View source for Farnesoid X receptor

{{Short description|Protein-coding gene in the species Homo sapiens}}
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{{Infobox_gene}}

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.<ref name="entrez">{{cite web | title = Entrez Gene: NR1H4 nuclear receptor subfamily 1, group H, member 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9971}}</ref><ref name="pmid7774010"/>

== Function ==
FXR is expressed at high levels in the liver and intestine.  [[Chenodeoxycholic acid]] and other [[bile acid]]s are natural [[Ligand (biochemistry)|ligands]] for FXR. Similar to other nuclear receptors, when activated, FXR translocates to the [[cell nucleus]], forms a [[protein dimer|dimer]] (in this case a heterodimer with [[Retinoid X receptor|RXR]]) and binds to [[hormone response element]]s on DNA, which up- or down-regulates the expression of certain [[gene]]s.<ref name="pmid7774010">{{cite journal | vauthors = Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW, Evans RM, Weinberger C | title = Identification of a nuclear receptor that is activated by farnesol metabolites | journal = Cell | volume = 81 | issue = 5 | pages = 687–693 | date = June 1995 | pmid = 7774010 | doi = 10.1016/0092-8674(95)90530-8 | doi-access = free }}</ref>

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.  FXR likewise stimulates the synthesis of [[FGF19|fibroblast growth factor 19]], which also inhibits expression of CYP7A1 and sterol 12-alpha-hydroxylase ([[CYP8B1]]) via [[FGFR4|fibroblast growth factor receptor 4]]. In this way, a [[negative feedback]] pathway is established in which synthesis of bile acids is inhibited when cellular levels are already high.<ref>{{cite journal | vauthors = Jiang L, Zhang H, Xiao D, Wei H, Chen Y | title = Farnesoid X receptor (FXR): Structures and ligands | journal = Computational and Structural Biotechnology Journal | volume = 19 | pages = 2148–2159 | year = 2021 | pmid = 33995909 | pmc = 8091178 | doi = 10.1016/j.csbj.2021.04.029 | doi-access = free }}</ref>

The absence of FXR in an ''FXR<sup>-/-</sup>'' mouse model led to increased bile acids in the liver, and the spontaneous development of [[liver cancer|liver tumors]].<ref>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</ref> Reducing the pool of bile acids in the ''FXR<sup>-/-</sup>'' mice by feeding the bile acid sequestering resin [[cholestyramine]] reduced the number and size of the malignant lesions.{{cn|date=December 2024}}

FXR has also been found to be important in regulation of hepatic [[triglyceride]] levels.<ref name="pmid25500875">{{cite journal | vauthors = Jiao Y, Lu Y, Li XY | title = Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis | journal = Acta Pharmacologica Sinica | volume = 36 | issue = 1 | pages = 44–50 | date = January 2015 | pmid = 25500875 | pmc = 4571315 | doi = 10.1038/aps.2014.116 }}</ref> Specifically, FXR activation suppresses [[lipogenesis]] and promotes [[free fatty acid]] [[oxidation]] by [[Peroxisome proliferator-activated receptor alpha|PPARα]] activation.<ref name="pmid25500875" />  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).<ref name="pmid23916961">{{cite journal | vauthors = Mroz MS, Keating N, Ward JB, Sarker R, Amu S, Aviello G, Donowitz M, Fallon PG, Keely SJ | title = Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo | journal = Gut | volume = 63 | issue = 5 | pages = 808–817 | date = May 2014 | pmid = 23916961 | doi = 10.1136/gutjnl-2013-305088 | s2cid = 15778582 | url = https://figshare.com/articles/journal_contribution/10786373 }}</ref>

Activation of FXR in diabetic mice reduces plasma glucose and improves [[Insulin resistance|insulin sensitivity]], whereas inactivation of FXR has the opposite effect.<ref name="pmid25500875" />

