Farnesoid X receptor: Difference between revisions

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{{Infobox_gene}}
{{PBB_Controls
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| accessdate = }}</ref><ref name="pmid7774010"/>
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| update_protein_box = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image = PBB_Protein_NR1H4_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1osh.
| PDB = {{PDB2|1osh}}, {{PDB2|1osv}}, {{PDB2|1ot7}}
| Name = Nuclear receptor subfamily 1, group H, member 4
| HGNCid = 7967
| Symbol = NR1H4
| AltSymbols =; BAR; FXR; HRR-1; HRR1; MGC163445; RIP14
| OMIM = 603826
| ECnumber = 
| Homologene = 3760
| MGIid = 1352464
| GeneAtlas_image1 = PBB_GE_NR1H4_206340_at_tn.png
| Function = {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0003707 |text = steroid hormone receptor activity}} {{GNF_GO|id=GO:0003713 |text = transcription coactivator activity}} {{GNF_GO|id=GO:0003714 |text = transcription corepressor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0043565 |text = sequence-specific DNA binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0008206 |text = bile acid metabolic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 9971
    | Hs_Ensembl = ENSG00000012504
    | Hs_RefseqProtein = NP_005114
    | Hs_RefseqmRNA = NM_005123
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 12
    | Hs_GenLoc_start = 99391810
    | Hs_GenLoc_end = 99481772
    | Hs_Uniprot = Q96RI1
    | Mm_EntrezGene = 20186
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = NM_009108
    | Mm_RefseqProtein = NP_033134
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end = 
    | Mm_Uniprot =
  }}
}}


The '''farnesoid X receptor''' ('''FXR'''), also known as '''NR1H4''' (nuclear receptor subfamily 1, group H, member 4) is a [[nuclear hormone receptor]] with activity similar to that seen in other steroid receptors such as [[estrogen]] or [[progesterone]] but more similar in form to [[PPAR]], [[LXR]] and [[RXR]]. FXR is encoded by the {{gene|NR1H4}} gene.<ref name="entrez">{{cite web | title = Entrez Gene: NR1H4 nuclear receptor subfamily 1, group H, member 4| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9971| accessdate = }}</ref>
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 = 687–93 | date = Jun 1995 | pmid = 7774010 | doi = 10.1016/0092-8674(95)90530-8 }}</ref>


[[Chenodeoxycholic acid]] and other [[bile acid]]s are the natural [[Ligand (biochemistry)|ligand]] for FXR and like other steroid receptors, when activated, it translocates to the [[cell nucleus]], forms a [[dimer]] (in this case a heterodimer) and binds to [[hormone response element]]s on DNA which elicits expression or [[transrepression]] of [[gene]] products. 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]].
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.


==References==
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 = Jan 2015 | pmid = 25500875 | doi = 10.1038/aps.2014.116 | pmc=4571315}}</ref> 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 = 808–17 | date = May 2014 | pmid = 23916961 | doi = 10.1136/gutjnl-2013-305088 }}</ref>
{{reflist|2}}


==Further reading==
== Interactions ==
{{refbegin | 2}}
 
{{PBB_Further_reading
Farnesoid X receptor has been shown to [[Protein-protein interaction|interact]] with:
| citations =
* [[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 = 157–69 | date = Jan 2004 | pmid = 14729567 | pmc = 324422 | doi = 10.1101/gad.1138104 }}</ref>  and
*{{cite journal  | author=Kalaany NY, Mangelsdorf DJ |title=LXRS and FXR: the yin and yang of cholesterol and fat metabolism. |journal=Annu. Rev. Physiol. |volume=68 |issue= |pages= 159-91 |year= 2006 |pmid= 16460270 |doi= 10.1146/annurev.physiol.68.033104.152158 }}
* [[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 = Jan 1995 | pmid = 7760852 | doi = 10.1210/mend.9.1.7760852 }}</ref>
*{{cite journal | author=Kuipers F, Stroeve JH, Caron S, Staels B |title=Bile acids, farnesoid X receptor, atherosclerosis and metabolic control. |journal=Curr. Opin. Lipidol. |volume=18 |issue= 3 |pages= 289-97 |year= 2007 |pmid= 17495603 |doi= 10.1097/MOL.0b013e3281338d08 }}
 
