The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.
LXR | |||||||
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Identifiers | |||||||
Symbol | NR1H3 | ||||||
NCBI gene | 10062 | ||||||
HGNC | 7966 | ||||||
OMIM | 602423 | ||||||
RefSeq | NM_005693 | ||||||
UniProt | Q13133 | ||||||
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LXR | |||||||
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Identifiers | |||||||
Symbol | NR1H2 | ||||||
Alt. symbols | UNR | ||||||
NCBI gene | 7376 | ||||||
HGNC | 7965 | ||||||
OMIM | 600380 | ||||||
RefSeq | NM_007121 | ||||||
UniProt | P55055 | ||||||
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Two isoforms of LXR have been identified and are referred to as LXR
LXR
Expression
editWhile the expression of LXR
Structure
editCrystal structure of human liver X receptor
Crystal structure of human liver X receptor
The phenyl group of T-0901317 extends toward the
Activation/ligands
editLXR
The hexacyclic aromatic ketones, (-)anthrabenzoxocinone and (-)bischloroanthrabenzoxocinone ((-)-BABX) derived from a Streptomyces sp. have micromolar affinity for LXR-
LXR-623 (WAY 252623) CAS: [875787-07-8].
Target genes
editLXR-RXR nuclear receptor heterodimers function as transcriptional regulators for genes involved in lipid metabolism, lipid homeostasis, and inflammation.[9] Target genes of LXRs are involved in cholesterol and lipid metabolism regulation,[17] including:
- ABC – ATP Binding Cassette transporter isoforms A1, G1, G5, and G8
- ApoE – Apolipoprotein E
- CETP – CholEsterylester Transfer Protein
- FAS – Fatty Acid Synthase
- CYP7A1 – CYtochrome P450 isoform 7A1 - cholesterol 7
α -hydroxylase - LPL – LipoProtein Lipase
- LXR-
α – Liver X Receptor-α (a somewhat unusual example of receptor up-regulating its own expression) - SREBP-1c – Sterol Regulatory Element Binding Protein 1c
- ChREBP – Carbohydrate Regulatory Element Binding Protein
Role in metabolism
editThe importance of LXRs in physiological lipid and cholesterol metabolism suggests that they may influence the development of metabolic disorders such as hyperlipidemia and atherosclerosis. Evidence for this idea has been observed by recent studies that linked LXR activity to the pathogenesis of atherosclerosis. LXR
Adiponectin induces ABCA1-mediated reverse cholesterol transport by activation of PPAR-
Potential therapeutic applications of LXR agonists
editLXR agonists are effective for treatment of murine models of atherosclerosis, diabetes, anti-inflammation, Alzheimer's disease, and cancer.
Cardiovascular
editTreatment with LXR agonists (hypocholamide, T0901317, GW3965, or N,N-dimethyl-3beta-hydroxy-cholenamide (DMHCA)) lowers the cholesterol level in serum and liver and inhibits the development of atherosclerosis in murine disease models.[24][25][26][27] Synthetic LXR agonist GW3965 improves glucose tolerance in a murine model of diet-induced obesity and insulin resistance by regulating genes involved in glucose metabolism in liver and adipose tissue.[28] GW3965 inhibits the expression of inflammatory mediators in cultured macrophage and inflammation in mice.[29]
Aberrant LXR signaling in macrophages due to the oxidized cholesterol 7-ketocholesterol promotes the inflammation that leads to atherosclerosis.[30] For this reason, 7-ketocholesterol is a therapeutic target for the prevention and treatment of atherosclerosis.[30]
When lipogenesis is increased by pharmacological activation of the liver X receptor, hepatic VLDL production is increased 2.5-fold, and the liver produces large TG-rich VLDL particles. Glucose induces expression of LXR target genes involved in cholesterol homeostasis like ABCA1 which is defective in Tangier disease. A common feature of many metabolic pathways is their control by retinoid X receptor (RXR) heterodimers. LXR heterodimerises with RXR. Promiscuous RXR also heterodimerises with PPAR members. PPAR-
Developing new potent and effective LXR agonists without the undesirable side effects may be beneficial for clinical usage.[32] In this regard, DMHCA was reported to reduce atherosclerosis in apolipoprotein E-deficient mice without inducing hypertriglyceridemia and liver steatosis.[27]
Alzheimer's disease
editTreatment with T0901317 decreases amyloidal beta production in an Alzheimer's disease mouse model.[33] However, both T0901317 and GW3965 have been reported to increase plasma and liver triglycerides in some mice models, indicating that T0901317 and GW3965 may not be a good candidate for a therapeutic agent.
