Farnesoid_X_receptor Knowpia

NR1H4
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1OSH, 3BEJ, 3DCT, 3DCU, 3FLI, 3FXV, 3GD2, 3HC5, 3HC6, 3L1B, 3OKH, 3OKI, 3OLF, 3OMK, 3OMM, 3OOF, 3OOK, 3RUT, 3RUU, 3RVF, 3P88, 3P89, 4OIV, 4WVD, 4QE6, 4QE8
Identifiers
Aliases	NR1H4, BAR, FXR, HRR-1, HRR1, RIP14, nuclear receptor subfamily 1 group H member 4, PFIC5
External IDs	OMIM: 603826 MGI: 1352464 HomoloGene: 3760 GeneCards: NR1H4
Gene location (Human)
Chr.	Chromosome 12 (human)
End	100,564,414 bp
Gene location (Mouse)
Chr.	Chromosome 10 (mouse)
End	89,369,447 bp
RNA expression pattern
	Top expressed in
	right lobe of liver; ; right adrenal gland; ; oocyte; ; left adrenal gland; ; jejunal mucosa; ; duodenum; ; secondary oocyte; ; kidney; ; kidney tubule; ; gallbladder;
	Top expressed in
	ileum; ; left lobe of liver; ; kidney; ; proximal tubule; ; Paneth cell; ; jejunum; ; duodenum; ; left colon; ; crypt of lieberkuhn of small intestine; ; proximal straight tubule;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	RNA polymerase II cis-regulatory region sequence-specific DNA binding; sequence-specific DNA binding; DNA binding; transcription corepressor activity; DNA-binding transcription factor activity; transcription coactivator activity; zinc ion binding; DNA-binding transcription activator activity, RNA polymerase II-specific; metal ion binding; retinoid X receptor binding; steroid hormone receptor activity; bile acid binding; protein binding; nuclear receptor binding; transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding; chenodeoxycholic acid binding; transcription cis-regulatory region binding; RNA polymerase II transcription regulatory region sequence-specific DNA binding; nuclear receptor activity; bile acid receptor activity; DNA-binding transcription factor activity, RNA polymerase II-specific; transcription factor binding; nuclear receptor coactivator activity; signaling receptor activity;
Cellular component	nucleoplasm; nucleus; RNA polymerase II transcription regulator complex;
Biological process	Notch signaling pathway; cellular triglyceride homeostasis; cellular response to organonitrogen compound; regulation of insulin secretion involved in cellular response to glucose stimulus; positive regulation of ammonia assimilation cycle; toll-like receptor 4 signaling pathway; immune system process; histone H3-R17 methylation; regulation of transcription by RNA polymerase II; positive regulation of glutamate metabolic process; intracellular bile acid receptor signaling pathway; negative regulation of apoptotic process; negative regulation of transcription by RNA polymerase II; transcription, DNA-templated; regulation of low-density lipoprotein particle clearance; regulation of bile acid biosynthetic process; regulation of cholesterol metabolic process; regulation of urea metabolic process; intracellular receptor signaling pathway; negative regulation of bile acid biosynthetic process; cellular response to fatty acid; bile acid and bile salt transport; nitrogen catabolite activation of transcription from RNA polymerase II promoter; transcription initiation from RNA polymerase II promoter; inflammatory response; innate immune response; signal transduction; steroid hormone mediated signaling pathway; fatty acid homeostasis; positive regulation of insulin receptor signaling pathway; cellular response to lipopolysaccharide; negative regulation of interleukin-2 production; positive regulation of insulin secretion involved in cellular response to glucose stimulus; negative regulation of inflammatory response; glucose homeostasis; negative regulation of NF-kappaB transcription factor activity; positive regulation of adipose tissue development; cell-cell junction assembly; toll-like receptor 9 signaling pathway; negative regulation of monocyte chemotactic protein-1 production; bile acid metabolic process; negative regulation of I-kappaB kinase/NF-kappaB signaling; negative regulation of tumor necrosis factor-mediated signaling pathway; defense response to bacterium; negative regulation of interleukin-1 production; negative regulation of tumor necrosis factor production; negative regulation of interleukin-6 production; triglyceride homeostasis; negative regulation of interferon-gamma production; regulation of transcription, DNA-templated; bile acid signaling pathway; positive regulation of transcription by RNA polymerase II; positive regulation of phosphatidic acid biosynthetic process; cholesterol homeostasis; lipid metabolism; multicellular organism development; cell differentiation; lipid homeostasis; cellular glucose homeostasis;
	Sources:Amigo / QuickGO
Orthologs
	9971
	20186
	ENSG00000012504
	ENSMUSG00000047638
	Q96RI1
	Q60641
NM_001206977; NM_001206978; NM_001206979; NM_001206992; NM_001206993;
	NM_005123
	NM_001163504; NM_001163700; NM_009108; NM_001385711
NP_001193906; NP_001193907; NP_001193908; NP_001193921; NP_001193922;
	NP_005114; NP_001193906.1; NP_001193908.1
	NP_001156976; NP_001157172; NP_033134; NP_001372640
	Wikidata
View/Edit Human	View/Edit Mouse