*{{cite journal | author=Seol W, Choi HS, Moore DD |title=Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors. |journal=Mol. Endocrinol. |volume=9 |issue= 1 |pages= 72-85 |year= 1995 |pmid= 7760852 |doi= }}
== Ligands ==
*{{cite journal | author=Forman BM, Goode E, Chen J, ''et al.'' |title=Identification of a nuclear receptor that is activated by farnesol metabolites. |journal=Cell |volume=81 |issue= 5 |pages= 687-93 |year= 1995 |pmid= 7774010 |doi= }}
 
*{{cite journal | author=Zavacki AM, Lehmann JM, Seol W, ''et al.'' |title=Activation of the orphan receptor RIP14 by retinoids. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue= 15 |pages= 7909-14 |year= 1997 |pmid= 9223286 |doi= }}
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 = 605–24 | 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 = 877–91 | 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 = 1003–16 | date = Nov 2012 | pmid = 22954251 | doi = 10.1517/17460441.2012.722992 }}</ref>
*{{cite journal | author=Makishima M, Okamoto AY, Repa JJ, ''et al.'' |title=Identification of a nuclear receptor for bile acids. |journal=Science |volume=284 |issue= 5418 |pages= 1362-5 |year= 1999 |pmid= 10334992 |doi= }}
 
*{{cite journal  | author=Parks DJ, Blanchard SG, Bledsoe RK, ''et al.'' |title=Bile acids: natural ligands for an orphan nuclear receptor. |journal=Science |volume=284 |issue= 5418 |pages= 1365-8 |year= 1999 |pmid= 10334993 |doi=  }}
;Agonists
*{{cite journal | author=Bramlett KS, Yao S, Burris TP |title=Correlation of farnesoid X receptor coactivator recruitment and cholesterol 7alpha-hydroxylase gene repression by bile acids. |journal=Mol. Genet. Metab. |volume=71 |issue= 4 |pages= 609-15 |year= 2001 |pmid= 11136553 |doi= 10.1006/mgme.2000.3106 }}
* [[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 = 1603–16 | date = Jul 2007 | pmid = 17456796 | doi = 10.1210/me.2007-0133 | url = http://press.endocrine.org/doi/10.1210/me.2007-0133?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed }}</ref>
*{{cite journal | author=Stegh AH, Barnhart BC, Volkland J, ''et al.'' |title=Inactivation of caspase-8 on mitochondria of Bcl-xL-expressing MCF7-Fas cells: role for the bifunctional apoptosis regulator protein. |journal=J. Biol. Chem. |volume=277 |issue= 6 |pages= 4351-60 |year= 2002 |pmid= 11733517 |doi= 10.1074/jbc.M108947200 }}
* [[Chenodeoxycholic acid]]
*{{cite journal | author=Cui J, Heard TS, Yu J, ''et al.'' |title=The amino acid residues asparagine 354 and isoleucine 372 of human farnesoid X receptor confer the receptor with high sensitivity to chenodeoxycholate. |journal=J. Biol. Chem. |volume=277 |issue= 29 |pages= 25963-9 |year= 2002 |pmid= 12004058 |doi= 10.1074/jbc.M200824200 }}
* [[Obeticholic acid]]
*{{cite journal | author=Huber RM, Murphy K, Miao B, ''et al.'' |title=Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. |journal=Gene |volume=290 |issue= 1-2 |pages= 35-43 |year= 2002 |pmid= 12062799 |doi= }}
* [[Fexaramine]]
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
 
*{{cite journal | author=Pineda Torra I, Claudel T, Duval C, ''et al.'' |title=Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. |journal=Mol. Endocrinol. |volume=17 |issue= 2 |pages= 259-72 |year= 2003 |pmid= 12554753 |doi= }}
;Antagonists
*{{cite journal | author=Anisfeld AM, Kast-Woelbern HR, Meyer ME, ''et al.'' |title=Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor. |journal=J. Biol. Chem. |volume=278 |issue= 22 |pages= 20420-8 |year= 2003 |pmid= 12660231 |doi= 10.1074/jbc.M302505200 }}
* [[Guggulsterone]]
*{{cite journal | author=Pircher PC, Kitto JL, Petrowski ML, ''et al.'' |title=Farnesoid X receptor regulates bile acid-amino acid conjugation. |journal=J. Biol. Chem. |volume=278 |issue= 30 |pages= 27703-11 |year= 2003 |pmid= 12754200 |doi= 10.1074/jbc.M302128200 }}
{{-}}
*{{cite journal | author=Zhao A, Lew JL, Huang L, ''et al.'' |title=Human kininogen gene is transactivated by the farnesoid X receptor. |journal=J. Biol. Chem. |volume=278 |issue= 31 |pages= 28765-70 |year= 2003 |pmid= 12761213 |doi= 10.1074/jbc.M304568200 }}
 