Cancer
editLXR agonists (T0901317, 22(R)-hydroxycholesterol, and 24(S)-hydroxycholesterol) were also shown to suppress the proliferation of prostate cancer and breast cancer cells[34] as well as delay progression of prostate cancer from androgen-dependent status to androgen-independent status.[35]
References
edit- ^ Apfel R, Benbrook D, Lernhardt E, Ortiz MA, Salbert G, Pfahl M (October 1994). "A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily". Mol. Cell. Biol. 14 (10): 7025–35. doi:10.1128/mcb.14.10.7025. PMC 359232. PMID 7935418.
- ^ Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ (May 1995). "LXR, a nuclear receptor that defines a distinct retinoid response pathway". Genes Dev. 9 (9): 1033–45. doi:10.1101/gad.9.9.1033. PMID 7744246.
- ^ Song C, Kokontis JM, Hiipakka RA, Liao S (November 1994). "Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors". Proc. Natl. Acad. Sci. U.S.A. 91 (23): 10809–13. Bibcode:1994PNAS...9110809S. doi:10.1073/pnas.91.23.10809. PMC 45115. PMID 7971966.
- ^ Shinar DM, Endo N, Rutledge SJ, Vogel R, Rodan GA, Schmidt A (September 1994). "NER, a new member of the gene family encoding the human steroid hormone nuclear receptor". Gene. 147 (2): 273–6. doi:10.1016/0378-1119(94)90080-9. PMID 7926814.
- ^ Teboul M, Enmark E, Li Q, Wikström AC, Pelto-Huikko M, Gustafsson JA (March 1995). "OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor". Proc. Natl. Acad. Sci. U.S.A. 92 (6): 2096–100. Bibcode:1995PNAS...92.2096T. doi:10.1073/pnas.92.6.2096. PMC 42430. PMID 7892230.
- ^ Seol W, Choi HS, Moore DD (January 1995). "Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors". Mol. Endocrinol. 9 (1): 72–85. doi:10.1210/mend.9.1.7760852. PMID 7760852.
- ^ Chuu CP, Kokontis JM, Hiipakka RA, Liao S (September 2007). "Modulation of liver X receptor signaling as novel therapy for prostate cancer". J. Biomed. Sci. 14 (5): 543–53. doi:10.1007/s11373-007-9160-8. PMID 17372849.
- ^ Lou X, Toresson G, Benod C, Suh JH, Philips KJ, Webb P, Gustafsson JA (March 2014). "Structure of the retinoid X receptor
α -liver X receptorβ (RXRα -LXRβ ) heterodimer on DNA". Nature Structural & Molecular Biology. 21 (3): 277–81. doi:10.1038/nsmb.2778. PMID 24561505. S2CID 23226682. - ^ a b c Hoerer S, Schmid A, Heckel A, Budzinski RM, Nar H (December 2003). "Crystal structure of the human liver X receptor beta ligand-binding domain in complex with a synthetic agonist". Journal of Molecular Biology. 334 (5): 853–61. doi:10.1016/j.jmb.2003.10.033. PMID 14643652. S2CID 43844694.
- ^ Rühl R, de Lera AD, Krezel W (June 2015). "9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice". PLOS Genetics. 11 (6): e1005213. doi:10.1371/journal.pgen.1005213. PMC 4451509. PMID 26030625.
- ^ Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ (October 1996). "An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha". Nature. 383 (6602): 728–31. Bibcode:1996Natur.383..728J. doi:10.1038/383728a0. PMID 8878485. S2CID 4361170.
