpha2, FXRalpha1(-)

The sequence of this isoform differs from the canonical sequence as follows:
     1-36: MVMQFQGLENPIQISLHHSHRLSGFVPEGMSVKPAK → MNLIGHSHLQATDEFSLSESLF
     208-211: Missing.

Note: Produced by alternative splicing of isoform 3.
Show »
Length:470
Mass (Da):53,987
Checksum:i01E7DDA2F92BD35B
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti28 – 281E → D in AAC53066 (PubMed:7760852).Curated
Sequence conflicti28 – 281E → D in AAH15261 (PubMed:15489334).Curated
Sequence conflicti199 – 1991K → R in AAC53065 (PubMed:7760852).Curated
Sequence conflicti199 – 1991K → R in AAC53066 (PubMed:7760852).Curated
Sequence conflicti199 – 1991K → R in AAC52978 (PubMed:7760852).Curated
Sequence conflicti199 – 1991K → R in AAH15261 (PubMed:15489334).Curated
Sequence conflicti235 – 2351A → V in AAC53065 (PubMed:7760852).Curated
Sequence conflicti235 – 2351A → V in AAC53066 (PubMed:7760852).Curated
Sequence conflicti235 – 2351A → V in AAC52978 (PubMed:7760852).Curated
Sequence conflicti235 – 2351A → V in AAH15261 (PubMed:15489334).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 3636MVMQF…VKPAK → MNLIGHSHLQATDEFSLSES LF in isoform 3 and isoform 4. 1 PublicationVSP_058157Add
BLAST
Alternative sequencei208 – 2114Missing in isoform 2 and isoform 4. 3 PublicationsVSP_003666

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U09416 mRNA. Translation: AAC53066.1.
U09417 mRNA. Translation: AAC53065.1.
U09418 mRNA. Translation: AAC52978.1.
AC152417 Genomic DNA. No translation available.
BC015261 mRNA. Translation: AAH15261.1.
CCDSiCCDS24116.1. [Q60641-2]
CCDS48668.1. [Q60641-1]
CCDS48669.1. [Q60641-3]
PIRiI49018.
I49019.
I49020.
RefSeqiNP_001156976.1. NM_001163504.1. [Q60641-3]
NP_001157172.1. NM_001163700.1. [Q60641-1]
XP_006513454.1. XM_006513391.2. [Q60641-3]
XP_006513456.1. XM_006513393.2. [Q60641-4]
UniGeneiMm.3095.

Genome annotation databases

EnsembliENSMUST00000058126; ENSMUSP00000053092; ENSMUSG00000047638. [Q60641-2]
ENSMUST00000105296; ENSMUSP00000100933; ENSMUSG00000047638. [Q60641-1]
ENSMUST00000105297; ENSMUSP00000100934; ENSMUSG00000047638. [Q60641-3]
GeneIDi20186.
KEGGimmu:20186.
UCSCiuc007gsg.2. mouse. [Q60641-1]

Keywords - Coding sequence diversityi

Alternative promoter usage, Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U09416 mRNA. Translation: AAC53066.1.
U09417 mRNA. Translation: AAC53065.1.
U09418 mRNA. Translation: AAC52978.1.
AC152417 Genomic DNA. No translation available.
BC015261 mRNA. Translation: AAH15261.1.
CCDSiCCDS24116.1. [Q60641-2]
CCDS48668.1. [Q60641-1]
CCDS48669.1. [Q60641-3]
PIRiI49018.
I49019.
I49020.
RefSeqiNP_001156976.1. NM_001163504.1. [Q60641-3]
NP_001157172.1. NM_001163700.1. [Q60641-1]
XP_006513454.1. XM_006513391.2. [Q60641-3]
XP_006513456.1. XM_006513393.2. [Q60641-4]
UniGeneiMm.3095.

3D structure databases

ProteinModelPortaliQ60641.
SMRiQ60641. Positions 129-487.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi203043. 7 interactions.
DIPiDIP-443N.
STRINGi10090.ENSMUSP00000100933.

Chemistry

BindingDBiQ60641.
ChEMBLiCHEMBL5343.

PTM databases

iPTMnetiQ60641.
PhosphoSiteiQ60641.