== Interactions ==
Farnesoid X receptor has been shown to [[Protein-protein interaction|interact]] with:
* [[PPARGC1A|Peroxisome proliferator-activated receptor gamma coactivator 1-alpha]]<ref name = pmid14729567>{{cite journal | vauthors = Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA | title = Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR | journal = Genes & Development | volume = 18 | issue = 2 | pages = 157–169 | date = January 2004 | pmid = 14729567 | pmc = 324422 | doi = 10.1101/gad.1138104 }}</ref>  and
* [[Retinoid X receptor alpha]].<ref name = pmid7760852>{{cite journal | vauthors = Seol W, Choi HS, Moore DD | title = Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors | journal = Molecular Endocrinology | volume = 9 | issue = 1 | pages = 72–85 | date = January 1995 | pmid = 7760852 | doi = 10.1210/mend.9.1.7760852 | doi-access = free }}</ref>

== Ligands ==
A number of ligands for FXR are known, of both natural and synthetic origin.<ref name="pmid22242859">{{cite journal | vauthors = Fiorucci S, Zampella A, Distrutti E | title = Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders | journal = Current Topics in Medicinal Chemistry | volume = 12 | issue = 6 | pages = 605–624 | year = 2012 | pmid = 22242859 | doi = 10.2174/156802612799436678 }}</ref><ref name="pmid22571613">{{cite journal | vauthors = Fiorucci S, Mencarelli A, Distrutti E, Zampella A | title = Farnesoid X receptor: from medicinal chemistry to clinical applications | journal = Future Medicinal Chemistry | volume = 4 | issue = 7 | pages = 877–891 | date = May 2012 | pmid = 22571613 | doi = 10.4155/fmc.12.41 }}</ref><ref name="pmid22954251">{{cite journal | vauthors = Vaz B, de Lera ÁR | title = Advances in drug design with RXR modulators | journal = Expert Opinion on Drug Discovery | volume = 7 | issue = 11 | pages = 1003–1016 | date = November 2012 | pmid = 22954251 | doi = 10.1517/17460441.2012.722992 | s2cid = 36317393 }}</ref>

;Agonists
* [[Cafestol]]<ref name=pmid17456796>{{cite journal | vauthors = 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 | title = The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors | journal = Molecular Endocrinology | volume = 21 | issue = 7 | pages = 1603–1616 | date = July 2007 | pmid = 17456796 | doi = 10.1210/me.2007-0133 | doi-access = free }}</ref>
* [[Chenodeoxycholic acid]]
* [[Fexaramine]]
* [[GW 4064]]<ref>{{cite journal | vauthors = Zhang S, Pan X, Jeong H | title = GW4064, an agonist of farnesoid X receptor, represses CYP3A4 expression in human hepatocytes by inducing small heterodimer partner expression | journal = Drug Metabolism and Disposition | volume = 43 | issue = 5 | pages = 743–748 | date = May 2015 | pmid = 25725071 | pmc = 4407707 | doi = 10.1124/dmd.114.062836 }}</ref>
* [[Ivermectin]]<ref name="pmid25388537">{{cite journal | vauthors = Carotti A, Marinozzi M, Custodi C, Cerra B, Pellicciari R, Gioiello A, Macchiarulo A | title = Beyond bile acids: targeting Farnesoid X Receptor (FXR) with natural and synthetic ligands | journal = Current Topics in Medicinal Chemistry | volume = 14 | issue = 19 | pages = 2129–2142 | year = 2014 | pmid = 25388537 | doi = 10.2174/1568026614666141112094058 | url = https://www.researchgate.net/publication/268231666 | archive-url = https://ghostarchive.org/archive/20211019/https://www.researchgate.net/publication/268231666 | archive-date = 2021-10-19 }}{{cbignore}}</ref><ref>{{cite journal | vauthors = Jin L, Feng X, Rong H, Pan Z, Inaba Y, Qiu L, Zheng W, Lin S, Wang R, Wang Z, Wang S, Liu H, Li S, Xie W, Li Y | title = The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism | journal = Nature Communications | volume = 4 | pages = 1937 | date = 2013 | pmid = 23728580 | doi = 10.1038/ncomms2924 | bibcode = 2013NatCo...4.1937J | doi-access = free }}</ref>
* [[Obeticholic acid]]
* [[Tropifexor]]
;Antagonists
* [[Guggulsterone]]