- ^ Forman BM, Ruan B, Chen J, Schroepfer GJ, Evans RM (September 1997). "The orphan nuclear receptor LXR
α is positively and negatively regulated by distinct products of mevalonate metabolism". Proc. Natl. Acad. Sci. U.S.A. 94 (20): 10588–93. Bibcode:1997PNAS...9410588F. doi:10.1073/pnas.94.20.10588. PMC 23411. PMID 9380679. - ^ Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM (February 1997). "Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway". J. Biol. Chem. 272 (6): 3137–40. doi:10.1074/jbc.272.6.3137. PMID 9013544.
- ^ Song C, Liao S (November 2000). "Cholestenoic acid is a naturally occurring ligand for liver X receptor alpha". Endocrinology. 141 (11): 4180–4. doi:10.1210/endo.141.11.7772. PMID 11089551.
- ^ Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B (November 2000). "Role of LXRs in control of lipogenesis". Genes Dev. 14 (22): 2831–8. doi:10.1101/gad.850400. PMC 317060. PMID 11090131.
- ^ Herath KB, Jayasuriya H, Guan Z, Schulman M, Ruby C, Sharma N, MacNaul K, Menke JG, Kodali S, Galgoci A, Wang J, Singh SB (September 2005). "Anthrabenzoxocinones from Streptomyces sp. as liver X receptor ligands and antibacterial agents". J. Nat. Prod. 68 (9): 1437–40. doi:10.1021/np050176k. PMID 16180833.
- ^ Edwards PA, Kennedy MA, Mak PA (April 2002). "LXRs; oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis". Vascul. Pharmacol. 38 (4): 249–56. doi:10.1016/S1537-1891(02)00175-1. PMID 12449021.
- ^ Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ (May 1998). "Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha". Cell. 93 (5): 693–704. doi:10.1016/S0092-8674(00)81432-4. PMID 9630215. S2CID 5856580.
- ^ Yoshikawa T, Shimano H, Amemiya-Kudo M, Yahagi N, Hasty AH, Matsuzaka T, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Kimura S, Ishibashi S, Yamada N (May 2001). "Identification of Liver X Receptor-Retinoid X Receptor as an Activator of the Sterol Regulatory Element-Binding Protein 1c Gene Promoter". Mol. Cell. Biol. 21 (9): 2991–3000. doi:10.1128/MCB.21.9.2991-3000.2001. PMC 86928. PMID 11287605.
- ^ Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ (November 2000). "Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXR
α and LXRβ ". Genes Dev. 14 (22): 2819–30. doi:10.1101/gad.844900. PMC 317055. PMID 11090130. - ^ Wang L, Schuster GU, Hultenby K, Zhang Q, Andersson S, Gustafsson JA (October 2002). "Liver X receptors in the central nervous system: From lipid homeostasis to neuronal degeneration". Proc. Natl. Acad. Sci. U.S.A. 99 (21): 13878–83. Bibcode:2002PNAS...9913878W. doi:10.1073/pnas.172510899. PMC 129791. PMID 12368482.
- ^ Andersson S, Gustafsson N, Warner M, Gustafsson JA (March 2005). "Inactivation of liver X receptor
β leads to adult-onset motor neuron degeneration in male mice". Proc. Natl. Acad. Sci. U.S.A. 102 (10): 3857–62. Bibcode:2005PNAS..102.3857A. doi:10.1073/pnas.0500634102. PMC 553330. PMID 15738425. - ^ Hafiane A, Gasbarrino K, Daskalopoulou SS (2019). "The role of adiponectin in cholesterol efflux and HDL biogenesis and metabolism". Metabolism: Clinical and Experimental. 100: 153953. doi:10.1016/j.metabol.2019.153953. PMID 31377319. S2CID 203413137.