Proteomic databases

MaxQBiQ60641.
PaxDbiQ60641.
PRIDEiQ60641.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000058126; ENSMUSP00000053092; ENSMUSG00000047638. [Q60641-2]
ENSMUST00000105296; ENSMUSP00000100933; ENSMUSG00000047638. [Q60641-1]
ENSMUST00000105297; ENSMUSP00000100934; ENSMUSG00000047638. [Q60641-3]
GeneIDi20186.
KEGGimmu:20186.
UCSCiuc007gsg.2. mouse. [Q60641-1]

Organism-specific databases

CTDi9971.
MGIiMGI:1352464. Nr1h4.

Phylogenomic databases

eggNOGiKOG3575. Eukaryota.
ENOG410XRZC. LUCA.
GeneTreeiENSGT00840000129681.
HOGENOMiHOG000220843.
HOVERGENiHBG108655.
InParanoidiQ60641.
KOiK08537.
OMAiMKPAKGV.
OrthoDBiEOG7DC25S.
TreeFamiTF316304.

Enzyme and pathway databases

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

Miscellaneous databases

NextBioi297725.
PROiQ60641.
SOURCEiSearch...

Gene expression databases

BgeeiQ60641.
CleanExiMM_NR1H4.
ExpressionAtlasiQ60641. baseline and differential.
GenevisibleiQ60641. MM.

