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Farnesoid X receptor

From Wikipedia, the free encyclopedia

NR1H4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNR1H4, BAR, FXR, HRR-1, HRR1, RIP14, nuclear receptor subfamily 1 group H member 4, PFIC5
External IDsOMIM: 603826; MGI: 1352464; HomoloGene: 3760; GeneCards: NR1H4; OMA:NR1H4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

9971

20186

Ensembl

ENSG00000012504

ENSMUSG00000047638

UniProt

Q96RI1

Q60641

RefSeq (mRNA)

NM_001163504
NM_001163700
NM_009108
NM_001385711

RefSeq (protein)

NP_001156976
NP_001157172
NP_033134
NP_001372640

Location (UCSC)Chr 12: 100.47 – 100.56 MbChr 10: 89.29 – 89.37 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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

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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. FXR likewise stimulates the synthesis of fibroblast growth factor 19, which also inhibits expression of CYP7A1 and sterol 12-alpha-hydroxylase (CYP8B1) via 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.[7]

The absence of FXR in an FXR-/- mouse model led to increased bile acids in the liver, and the spontaneous development of liver tumors.[8] 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.[9] Specifically, FXR activation suppresses lipogenesis and promotes free fatty acid oxidation by PPARα activation.[9] 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).[10]

Activation of FXR in diabetic mice reduces plasma glucose and improves insulin sensitivity, whereas inactivation of FXR has the opposite effect.[9]

Interactions

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Farnesoid X receptor has been shown to interact with:

Ligands

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A number of ligands for FXR are known, of both natural and synthetic origin.[13][14][15]

Agonists
Antagonists

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000012504 – Ensembl, May 2017
  2. ^ a b c 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.
  5. ^ "Entrez Gene: NR1H4 nuclear receptor subfamily 1, group H, member 4".
  6. ^ 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): 687–693. doi:10.1016/0092-8674(95)90530-8. PMID 7774010.
  7. ^ 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. doi:10.1016/j.csbj.2021.04.029. PMC 8091178. PMID 33995909.
  8. ^ 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
  9. ^ a b c Jiao Y, Lu Y, Li XY (January 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.
  10. ^ Mroz MS, Keating N, Ward JB, Sarker R, Amu S, Aviello G, et al. (May 2014). "Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo". Gut. 63 (5): 808–817. doi:10.1136/gutjnl-2013-305088. PMID 23916961. S2CID 15778582.
  11. ^ 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 & Development. 18 (2): 157–169. doi:10.1101/gad.1138104. PMC 324422. PMID 14729567.
  12. ^ Seol W, Choi HS, Moore DD (January 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.
  13. ^ 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. doi:10.2174/156802612799436678. PMID 22242859.
  14. ^ Fiorucci S, Mencarelli A, Distrutti E, Zampella A (May 2012). "Farnesoid X receptor: from medicinal chemistry to clinical applications". Future Medicinal Chemistry. 4 (7): 877–891. doi:10.4155/fmc.12.41. PMID 22571613.
  15. ^ Vaz B, de Lera ÁR (November 2012). "Advances in drug design with RXR modulators". Expert Opinion on Drug Discovery. 7 (11): 1003–1016. doi:10.1517/17460441.2012.722992. PMID 22954251. S2CID 36317393.
  16. ^ Ricketts ML, Boekschoten MV, Kreeft AJ, Hooiveld GJ, Moen CJ, Müller M, et al. (July 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. doi:10.1210/me.2007-0133. PMID 17456796.
  17. ^ Zhang S, Pan X, Jeong H (May 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.
  18. ^ Carotti A, Marinozzi M, Custodi C, Cerra B, Pellicciari R, Gioiello A, et al. (2014). "Beyond bile acids: targeting Farnesoid X Receptor (FXR) with natural and synthetic ligands". Current Topics in Medicinal Chemistry. 14 (19): 2129–2142. doi:10.2174/1568026614666141112094058. PMID 25388537. Archived from the original on 2021-10-19.
  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.

Further reading

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