The bile acid receptor (BAR), also known as farnesoid X receptor (FXR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4), is a nuclear receptor that is encoded by the NR1H4 gene in humans.^[5]^[6]

Function edit

FXR is expressed at high levels in the liver and intestine. Chenodeoxycholic acid and other bile acids are natural ligands for FXR. Similar to other nuclear receptors, when activated, FXR translocates to the cell nucleus, forms a dimer (in this case a heterodimer with RXR) and binds to hormone response elements on DNA, which up- or down-regulates the expression of certain genes.^[6]

One of the primary functions of FXR activation is the suppression of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis from cholesterol. FXR does not directly bind to the CYP7A1 promoter. Rather, FXR induces expression of small heterodimer partner (SHP), which then functions to inhibit transcription of the CYP7A1 gene. In this way, a negative feedback pathway is established in which synthesis of bile acids is inhibited when cellular levels are already high.

The absence of FXR in an FXR^-/- mouse model led to increased bile acids in the liver, and the spontaneous development of liver tumors.^[7] Reducing the pool of bile acids in the FXR^-/- mice by feeding the bile acid sequestering resin cholestyramine reduced the number and size of the malignant lesions.

FXR has also been found to be important in regulation of hepatic triglyceride levels.^[8] Specifically, FXR activation suppresses lipogenesis and promotes free fatty acid oxidation by PPARα activation.^[8] Studies have also shown the FXR to regulate the expression and activity of epithelial transport proteins involved in fluid homeostasis in the intestine, such as the cystic fibrosis transmembrane conductance regulator (CFTR).^[9]

Activation of FXR in diabetic mice reduces plasma glucose and improves insulin sensitivity, whereas inactivation of FXR has the opposite effect.^[8]

Interactions edit

Farnesoid X receptor has been shown to interact with:

Ligands edit

A number of ligands for FXR are known, of both natural and synthetic origin.^[12]^[13]^[14]

Agonists

Antagonists

Guggulsterone

References edit

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000012504 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000047638 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Entrez Gene: NR1H4 nuclear receptor subfamily 1, group H, member 4".
^ ^a ^b Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW, Evans RM, Weinberger C (Jun 1995). "Identification of a nuclear receptor that is activated by farnesol metabolites". Cell. 81 (5): 687–93. doi:10.1016/0092-8674(95)90530-8. PMID 7774010.
^ Yang F, Huang X, Yi T, Yen Y, Moore DD, Huang W. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res. 2007 Feb 1;67(3):863-7. doi: 10.1158/0008-5472.CAN-06-1078. PMID 17283114
^ ^a ^b ^c Jiao Y, Lu Y, Li XY (Jan 2015). "Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis". Acta Pharmacologica Sinica. 36 (1): 44–50. doi:10.1038/aps.2014.116. PMC 4571315. PMID 25500875.
^ Mroz MS, Keating N, Ward JB, Sarker R, Amu S, Aviello G, Donowitz M, Fallon PG, Keely SJ (May 2014). "Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo" (PDF). Gut. 63 (5): 808–17. doi:10.1136/gutjnl-2013-305088. PMID 23916961. S2CID 15778582.
^ Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA (Jan 2004). "Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR". Genes & Development. 18 (2): 157–69. doi:10.1101/gad.1138104. PMC 324422. PMID 14729567.
^ Seol W, Choi HS, Moore DD (Jan 1995). "Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors". Molecular Endocrinology. 9 (1): 72–85. doi:10.1210/mend.9.1.7760852. PMID 7760852.
^ Fiorucci S, Zampella A, Distrutti E (2012). "Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders". Current Topics in Medicinal Chemistry. 12 (6): 605–24. doi:10.2174/156802612799436678. PMID 22242859.
^ Fiorucci S, Mencarelli A, Distrutti E, Zampella A (May 2012). "Farnesoid X receptor: from medicinal chemistry to clinical applications". Future Medicinal Chemistry. 4 (7): 877–91. doi:10.4155/fmc.12.41. PMID 22571613.
^ Vaz B, de Lera ÁR (Nov 2012). "Advances in drug design with RXR modulators". Expert Opinion on Drug Discovery. 7 (11): 1003–16. doi:10.1517/17460441.2012.722992. PMID 22954251. S2CID 36317393.
^ Ricketts ML, Boekschoten MV, Kreeft AJ, Hooiveld GJ, Moen CJ, Müller M, Frants RR, Kasanmoentalib S, Post SM, Princen HM, Porter JG, Katan MB, Hofker MH, Moore DD (Jul 2007). "The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors". Molecular Endocrinology. 21 (7): 1603–16. doi:10.1210/me.2007-0133. PMID 17456796.
^ Zhang, S.; Pan, X.; Jeong, H. (2015). "GW4064, an Agonist of Farnesoid X Receptor, Represses CYP3A4 Expression in Human Hepatocytes by Inducing Small Heterodimer Partner Expression". Drug Metabolism and Disposition. 43 (5): 743–748. doi:10.1124/dmd.114.062836. PMC 4407707. PMID 25725071.
^ Carotti A, Marinozzi M, Custodi C, Cerra B, Pellicciari R, Gioiello A, Macchiarulo A (2014). "Beyond bile acids: targeting Farnesoid X Receptor (FXR) with natural and synthetic ligands". Current Topics in Medicinal Chemistry. 14 (19): 2129–42. doi:10.2174/1568026614666141112094058. PMID 25388537. Archived from the original on 2021-10-19.
^ Jin L, Feng X, Rong H, Pan Z, Inaba Y, Qiu L, et al. (2013). "The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism". Nature Communications. 4: 1937. Bibcode:2013NatCo...4.1937J. doi:10.1038/ncomms2924. PMID 23728580.