Family and domain databases

Gene3Di1.10.565.10. 2 hits.
3.30.50.10. 1 hit.
InterProiIPR000536. Nucl_hrmn_rcpt_lig-bd.
IPR001723. Nuclear_hrmn_rcpt.
IPR001728. ThyrH_rcpt.
IPR001628. Znf_hrmn_rcpt.
IPR013088. Znf_NHR/GATA.
[Graphical view]
PfamiPF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]
PRINTSiPR00398. STRDHORMONER.
PR00047. STROIDFINGER.
PR00546. THYROIDHORMR.
SMARTiSM00430. HOLI. 1 hit.
SM00399. ZnF_C4. 1 hit.
[Graphical view]
SUPFAMiSSF48508. SSF48508. 1 hit.
PROSITEiPS00031. NUCLEAR_REC_DBD_1. 1 hit.
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors."
    Seol W., Choi H.S., Moore D.D.
    Mol. Endocrinol. 9:72-85(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), INTERACTION WITH RXRA.
    Tissue: Liver.
  2. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: C57BL/6J.
  3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
    Tissue: Kidney.
  4. "Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis."
    Sinal C.J., Tohkin M., Miyata M., Ward J.M., Lambert G., Gonzalez F.J.
    Cell 102:731-744(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  5. "Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids."
    Kast H.R., Nguyen C.M., Sinal C.J., Jones S.A., Laffitte B.A., Reue K., Gonzalez F.J., Willson T.M., Edwards P.A.
    Mol. Endocrinol. 15:1720-1728(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN LIPID HOMEOSTASIS.
  6. "The amino acid residues asparagine 354 and isoleucine 372 of human farnesoid X receptor confer the receptor with high sensitivity to chenodeoxycholate."
    Cui J., Heard T.S., Yu J., Lo J.L., Huang L., Li Y., Schaeffer J.M., Wright S.D.
    J. Biol. Chem. 277:25963-25969(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF LYS-370 AND VAL-388.
  7. "Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor."
    Kast H.R., Goodwin B., Tarr P.T., Jones S.A., Anisfeld A.M., Stoltz C.M., Tontonoz P., Kliewer S., Willson T.M., Edwards P.A.
    J. Biol. Chem. 277:2908-2915(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  8. Cited for: FUNCTION IN LIPID HOMEOSTASIS.
  9. "Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation."
    Zhang Y., Kast-Woelbern H.R., Edwards P.A.
    J. Biol. Chem. 278:104-110(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, ALTERNATIVE SPLICING.
  10. "The farnesoid X-receptor is an essential regulator of cholesterol homeostasis."
    Lambert G., Amar M.J., Guo G., Brewer H.B. Jr., Gonzalez F.J., Sinal C.J.
    J. Biol. Chem. 278:2563-2570(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN LIPID HOMEOSTASIS.
  11. "Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor."
    Anisfeld A.M., Kast-Woelbern H.R., Meyer M.E., Jones S.A., Zhang Y., Williams K.J., Willson T., Edwards P.A.
    J. Biol. Chem. 278:20420-20428(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN LIPID HOMEOSTASIS.
  12. "Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR."
    Zhang Y., Castellani L.W., Sinal C.J., Gonzalez F.J., Edwards P.A.
    Genes Dev. 18:157-169(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH PPARGC1A.
  13. "Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c."
    Watanabe M., Houten S.M., Wang L., Moschetta A., Mangelsdorf D.J., Heyman R.A., Moore D.D., Auwerx J.
    J. Clin. Invest. 113:1408-1418(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN LIPID HOMEOSTASIS.
  14. "Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis."
    Inagaki T., Choi M., Moschetta A., Peng L., Cummins C.L., McDonald J.G., Luo G., Jones S.A., Goodwin B., Richardson J.A., Gerard R.D., Repa J.J., Mangelsdorf D.J., Kliewer S.A.
    Cell Metab. 2:217-225(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN BA HOMEOSTASIS.
  15. Cited for: FUNCTION IN GLUCOSE HOMEOSTASIS.
  16. "Chenodeoxycholic acid-mediated activation of the farnesoid X receptor negatively regulates hydroxysteroid sulfotransferase."
    Miyata M., Matsuda Y., Tsuchiya H., Kitada H., Akase T., Shimada M., Nagata K., Gonzalez F.J., Yamazoe Y.
    Drug Metab. Pharmacokinet. 21:315-323(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION BA HOMEOSTASIS.
  17. Cited for: FUNCTION IN GLUCOSE HOMEOSTASIS.
  18. "Farnesoid X receptor is essential for normal glucose homeostasis."
    Ma K., Saha P.K., Chan L., Moore D.D.
    J. Clin. Invest. 116:1102-1109(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN GLUCOSE HOMEOSTASIS.
  19. "Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice."
    Zhang Y., Lee F.Y., Barrera G., Lee H., Vales C., Gonzalez F.J., Willson T.M., Edwards P.A.
    Proc. Natl. Acad. Sci. U.S.A. 103:1006-1011(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN GLUCOSE HOMEOSTASIS.
  20. Cited for: FUNCTION IN ANTIBACTERIAL DEFENSE, TISSUE SPECIFICITY.
  21. "Nuclear bile acid receptor FXR protects against intestinal tumorigenesis."
    Modica S., Murzilli S., Salvatore L., Schmidt D.R., Moschetta A.
    Cancer Res. 68:9589-9594(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: POSSIBLE FUNCTION IN TUMOR SUPPRESSION.
  22. "The p300 acetylase is critical for ligand-activated farnesoid X receptor (FXR) induction of SHP."
    Fang S., Tsang S., Jones R., Ponugoti B., Yoon H., Wu S.Y., Chiang C.M., Willson T.M., Kemper J.K.
