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.[1][2]
Function
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.[2]
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. FXR has also been found to be important in regulation of hepatic triglyceride levels.[3] Studies have also shown the FXR to regulate the expression and activity of epithelial transport proteins involved in fluid homestasis in the intestine, such as the cystic fibrosis conductance transmembrane regulator (CFTR)[4]
Interactions
Farnesoid X receptor has been shown to interact with:
- Peroxisome proliferator-activated receptor gamma coactivator 1-alpha[5] and
- Retinoid X receptor alpha.[6]
Ligands
A number of ligands for FXR are known, of both natural and synthetic origin.[7][8][9]
- Agonists
- Antagonists
References
- ^ "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 et al. (June 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.
- ^ Jiao Y, Lu Y, Li X (2015). "Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis". Acta Pharmacol. Sin. 36 (1): 44–50. doi:10.1038/aps.2014.116. PMID 25500875.
- ^ Mroz MS, Keating N, Ward JB, Sarker R, Amu S, Aviello G et al. (2014). "Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo". Gut 63 (5): 808–17. doi:10.1136/gutjnl-2013-305088. PMID 23916961.
- ^ Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA (January 2004). "Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR". Genes Dev. 18 (2): 157–69. doi:10.1101/gad.1138104. PMC 324422. PMID 14729567.
- ^ Seol W, Choi HS, Moore DD (January 1995). "Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors". Mol. Endocrinol. 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". Curr Top Med Chem 12 (6): 605–24. doi:10.2174/156802612799436678. PMID 22242859.
- ^ Fiorucci S, Mencarelli A, Distrutti E, Zampella A (2012). "Farnesoid X receptor: from medicinal chemistry to clinical applications". Future Med Chem 4 (7): 877–91. doi:10.4155/fmc.12.41. PMID 22571613.
- ^ Vaz B, de Lera ÁR (2012). "Advances in drug design with RXR modulators". Expert Opin Drug Discov 7 (11): 1003–16. doi:10.1517/17460441.2012.722992. PMID 22954251.
Further reading
- Kalaany NY, Mangelsdorf DJ (2006). "LXRS and FXR: the yin and yang of cholesterol and fat metabolism.". Annu. Rev. Physiol. 68: 159–91. doi:10.1146/annurev.physiol.68.033104.152158. PMID 16460270.
- Kuipers F, Stroeve JH, Caron S, Staels B (2007). "Bile acids, farnesoid X receptor, atherosclerosis and metabolic control.". Curr. Opin. Lipidol. 18 (3): 289–97. doi:10.1097/MOL.0b013e3281338d08. PMID 17495603.
- Seol W, Choi HS, Moore DD (1995). "Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors.". Mol. Endocrinol. 9 (1): 72–85. doi:10.1210/mend.9.1.7760852. PMID 7760852.
- Zavacki AM, Lehmann JM, Seol W, Willson TM, Kliewer SA, Moore DD (1997). "Activation of the orphan receptor RIP14 by retinoids.". Proc. Natl. Acad. Sci. U.S.A. 94 (15): 7909–14. doi:10.1073/pnas.94.15.7909. PMC 21528. PMID 9223286.
- Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A et al. (1999). "Identification of a nuclear receptor for bile acids.". Science 284 (5418): 1362–5. doi:10.1126/science.284.5418.1362. PMID 10334992.
- Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA et al. (1999). "Bile acids: natural ligands for an orphan nuclear receptor.". Science 284 (5418): 1365–8. doi:10.1126/science.284.5418.1365. PMID 10334993.
- Bramlett KS, Yao S, Burris TP (2001). "Correlation of farnesoid X receptor coactivator recruitment and cholesterol 7alpha-hydroxylase gene repression by bile acids.". Mol. Genet. Metab. 71 (4): 609–15. doi:10.1006/mgme.2000.3106. PMID 11136553.
- Stegh AH, Barnhart BC, Volkland J, Algeciras-Schimnich A, Ke N, Reed JC et al. (2002). "Inactivation of caspase-8 on mitochondria of Bcl-xL-expressing MCF7-Fas cells: role for the bifunctional apoptosis regulator protein.". J. Biol. Chem. 277 (6): 4351–60. doi:10.1074/jbc.M108947200. PMID 11733517.
- Cui J, Heard TS, Yu J, Lo JL, Huang L, Li Y et al. (2002). "The amino acid residues asparagine 354 and isoleucine 372 of human farnesoid X receptor confer the receptor with high sensitivity to chenodeoxycholate.". J. Biol. Chem. 277 (29): 25963–9. doi:10.1074/jbc.M200824200. PMID 12004058.
- Huber RM, Murphy K, Miao B, Link JR, Cunningham MR, Rupar MJ et al. (2002). "Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters.". Gene 290 (1–2): 35–43. doi:10.1016/S0378-1119(02)00557-7. PMID 12062799.
- Pineda Torra I, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B (2003). "Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor". Mol. Endocrinol. 17 (2): 259–72. doi:10.1210/me.2002-0120. PMID 12554753.
- Anisfeld AM, Kast-Woelbern HR, Meyer ME, Jones SA, Zhang Y, Williams KJ et al. (2003). "Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor". J. Biol. Chem. 278 (22): 20420–8. doi:10.1074/jbc.M302505200. PMID 12660231.
- Pircher PC, Kitto JL, Petrowski ML, Tangirala RK, Bischoff ED, Schulman IG et al. (2003). "Farnesoid X receptor regulates bile acid-amino acid conjugation". J. Biol. Chem. 278 (30): 27703–11. doi:10.1074/jbc.M302128200. PMID 12754200.
- Zhao A, Lew JL, Huang L, Yu J, Zhang T, Hrywna Y et al. (2003). "Human kininogen gene is transactivated by the farnesoid X receptor". J. Biol. Chem. 278 (31): 28765–70. doi:10.1074/jbc.M304568200. PMID 12761213.
- Barbier O, Torra IP, Sirvent A, Claudel T, Blanquart C, Duran-Sandoval D et al. (2003). "FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity". Gastroenterology 124 (7): 1926–40. doi:10.1016/S0016-5085(03)00388-3. PMID 12806625.
- Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF et al. (2003). "Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis". Genes Dev. 17 (13): 1581–91. doi:10.1101/gad.1083503. PMC 196131. PMID 12815072.
- Claudel T, Inoue Y, Barbier O, Duran-Sandoval D, Kosykh V, Fruchart J et al. (2003). "Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression". Gastroenterology 125 (2): 544–55. doi:10.1016/S0016-5085(03)00896-5. PMID 12891557.
- Hsiao PW, Fryer CJ, Trotter KW, Wang W, Archer TK (2003). "BAF60a mediates critical interactions between nuclear receptors and the BRG1 chromatin-remodeling complex for transactivation". Mol. Cell. Biol. 23 (17): 6210–20. doi:10.1128/MCB.23.17.6210-6220.2003. PMC 180928. PMID 12917342.
- Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R et al. (2014). "FXR is a molecular target for the effects of vertical sleeve gastrectomy". Nature 509 (7499): 183–8. doi:10.1038/nature13135. PMC 4016120. PMID 24670636.
External links
- "Farnesoid X Receptor (NR1H4)". Nuclear Receptor Resource.
- farnesoid X-activated receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
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