Farnesoid X receptor

From Wikipedia, the free encyclopedia
Jump to: navigation, search
NR1H4
Protein NR1H4 PDB 1osh.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NR1H4, BAR, FXR, HRR-1, HRR1, RIP14, nuclear receptor subfamily 1 group H member 4
External IDs OMIM: 603826 MGI: 1352464 HomoloGene: 3760 GeneCards: 9971
RNA expression pattern
PBB GE NR1H4 206340 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001163504
NM_001163700
NM_009108

RefSeq (protein)

NP_001157172.1
NP_001156976.1

Location (UCSC) Chr 12: 100.47 – 100.56 Mb Chr 10: 89.45 – 89.53 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/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.[3][4]

Function[edit]

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.[4]

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.[5] 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 transmembrane conductance regulator (CFTR).[6]

Interactions[edit]

Farnesoid X receptor has been shown to interact with:

Ligands[edit]

A number of ligands for FXR are known, of both natural and synthetic origin.[9][10][11]

Agonists
Antagonists

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ "Entrez Gene: NR1H4 nuclear receptor subfamily 1, group H, member 4". 
  4. ^ a b 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. 
  5. ^ 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. PMID 25500875. 
  6. ^ 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. 
  7. ^ 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 324422free to read. PMID 14729567. 
  8. ^ 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. 
  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): 605–24. doi:10.2174/156802612799436678. PMID 22242859. 
  10. ^ 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. 
  11. ^ Vaz B, de Lera Á (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. 
  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 (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[edit]

External links[edit]