External links edit

"Farnesoid X Receptor (NR1H4)". Nuclear Receptor Resource. Archived from the original on 2015-01-12. Retrieved 2015-01-12.
farnesoid+X-activated+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000012504 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000047638 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: NR1H4 nuclear receptor subfamily 1, group H, member 4".

[pmid7774010-6] Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW, Evans RM, Weinberger C (Jun 1995). "Identification of a nuclear receptor that is activated by farnesol metabolites". Cell. 81 (5): 687–93. doi:10.1016/0092-8674(95)90530-8. PMID 7774010.

[7] Yang F, Huang X, Yi T, Yen Y, Moore DD, Huang W. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res. 2007 Feb 1;67(3):863-7. doi: 10.1158/0008-5472.CAN-06-1078. PMID 17283114

[pmid25500875-8] Jiao Y, Lu Y, Li XY (Jan 2015). "Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis". Acta Pharmacologica Sinica. 36 (1): 44–50. doi:10.1038/aps.2014.116. PMC 4571315. PMID 25500875.

[pmid23916961-9] Mroz MS, Keating N, Ward JB, Sarker R, Amu S, Aviello G, Donowitz M, Fallon PG, Keely SJ (May 2014). "Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo" (PDF). Gut. 63 (5): 808–17. doi:10.1136/gutjnl-2013-305088. PMID 23916961. S2CID 15778582.

[pmid14729567-10] Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA (Jan 2004). "Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR". Genes & Development. 18 (2): 157–69. doi:10.1101/gad.1138104. PMC 324422. PMID 14729567.

[pmid7760852-11] Seol W, Choi HS, Moore DD (Jan 1995). "Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors". Molecular Endocrinology. 9 (1): 72–85. doi:10.1210/mend.9.1.7760852. PMID 7760852.

[pmid22242859-12] Fiorucci S, Zampella A, Distrutti E (2012). "Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders". Current Topics in Medicinal Chemistry. 12 (6): 605–24. doi:10.2174/156802612799436678. PMID 22242859.

[pmid22571613-13] Fiorucci S, Mencarelli A, Distrutti E, Zampella A (May 2012). "Farnesoid X receptor: from medicinal chemistry to clinical applications". Future Medicinal Chemistry. 4 (7): 877–91. doi:10.4155/fmc.12.41. PMID 22571613.

[pmid22954251-14] Vaz B, de Lera ÁR (Nov 2012). "Advances in drug design with RXR modulators". Expert Opinion on Drug Discovery. 7 (11): 1003–16. doi:10.1517/17460441.2012.722992. PMID 22954251. S2CID 36317393.

[pmid17456796-15] Ricketts ML, Boekschoten MV, Kreeft AJ, Hooiveld GJ, Moen CJ, Müller M, Frants RR, Kasanmoentalib S, Post SM, Princen HM, Porter JG, Katan MB, Hofker MH, Moore DD (Jul 2007). "The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors". Molecular Endocrinology. 21 (7): 1603–16. doi:10.1210/me.2007-0133. PMID 17456796.

[16] Zhang, S.; Pan, X.; Jeong, H. (2015). "GW4064, an Agonist of Farnesoid X Receptor, Represses CYP3A4 Expression in Human Hepatocytes by Inducing Small Heterodimer Partner Expression". Drug Metabolism and Disposition. 43 (5): 743–748. doi:10.1124/dmd.114.062836. PMC 4407707. PMID 25725071.

[pmid25388537-17] Carotti A, Marinozzi M, Custodi C, Cerra B, Pellicciari R, Gioiello A, Macchiarulo A (2014). "Beyond bile acids: targeting Farnesoid X Receptor (FXR) with natural and synthetic ligands". Current Topics in Medicinal Chemistry. 14 (19): 2129–42. doi:10.2174/1568026614666141112094058. PMID 25388537. Archived from the original on 2021-10-19.

[18] Jin L, Feng X, Rong H, Pan Z, Inaba Y, Qiu L, et al. (2013). "The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism". Nature Communications. 4: 1937. Bibcode:2013NatCo...4.1937J. doi:10.1038/ncomms2924. PMID 23728580.

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Summary

Function edit

Interactions edit

Ligands edit

References edit

Further reading edit

External links edit