== References ==
{{Reflist}}

== Further reading ==
{{Refbegin|33em}}
* {{cite journal | vauthors = Kalaany NY, Mangelsdorf DJ | title = LXRS and FXR: the yin and yang of cholesterol and fat metabolism | journal = Annual Review of Physiology | volume = 68 | pages = 159–191 | year = 2006 | pmid = 16460270 | doi = 10.1146/annurev.physiol.68.033104.152158 }}
* {{cite journal | vauthors = Kuipers F, Stroeve JH, Caron S, Staels B | title = Bile acids, farnesoid X receptor, atherosclerosis and metabolic control | journal = Current Opinion in Lipidology | volume = 18 | issue = 3 | pages = 289–297 | date = June 2007 | pmid = 17495603 | doi = 10.1097/MOL.0b013e3281338d08 | s2cid = 7385142 }}
* {{cite journal | vauthors = Seol W, Choi HS, Moore DD | title = Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors | journal = Molecular Endocrinology | volume = 9 | issue = 1 | pages = 72–85 | date = January 1995 | pmid = 7760852 | doi = 10.1210/mend.9.1.7760852 | doi-access = free }}
* {{cite journal | vauthors = Zavacki AM, Lehmann JM, Seol W, Willson TM, Kliewer SA, Moore DD | title = Activation of the orphan receptor RIP14 by retinoids | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 15 | pages = 7909–7914 | date = July 1997 | pmid = 9223286 | pmc = 21528 | doi = 10.1073/pnas.94.15.7909 | doi-access = free | bibcode = 1997PNAS...94.7909Z }}
* {{cite journal | vauthors = Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B | title = Identification of a nuclear receptor for bile acids | journal = Science | volume = 284 | issue = 5418 | pages = 1362–1365 | date = May 1999 | pmid = 10334992 | doi = 10.1126/science.284.5418.1362 | bibcode = 1999Sci...284.1362M }}
* {{cite journal | vauthors = Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM | title = Bile acids: natural ligands for an orphan nuclear receptor | journal = Science | volume = 284 | issue = 5418 | pages = 1365–1368 | date = May 1999 | pmid = 10334993 | doi = 10.1126/science.284.5418.1365 | bibcode = 1999Sci...284.1365P }}
* {{cite journal | vauthors = Bramlett KS, Yao S, Burris TP | title = Correlation of farnesoid X receptor coactivator recruitment and cholesterol 7alpha-hydroxylase gene repression by bile acids | journal = Molecular Genetics and Metabolism | volume = 71 | issue = 4 | pages = 609–615 | date = December 2000 | pmid = 11136553 | doi = 10.1006/mgme.2000.3106 }}
* {{cite journal | vauthors = Stegh AH, Barnhart BC, Volkland J, Algeciras-Schimnich A, Ke N, Reed JC, Peter ME | title = Inactivation of caspase-8 on mitochondria of Bcl-xL-expressing MCF7-Fas cells: role for the bifunctional apoptosis regulator protein | journal = The Journal of Biological Chemistry | volume = 277 | issue = 6 | pages = 4351–4360 | date = February 2002 | pmid = 11733517 | doi = 10.1074/jbc.M108947200 | doi-access = free }}
* {{cite journal | vauthors = Cui J, Heard TS, Yu J, Lo JL, Huang L, Li Y, Schaeffer JM, Wright SD | title = The amino acid residues asparagine 354 and isoleucine 372 of human farnesoid X receptor confer the receptor with high sensitivity to chenodeoxycholate | journal = The Journal of Biological Chemistry | volume = 277 | issue = 29 | pages = 25963–25969 | date = July 2002 | pmid = 12004058 | doi = 10.1074/jbc.M200824200 | doi-access = free }}
* {{cite journal | vauthors = Huber RM, Murphy K, Miao B, Link JR, Cunningham MR, Rupar MJ, Gunyuzlu PL, Haws TF, Kassam A, Powell F, Hollis GF, Young PR, Mukherjee R, Burn TC | title = Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters | journal = Gene | volume = 290 | issue = 1–2 | pages = 35–43 | date = May 2002 | pmid = 12062799 | doi = 10.1016/S0378-1119(02)00557-7 }}
* {{cite journal | vauthors = Pineda Torra I, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B | title = Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor | journal = Molecular Endocrinology | volume = 17 | issue = 2 | pages = 259–272 | date = February 2003 | pmid = 12554753 | doi = 10.1210/me.2002-0120 | doi-access = free }}
