Overview: Liver X and farnesoid X receptors (LXR and FXR, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, see Moore et al., 2006) are members of a steroid analogue-activated nuclear receptor subfamily (ENSF00000000720), which form heterodimers with members of the retinoid X receptor family. Endogenous ligands for LXRs include hydroxycholesterols (OHC), while FXRs appear to be activated by bile acids.
| Nomenclature | LXRα | LXRβ | FXRα | FXRβ |
|---|---|---|---|---|
| Systematic nomenclature | NR1H3 | NR1H2 | NR1H4 | NR1H5 |
| Other names | Oxysterols receptor α | Oxysterols receptor β, ubiquitously expressed nuclear receptor | Bile acid receptor | Lanosterol receptor |
| Ensembl ID | ENSG00000025434 | ENSG00000131408 | ENSG00000012504 | ENSMUSG00000048938 (pseudogene in man) |
| Potency order | 20s-OHC, 22r-OHC, 24s-OHC > 25-OHC, 27-OHC (Lehmann et al., 1997) | 20s-OHC, 22r-OHC, 24s-OHC > 25-OHC, 27-OHC (Lehmann et al., 1997) | Chenodeoxycholate > lithocholate, deoxycholate (Makishima et al., 1999; Parks et al., 1999) | – |
| Selective agonists | – | – | ECDCA (Pellicciari et al., 2002) | Lanosterol (Otte et al., 2003) |
| Selective antagonists | – | – | Guggulsterone (Urizar et al., 2002) | – |
TO901317 (Repa et al., 2000) and GW3965 (Collins et al., 2002) are synthetic agonists acting at both LXRα and LXRβ with less than 10-fold selectivity.
Glossary
Abbreviations:
- ECDCA
6α-ethyl-chenodeoxycholate, also known as INT747
- guggulsterone
trans-4,17(20)-pregnadiene-3,16-dione
- GW3965
3-(3-[N-{2-chloro-3-trifluoromethylbenzyl}-{2,2-diphenylethyl}amino]propyloxy)phenylacetic acid hydrochloride
- OHC
hydroxycholesterol
- TO901317
N-(2,2,2-trifluoroethyl)-N-(4-[2,2,2-trifluoro-1-hydroxy-1-{trifluoromethyl}ethyl]phenyl)-benzenesulfonamide
Further Reading
Barish GD (2006). Peroxisome proliferator-activated receptors and liver X receptors in atherosclerosis and immunity. J Nutr136: 690–694.
Cariou B, Staels B (2007). FXR: a promising target for the metabolic syndrome? Trends Pharmacol Sci28: 236–243.
Fievet C, Staels B (2009). Liver X receptor modulators: effects on lipid metabolism and potential use in the treatment of atherosclerosis. Biochem Pharmacol77: 1316–1327.
Fiorucci S, Rizzo G, Donini A, Distrutti E, Santucci L (2007). Targeting farnesoid X receptor for liver and metabolic disorders. Trends Mol Med13: 298–309.
Gabbi C, Warner M, Gustafsson JA (2009). Minireview: liver X receptor beta: emerging roles in physiology and diseases. Mol Endocrinol23: 129–136.
Geyeregger R, Zeyda M, Stulnig TM (2006). Liver X receptors in cardiovascular and metabolic disease. Cell Mol Life Sci63: 524–539.
Houten SM, Watanabe M, Auwerx J (2006). Endocrine functions of bile acids. EMBO J25: 1419–1425.
Kalaany NY, Mangelsdorf DJ (2006). LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu Rev Physiol68: 159–191.
Kuipers F, Stroeve JH, Caron S, Staels B (2007). Bile acids, farnesoid X receptor, atherosclerosis and metabolic control. Curr Opin Lipidol18: 289–297.
Lee CH, Plutzky J (2006). Liver X receptor activation and high-density lipoprotein biology: a reversal of fortune? Circulation113: 5–8.
Moore DD, Kato S, Xie W, Mangelsdorf DJ, Schmidt DR, Xiao R et al. (2006). International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor α, farnesoid X receptor β, liver X receptor α, liver X receptor β, and vitamin D receptor. Pharmacol Rev58: 742–759.
Schmuth M, Jiang YJ, Dubrac S, Elias PM, Feingold KR (2008). Thematic review series: skin lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology. J Lipid Res49: 499–509.
Wang YD, Chen WD, Moore DD, Huang W (2008). FXR: a metabolic regulator and cell protector. Cell Res18: 1087–1095.
Zelcer N, Tontonoz P (2006). Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest116: 607–614.
Zhang Y, Edwards PA (2008). FXR signaling in metabolic disease. FEBS Lett582: 10–18.
References
- Collins JL, et al. J Med Chem. 2002;45:1963–1966. doi: 10.1021/jm0255116. [DOI] [PubMed] [Google Scholar]
- Lehmann JM, et al. J Biol Chem. 1997;272:3137–3140. doi: 10.1074/jbc.272.6.3137. [DOI] [PubMed] [Google Scholar]
- Makishima M, et al. Science. 1999;284:1362–1365. doi: 10.1126/science.284.5418.1362. [DOI] [PubMed] [Google Scholar]
- Otte K, et al. Mol Cell Biol. 2003;23:864–872. doi: 10.1128/MCB.23.3.864-872.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Parks DJ, et al. Science. 1999;284:1365–1368. doi: 10.1126/science.284.5418.1365. [DOI] [PubMed] [Google Scholar]
- Pellicciari R, et al. J Med Chem. 2002;45:3569–3572. doi: 10.1021/jm025529g. [DOI] [PubMed] [Google Scholar]
- Repa JJ, et al. Science. 2000;289:1524–1529. doi: 10.1126/science.289.5484.1524. [DOI] [PubMed] [Google Scholar]
- Urizar NL, et al. Science. 2002;296:1703–1706. doi: 10.1126/science.1072891. [DOI] [PubMed] [Google Scholar]