*{{cite journal | author=Barbier O, Torra IP, Sirvent A, ''et al.'' |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= 1926-40 |year= 2003 |pmid= 12806625 |doi= }}
== References ==
*{{cite journal | author=Holt JA, Luo G, Billin AN, ''et al.'' |title=Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. |journal=Genes Dev. |volume=17 |issue= 13 |pages= 1581-91 |year= 2003 |pmid= 12815072 |doi= 10.1101/gad.1083503 }}
{{reflist|33em}}
*{{cite journal | author=Claudel T, Inoue Y, Barbier O, ''et al.'' |title=Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression. |journal=Gastroenterology |volume=125 |issue= 2 |pages= 544-55 |year= 2003 |pmid= 12891557 |doi= }}
 
*{{cite journal | author=Hsiao PW, Fryer CJ, Trotter KW, ''et al.'' |title=BAF60a mediates critical interactions between nuclear receptors and the BRG1 chromatin-remodeling complex for transactivation. |journal=Mol. Cell. Biol. |volume=23 |issue= 17 |pages= 6210-20 |year= 2003 |pmid= 12917342 |doi= }}
== 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 | issue = | pages = 159–91 | 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 = 289–97 | date = Jun 2007 | pmid = 17495603 | doi = 10.1097/MOL.0b013e3281338d08 }}
* {{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 = Jan 1995 | pmid = 7760852 | doi = 10.1210/mend.9.1.7760852 }}
* {{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 = 7909–14 | date = Jul 1997 | pmid = 9223286 | pmc = 21528 | doi = 10.1073/pnas.94.15.7909 }}
* {{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 = 1362–5 | date = May 1999 | pmid = 10334992 | doi = 10.1126/science.284.5418.1362 }}
* {{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 = 1365–8 | date = May 1999 | pmid = 10334993 | doi = 10.1126/science.284.5418.1365 }}
* {{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 = 609–15 | date = Dec 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 = 4351–60 | date = Feb 2002 | pmid = 11733517 | doi = 10.1074/jbc.M108947200 }}
* {{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 = 25963–9 | date = Jul 2002 | pmid = 12004058 | doi = 10.1074/jbc.M200824200 }}
* {{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 = 259–72 | date = Feb 2003 | pmid = 12554753 | doi = 10.1210/me.2002-0120 }}
* {{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 = 20420–8 | date = May 2003 | pmid = 12660231 | doi = 10.1074/jbc.M302505200 }}
* {{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 = 27703–11 | date = Jul 2003 | pmid = 12754200 | doi = 10.1074/jbc.M302128200 }}
* {{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 = 28765–70 | date = Aug 2003 | pmid = 12761213 | doi = 10.1074/jbc.M304568200 }}
* {{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 = 1926–40 | date = Jun 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 = 1581–91 | date = Jul 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 = 544–55 | date = Aug 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 = 6210–20 | date = Sep 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 = 183–8 | date = May 2014 | pmid = 24670636 | pmc = 4016120 | doi = 10.1038/nature13135 }}
{{refend}}
{{refend}}


==External links==
== 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) }}
* {{MeshName|farnesoid+X-activated+receptor}}
* {{MeshName|farnesoid+X-activated+receptor}}


{{biochem-stub}}
{{PDB Gallery|geneid=9971}}
{{Transcription factors}}
{{Transcription factors|g2}}
{{Nuclear receptor ligands}}


[[Category:Intracellular receptors]]
[[Category:Intracellular receptors|g2]]
[[Category:Transcription factors]]
[[Category:Transcription factors]]
[[fr:Farnesoid X receptor]]
{{WikiDoc Sources}}

Revision as of 20:00, 8 November 2017

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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 homeostasis in the intestine, such as the cystic fibrosis transmembrane conductance regulator (CFTR).[4]

Interactions

Farnesoid X receptor has been shown to interact with:

Ligands

A number of ligands for FXR are known, of both natural and synthetic origin.[7][8][9]

Agonists
Antagonists

References

  1. ↑ "Entrez Gene: NR1H4 nuclear receptor subfamily 1, group H, member 4".
  2. ↑ 2.0 2.1 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.
  3. ↑ 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.
  4. ↑ 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". Gut. 63 (5): 808–17. doi:10.1136/gutjnl-2013-305088. PMID 23916961.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.

Further reading

External links

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