    J. Biol. Chem. 283:35086-35095(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH EP300, ACETYLATION.
  23. "Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response."
    Wang Y.D., Chen W.D., Wang M., Yu D., Forman B.M., Huang W.
    Hepatology 48:1632-1643(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN INFLAMMATORY RESPONSE.
  24. "Reciprocal regulation of the bile acid-activated receptor FXR and the interferon-gamma-STAT-1 pathway in macrophages."
    Renga B., Migliorati M., Mencarelli A., Fiorucci S.
    Biochim. Biophys. Acta 1792:564-573(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY.
  25. "FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states."
    Kemper J.K., Xiao Z., Ponugoti B., Miao J., Fang S., Kanamaluru D., Tsang S., Wu S.Y., Chiang C.M., Veenstra T.D.
    Cell Metab. 10:392-404(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: ACETYLATION.
  26. "The bile acid receptor FXR is a modulator of intestinal innate immunity."
    Vavassori P., Mencarelli A., Renga B., Distrutti E., Fiorucci S.
    J. Immunol. 183:6251-6261(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN INTESTINAL INNATE IMMUNITY, TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
  27. "Functional specificities of Brm and Brg-1 Swi/Snf ATPases in the feedback regulation of hepatic bile acid biosynthesis."
    Miao J., Fang S., Lee J., Comstock C., Knudsen K.E., Kemper J.K.
    Mol. Cell. Biol. 29:6170-6181(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH SMARCA4.
  28. "The nuclear receptor FXR is expressed in pancreatic beta-cells and protects human islets from lipotoxicity."
    Popescu I.R., Helleboid-Chapman A., Lucas A., Vandewalle B., Dumont J., Bouchaert E., Derudas B., Kerr-Conte J., Caron S., Pattou F., Staels B.
    FEBS Lett. 584:2845-2851(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN GLUCOSE HOMEOSTASIS, TISSUE SPECIFICITY.
  29. "Genome-wide tissue-specific farnesoid X receptor binding in mouse liver and intestine."
    Thomas A.M., Hart S.N., Kong B., Fang J., Zhong X.B., Guo G.L.
    Hepatology 51:1410-1419(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: DNA-BINDING.
  30. "Genome-wide interrogation of hepatic FXR reveals an asymmetric IR-1 motif and synergy with LRH-1."
    Chong H.K., Infante A.M., Seo Y.K., Jeon T.I., Zhang Y., Edwards P.A., Xie X., Osborne T.F.
    Nucleic Acids Res. 38:6007-6017(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: DNA-BINDING, INTERACTION WITH NR5A2.
  31. "Deciphering the nuclear bile acid receptor FXR paradigm."
    Modica S., Gadaleta R.M., Moschetta A.
    Nucl. Recept. Signal. 8:E005-E005(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW.
  32. "Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease."
    Gadaleta R.M., van Erpecum K.J., Oldenburg B., Willemsen E.C., Renooij W., Murzilli S., Klomp L.W., Siersema P.D., Schipper M.E., Danese S., Penna G., Laverny G., Adorini L., Moschetta A., van Mil S.W.
    Gut 60:463-472(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN INTESTINAL INFLAMMATION.
  33. Cited for: FUNCTION IN LIPID HOMEOSTASIS.
  34. "Anti-inflammatory and metabolic actions of FXR: insights into molecular mechanisms."
    Hollman D.A., Milona A., van Erpecum K.J., van Mil S.W.
    Biochim. Biophys. Acta 1821:1443-1452(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW.
  35. "Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis."
    Modica S., Petruzzelli M., Bellafante E., Murzilli S., Salvatore L., Celli N., Di Tullio G., Palasciano G., Moustafa T., Halilbasic E., Trauner M., Moschetta A.
    Gastroenterology 142:355-365(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: POSSIBLE FUNCTION IN PROTECTION AGAINST CHOLESTASIS.
  36. "The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation."
    Renga B., Mencarelli A., Cipriani S., D'Amore C., Carino A., Bruno A., Francisci D., Zampella A., Distrutti E., Fiorucci S.
    PLoS ONE 8:E54472-E54472(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN INFLAMMATORY RESPONSE.
  37. Cited for: FUNCTION IN BA HOMEOSTASIS.
  38. "Farnesoid X receptor-induced lysine-specific histone demethylase reduces hepatic bile acid levels and protects the liver against bile acid toxicity."
    Kim Y.C., Fang S., Byun S., Seok S., Kemper B., Kemper J.K.
    Hepatology 62:220-231(2015) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN BA HOMEOSTASIS***INTACT.
  39. "FXR primes the liver for intestinal FGF15 signaling by transient induction of beta-Klotho."
    Fu T., Kim Y.C., Byun S., Kim D.H., Seok S., Suino-Powell K., Xu H.E., Kemper B., Kemper J.K.
    Mol. Endocrinol. 30:92-103(2016) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN BA HOMEOSTASIS.

Entry informationi

Entry nameiNR1H4_MOUSE
AccessioniPrimary (citable) accession number: Q60641
Secondary accession number(s): D3YTT2
, E9QJW2, Q60642, Q60643
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 27, 2002
Last sequence update: July 27, 2011
Last modified: May 11, 2016
This is version 156 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

Mouse Nr1h4/FXR is less responsive to CDCA and more responsive to cholic acid (CA) than human FXR.2 Publications

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.