Receptor X farnesoide

Estruturas dispoñibles
PDB	Buscar ortólogos: PDBe, RCSB  Lista de códigos PDB 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
Identificadores
Símbolos	NR1H4 (HGNC: 7967) BAR, FXR, HRR-1, HRR1, RIP14, PFIC5
Identificadores externos	OMIM: 603826 MGI: 1352464 HomoloGene: 3760 EBI: NR1H4 GeneCards: Xene NR1H4 UniProt: NR1H4
Locus	Cr. 12 q23.1
Ontoloxía Xénica Referencias: AmiGO / QuickGO
Padrón de expresión de ARNm
Máis información
Ortólogos
Especies	Humano Rato
Entrez	9971 20186
Ensembl	Véxase HS Véxase MM
UniProt	Q96RI1 Q60641
RefSeq (ARNm)	NM_001206 NM_001163504
RefSeq (proteína) NCBI	NP_001193 NP_001156976
Localización (UCSC)	Cr. 12: 100.47 – 100.56 Mb Cr. 10: 89.29 – 89.37 Mb
PubMed (Busca)	9971 20186

O receptor X farnesoide (FXR), tamén coñecido como receptor de ácidos biliares (BAR) ou NR1H4 (receptor nuclear subfamilia 1, grupo H, membro 4), é un receptor nuclear que está codificado no xene NR1H4 nos humanos, situado no cromosoma 12.^[1][2]

Función

O FXR exprésase a alto nivel no fígado e intestinos. O ácido quenodesoxicólico e outros ácidos biliares son ligandos naturais do FXR. Igual que outros receptores nucleares, cando é activado, o FXR trasládase ao núcleo celular, forma un dímero (neste caso un heterodímero co RXR) e únese a elementos de resposta a hormonas do ADN, o cal regula á alza ou á baixa a expresión de certos xenes.^[2]

Unha das funcións primarias da activación do FXR é a supresión da colesterol 7 alfa-hidroxilase (CYP7A1), o encima limitante na síntese de ácidos biliares a partir de colesterol. O FXR non se une directamente ao promotor de CYP7A1. Ao contrario, o FXR induce a expresión do SHP (do inglés small heterodimer partner, compañeiro heterodímero pequeno), que despois funciona inhibindo a transcrición do xene CYP7A1. O FXR estimula tamén a síntese do factor de crecemento de fibroblastos 19, que tamén inhibe a expresión de CYP7A1 e da esterol 12-alfa-hidroxilase (CYP8B1) por medio do factor de crecemento de fibroblastos 4. Deste modo, establécese unha vía de retroalimentación negativa na cal a síntese dos ácidos biliares é inhibida cando os niveis celulares son xa altos.^[3]

A ausencia de FXR nun modelo de ratos FXR^-/- causa o incremento de ácidos biliares no fígado e o desenvolvemento espontáneo de tumores hepáticos.^[4] Reducir o conxunto de ácidos biliares nos ratos FXR^-/- alimentándoos coa resina colestiramina que secuestra os ácidos biliares, reducía o número e tamaño das lesións malignas.

O FXR tamén é importante na regulación dos niveis hepáticos de triglicéridos.^[5] Especificamente, a activación do FXR suprime a lipoxénese e promove a oxidación de ácidos graxos libres pola activación do PPARα.^[5] O FXR regula a expresión e actividade de proteínas de transporte epiteliais implicadas na homeostase dos fluídos no intestino, como o regulador da condutancia transmembrana da fibrose quística (CFTR).^[6]

A activación do FXR en ratos diabéticos reduce a glicosa do plasma e mellora a sensibilidade á insulina, mentes que a inactivación do FXR ten o efecto oposto.^[5]

Interaccións

O receptor X farnesoide presenta interaccións con:

• Coactivador 1-alfa do receptor activado polo proliferador do peroxisoma gamma^[7] e
• Receptor X retinoide alfa.^[8]

Ligandos

Coñécense varios ligandos do FXR, tanto de orixe natural coma sintética.^[9][10][11]

Agonistas

• Cafestol^[12]
• Ácido quenodesoxicólico
• Fexaramina
• GW 4064^[13]
• Ivermectina^[14][15]
• Ácido obeticólico
• Tropifexor

Antagonistas

• Guggulsterona

Notas

1. "Entrez Gene: NR1H4 nuclear receptor subfamily 1, group H, member 4". 
2. Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW, Evans RM, Weinberger C (xuño de 1995). "Identification of a nuclear receptor that is activated by farnesol metabolites". Cell 81 (5): 687–693. PMID 7774010. doi:10.1016/0092-8674(95)90530-8. 
3. Jiang L, Zhang H, Xiao D, Wei H, Chen Y (2021). "Farnesoid X receptor (FXR): Structures and ligands". Computational and Structural Biotechnology Journal 19: 2148–2159. PMC 8091178. PMID 33995909. doi:10.1016/j.csbj.2021.04.029. 
4. 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
5. Jiao Y, Lu Y, Li XY (xaneiro de 2015). "Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis". Acta Pharmacologica Sinica 36 (1): 44–50. PMC 4571315. PMID 25500875. doi:10.1038/aps.2014.116. 
6. Mroz MS, Keating N, Ward JB, Sarker R, Amu S, Aviello G, Donowitz M, Fallon PG, Keely SJ (maio de 2014). "Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo". Gut 63 (5): 808–817. PMID 23916961. doi:10.1136/gutjnl-2013-305088. 
7. Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA (xaneiro de 2004). "Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR". Genes & Development 18 (2): 157–169. PMC 324422. PMID 14729567. doi:10.1101/gad.1138104. 
8. Seol W, Choi HS, Moore DD (xaneiro de 1995). "Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors". Molecular Endocrinology 9 (1): 72–85. PMID 7760852. doi:10.1210/mend.9.1.7760852. 
9. 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): 605–624. PMID 22242859. doi:10.2174/156802612799436678. 
10. Fiorucci S, Mencarelli A, Distrutti E, Zampella A (maio de 2012). "Farnesoid X receptor: from medicinal chemistry to clinical applications". Future Medicinal Chemistry 4 (7): 877–891. PMID 22571613. doi:10.4155/fmc.12.41. 
11. Vaz B, de Lera Á (novembro de 2012). "Advances in drug design with RXR modulators". Expert Opinion on Drug Discovery 7 (11): 1003–1016. PMID 22954251. doi:10.1517/17460441.2012.722992. 
12. 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 (xullo de 2007). "The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors". Molecular Endocrinology 21 (7): 1603–1616. PMID 17456796. doi:10.1210/me.2007-0133. 
13. Zhang S, Pan X, Jeong H (maio de 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. PMC 4407707. PMID 25725071. doi:10.1124/dmd.114.062836. 
14. 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): 2129–2142. PMID 25388537. doi:10.2174/1568026614666141112094058. Arquivado dende o orixinal o 2021-10-19. 
15. 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 (2013). "The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism". Nature Communications 4: 1937. Bibcode:2013NatCo...4.1937J. PMID 23728580. doi:10.1038/ncomms2924. 

Véxase tamén

Bibliografía

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

Ligazóns externas

• "Farnesoid X Receptor (NR1H4)". Nuclear Receptor Resource. Arquivado dende o orixinal o 2015-01-12. Consultado o 2015-01-12. 
• farnesoid X-activated receptor Medical Subject Headings (MeSH) na Biblioteca Nacional de Medicina dos EUA.