* {{cite journal | vauthors = Anisfeld AM, Kast-Woelbern HR, Meyer ME, Jones SA, Zhang Y, Williams KJ, Willson T, Edwards PA | title = Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor | journal = The Journal of Biological Chemistry | volume = 278 | issue = 22 | pages = 20420–20428 | date = May 2003 | pmid = 12660231 | doi = 10.1074/jbc.M302505200 | doi-access = free }}
* {{cite journal | vauthors = Pircher PC, Kitto JL, Petrowski ML, Tangirala RK, Bischoff ED, Schulman IG, Westin SK | title = Farnesoid X receptor regulates bile acid-amino acid conjugation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 30 | pages = 27703–27711 | date = July 2003 | pmid = 12754200 | doi = 10.1074/jbc.M302128200 | doi-access = free }}
* {{cite journal | vauthors = Zhao A, Lew JL, Huang L, Yu J, Zhang T, Hrywna Y, Thompson JR, de Pedro N, Blevins RA, Peláez F, Wright SD, Cui J | title = Human kininogen gene is transactivated by the farnesoid X receptor | journal = The Journal of Biological Chemistry | volume = 278 | issue = 31 | pages = 28765–28770 | date = August 2003 | pmid = 12761213 | doi = 10.1074/jbc.M304568200 | doi-access = free }}
* {{cite journal | vauthors = Barbier O, Torra IP, Sirvent A, Claudel T, Blanquart C, Duran-Sandoval D, Kuipers F, Kosykh V, Fruchart JC, Staels B | title = FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity | journal = Gastroenterology | volume = 124 | issue = 7 | pages = 1926–1940 | date = June 2003 | pmid = 12806625 | doi = 10.1016/S0016-5085(03)00388-3 }}
* {{cite journal | vauthors = Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, Donahee M, Wang DY, Mansfield TA, Kliewer SA, Goodwin B, Jones SA | title = Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis | journal = Genes & Development | volume = 17 | issue = 13 | pages = 1581–1591 | date = July 2003 | pmid = 12815072 | pmc = 196131 | doi = 10.1101/gad.1083503 }}
* {{cite journal | vauthors = Claudel T, Inoue Y, Barbier O, Duran-Sandoval D, Kosykh V, Fruchart J, Fruchart JC, Gonzalez FJ, Staels B | title = Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression | journal = Gastroenterology | volume = 125 | issue = 2 | pages = 544–555 | date = August 2003 | pmid = 12891557 | doi = 10.1016/S0016-5085(03)00896-5 }}
* {{cite journal | vauthors = Hsiao PW, Fryer CJ, Trotter KW, Wang W, Archer TK | title = BAF60a mediates critical interactions between nuclear receptors and the BRG1 chromatin-remodeling complex for transactivation | journal = Molecular and Cellular Biology | volume = 23 | issue = 17 | pages = 6210–6220 | date = September 2003 | pmid = 12917342 | pmc = 180928 | doi = 10.1128/MCB.23.17.6210-6220.2003 }}
* {{cite journal | vauthors = Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Pérez HE, Sandoval DA, Kohli R, Bäckhed F, Seeley RJ | title = FXR is a molecular target for the effects of vertical sleeve gastrectomy | journal = Nature | volume = 509 | issue = 7499 | pages = 183–188 | date = May 2014 | pmid = 24670636 | pmc = 4016120 | doi = 10.1038/nature13135 | author-link11 = Randy Seeley | bibcode = 2014Natur.509..183R }}
* Chamoli, M., Rane, A., Foulger, A. et al. A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan. Nat Aging (2023). [https://doi.org/10.1038/s43587-023-00524-9 A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan]
{{Refend}}

== External links ==
* {{cite web | url = http://nrresource.org/nr_page_collection/older-nr-pages/general_information_2.html | work = Nuclear Receptor Resource | title = Farnesoid X Receptor (NR1H4) | access-date = 2015-01-12 | archive-url = https://web.archive.org/web/20150112123953/http://nrresource.org/nr_page_collection/older-nr-pages/general_information_2.html | archive-date = 2015-01-12 | url-status = dead }}
* {{MeshName|farnesoid+X-activated+receptor}}

{{PDB Gallery|geneid=9971}}
{{Transcription factors|g2}}
{{FXR and LXR modulators}}

[[Category:Intracellular receptors|g2]]
[[Category:Transcription factors]]