Biology:Farnesoid X receptor

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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.

The absence of FXR in an FXR-/- mouse model led to increased bile acids in the liver, and the spontaneous development of liver tumors.[3] 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.[4] Specifically, FXR activation suppresses lipogenesis and promotes free fatty acid oxidation by PPARα activation.[4] 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).[5]

Activation of FXR in diabetic mice reduces plasma glucose and improves insulin sensitivity, whereas inactivation of FXR has the opposite effect.[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.[8][9][10]

Agonists
Antagonists

References

  1. ↑ "Entrez Gene: NR1H4 nuclear receptor subfamily 1, group H, member 4". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9971. 
  2. ↑ 2.0 2.1 "Identification of a nuclear receptor that is activated by farnesol metabolites". Cell 81 (5): 687–93. Jun 1995. doi:10.1016/0092-8674(95)90530-8. PMID 7774010. 
  3. ↑ 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
  4. ↑ 4.0 4.1 4.2 "Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis". Acta Pharmacologica Sinica 36 (1): 44–50. Jan 2015. doi:10.1038/aps.2014.116. PMID 25500875. 
  5. ↑ "Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo". Gut 63 (5): 808–17. May 2014. doi:10.1136/gutjnl-2013-305088. PMID 23916961. https://figshare.com/articles/journal_contribution/Farnesoid_X_receptor_agonists_attenuate_colonic_epithelial_secretory_function_and_prevent_experimental_diarrhoea_in_vivo_/10786373/2/files/19299278.pdf. 
  6. ↑ "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. Jan 2004. doi:10.1101/gad.1138104. PMID 14729567. 
  7. ↑ "Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors". Molecular Endocrinology 9 (1): 72–85. Jan 1995. doi:10.1210/mend.9.1.7760852. PMID 7760852. 
  8. ↑ "Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders". Current Topics in Medicinal Chemistry 12 (6): 605–24. 2012. doi:10.2174/156802612799436678. PMID 22242859. 
  9. ↑ "Farnesoid X receptor: from medicinal chemistry to clinical applications". Future Medicinal Chemistry 4 (7): 877–91. May 2012. doi:10.4155/fmc.12.41. PMID 22571613. 
  10. ↑ "Advances in drug design with RXR modulators". Expert Opinion on Drug Discovery 7 (11): 1003–16. Nov 2012. doi:10.1517/17460441.2012.722992. PMID 22954251. 
  11. ↑ "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. Jul 2007. doi:10.1210/me.2007-0133. PMID 17456796. 
  12. ↑ Zhang, S.; Pan, X.; Jeong, H. (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. PMID 25725071. 
  13. ↑ "Beyond bile acids: targeting Farnesoid X Receptor (FXR) with natural and synthetic ligands". Current Topics in Medicinal Chemistry 14 (19): 2129–42. 2014. doi:10.2174/1568026614666141112094058. PMID 25388537. https://www.researchgate.net/publication/268231666. 
  14. ↑ "The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism". Nature Communications 4: 1937. 2013. doi:10.1038/ncomms2924. PMID 23728580. Bibcode: 2013NatCo...4.1937J. 

Further reading

External links



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