- ^ Alberti S, Schuster G, Parini P, Feltkamp D, Diczfalusy U, Rudling M, Angelin B, Björkhem I, Pettersson S, Gustafsson JA (March 2001). "Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXR
β -deficient mice". J. Clin. Invest. 107 (5): 565–73. doi:10.1172/JCI9794. PMC 199420. PMID 11238557. - ^ Joseph SB, McKilligin E, Pei L, Watson MA, Collins AR, Laffitte BA, Chen M, Noh G, Goodman J, Hagger GN, Tran J, Tippin TK, Wang X, Lusis AJ, Hsueh WA, Law RE, Collins JL, Willson TM, Tontonoz P (May 2002). "Synthetic LXR ligand inhibits the development of atherosclerosis in mice". Proc. Natl. Acad. Sci. U.S.A. 99 (11): 7604–9. Bibcode:2002PNAS...99.7604J. doi:10.1073/pnas.112059299. PMC 124297. PMID 12032330.
- ^ Song C, Hiipakka RA, Liao S (June 2001). "Auto-oxidized cholesterol sulfates are antagonistic ligands of liver X receptors: implications for the development and treatment of atherosclerosis". Steroids. 66 (6): 473–9. doi:10.1016/S0039-128X(00)00239-7. PMID 11182136. S2CID 11199331.
- ^ a b Kratzer A, Buchebner M, Pfeifer T, Becker TM, Uray G, Miyazaki M, Miyazaki-Anzai S, Ebner B, Chandak PG, Kadam RS, Calayir E, Rathke N, Ahammer H, Radovic B, Trauner M, Hoefler G, Kompella UB, Fauler G, Levi M, Levak-Frank S, Kostner GM, Kratky D (February 2009). "Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia". J. Lipid Res. 50 (2): 312–26. doi:10.1194/jlr.M800376-JLR200. PMC 2636920. PMID 18812595.
- ^ Laffitte BA, Chao LC, Li J, Walczak R, Hummasti S, Joseph SB, Castrillo A, Wilpitz DC, Mangelsdorf DJ, Collins JL, Saez E, Tontonoz P (April 2003). "Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue". Proc. Natl. Acad. Sci. U.S.A. 100 (9): 5419–24. Bibcode:2003PNAS..100.5419L. doi:10.1073/pnas.0830671100. PMC 154360. PMID 12697904.
- ^ Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P (February 2003). "Reciprocal regulation of inflammation and lipid metabolism by liver X receptors". Nat. Med. 9 (2): 213–9. doi:10.1038/nm820. PMID 12524534. S2CID 10356659.
- ^ a b Anderson A, Campo A, Fulton E, Corwin A, Jerome WG 3rd, O'Connor MS (2020). "7-Ketocholesterol in disease and aging". Redox Biology. 29: 101380. doi:10.1016/j.redox.2019.101380. PMC 6926354. PMID 31926618.
- ^ Sanal MG (2008). "The blind men 'see' the elephant-the many faces of fatty liver disease". World J. Gastroenterol. 14 (6): 831–44. doi:10.3748/wjg.14.831. PMC 2687050. PMID 18240340.
- ^ Im SS, Osborne TF (April 2011). "Liver x receptors in atherosclerosis and inflammation". Circulation Research. 108 (8): 996–1001. doi:10.1161/CIRCRESAHA.110.226878. PMC 3082200. PMID 21493922.
- ^ Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, Walter M, Roth MG, Lazo JS (February 2005). "The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease". J. Biol. Chem. 280 (6): 4079–88. doi:10.1074/jbc.M411420200. PMID 15557325.
- ^ Fukuchi J, Kokontis JM, Hiipakka RA, Chuu CP, Liao S (November 2004). "Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells". Cancer Res. 64 (21): 7686–9. doi:10.1158/0008-5472.CAN-04-2332. PMID 15520170.
- ^ Chuu CP, Hiipakka RA, Kokontis JM, Fukuchi J, Chen RY, Liao S (July 2006). "Inhibition of tumor growth and progression of LNCaP prostate cancer cells in athymic mice by androgen and liver X receptor agonist". Cancer Res. 66 (13): 6482–6. doi:10.1158/0008-5472.CAN-06-0632. PMID 16818617.
External links
edit- liver+X+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- [1] (Nuclear Receptor Resource).