TABLE 6

LXRα

Receptor Nomenclature NR1H3
Receptor code 4.10.1:OXY:1:H3
Other names LXR-a, RLD-1
Molecular information Hs: 447aa, Q13133, chr. 11p11.21
Rn: 445aa, Q62685, chr. 3q242
Mm: 445 aa, Q9Z0Y9, chr. 2 E13
DNA binding
   Structure RXR partner
   HRE core sequence AGGTCANNNNAGGTCA (DR-4)
Partners RXR (physical, functional): required for transactivation1; SHP (physical, functional): represses transactivation4; LRH-1 (functional): competence factor5
Agonists Acetyl-podocarpic dimer (1 nM), T0901317 (50 nM), 27-hydroxycholesterol (85 nM), GW3965 (190 nM), 24(S)-hydroxycholesterol (4 μM), 24(S),25-epoxycholesterol (4 μM), paxilline (4 μM), 22(R)-hydroxycholesterol (5 μM) [EC50]6–12; F(3)methylAA (13 nM) [Kd]13
Antagonists
Coactivator NCOA1, p300, TRRAP, GRIP1/TIF2, PGC1a, PGC1b14–18
Corepressor NCOR1, NCOR219
Biologically important isoforms
Tissue distribution Liver, small intestine, kidney, adipose tissue, macrophages, spleen, adrenal gland {Rn} [Northern blot]1
Functional assay
Main target genes Activated: ABCA1 {Hs},20,21 ABCG1 {Hs},22,23 SREBP1c {Hs},24 APOCI/IV/II {Hs},25 APOE {Hs},26 APOD {Hs},27 CETP {Hs},5 LPL {Hs},28 PLTP {Hs},29,30 Cyp7A {Mm},10 FAS {Hs},31 GLUT4 {Hs}32
Mutant phenotype Inability to tolerate dietary cholesterol; accumulation of hepatic cholesteryl esters resulting in hepatomegaly; increased serum LDL; decreased serum HDL, VLDL, and triglycerides {Mm} [knockout]11,33,34; resistant to obesity when challenged with a diet containing high fat and cholesterol {Mm} [knockout]35
Human disease

  • aa, amino acids; chr., chromosome; HRE, hormone response element; LDL, low-density lipoprotein; HDL, high-density lipoprotein; VLDL, very-low-density lipoprotein; TRRAP, transformation/transcription domain-associated protein; APOC, apolipoprotein C; APOE, apolipoprotein E; APOD, apolipoprotein D; CETP, cholesteryl ester transfer protein; LPL, lipoprotein lipase; PLTP, phospholipid transfer protein; FAS, fatty acid synthase

  • ↵1. illy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, and Mangelsdorf DJ (1995) LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 9: 1033-1045

  • ↵2. pfel R, Benbrook D, Lernhardt E, Ortiz MA, Salbert G, and Pfahl M (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: 7025-7035

  • ↵3. lberti S, Steffensen KR, and Gustafsson JA (2000) Structural characterisation of the mouse nuclear oxysterol receptor genes LXRα and LXRβ. Gene 243: 93-103

  • ↵4. rendel C, Schoonjans K, Botrugno OA, Treuter E, and Auwerx J (2002) The small heterodimer partner interacts with the liver X receptor α and represses its transcriptional activity. Mol Endocrinol 16: 2065-2076

  • ↵5. uo Y and Tall AR (2000) Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J Clin Investig 105: 513-520

  • ↵6. ramlett KS, Houck KA, Borchert KM, Dowless MS, Kulanthaivel P, Zhang Y, Beyer TP, Schmidt R, Thomas JS, Michael LF, et al. (2003) A natural product ligand of the oxysterol receptor, liver X receptor. J Pharmacol Exp Ther 307: 291-296

  • ↵7. ollins JL, Fivush AM, Watson MA, Galardi CM, Lewis MC, Moore LB, Parks DJ, Wilson JG, Tippin TK, Binz JG, et al. (2002) Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem 45: 1963-1966

  • ↵8. u X, Menke JG, Chen Y, Zhou G, MacNaul KL, Wright SD, Sparrow CP, and Lund EG (2001) 27-Hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem 276: 38378-38387

  • ↵9. anowski BA, Willy PJ, Devi TR, Falck JR, and Mangelsdorf DJ (1996) An oxysterol signalling pathway mediated by the nuclear receptor LXRα. Nature (Lond) 383: 728-731

  • ↵10. ehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, and Willson TM (1997) Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272: 3137-3140

  • ↵11. chultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, et al. (2000) Role of LXRs in control of lipogenesis. Genes Dev 14: 2831-2838

  • ↵12. parrow CP, Baffic J, Lam MH, Lund EG, Adams AD, Fu X, Hayes N, Jones AB, Macnaul KL, Ondeyka J, et al. (2002) A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 MRNA and stimulating cholesterol efflux. J Biol Chem 277: 10021-10027

  • ↵12. enke JG, Macnaul KL, Hayes NS, Baffic J, Chao YS, Elbrecht A, Kelly LJ, Lam MH, Schmidt A, Sahoo S, et al. (2002) A novel liver X receptor agonist establishes species differences in the regulation of cholesterol 7α -hydroxylase (CYP7a). Endocrinology 143: 2548-2558

  • ↵14. uuskonen J, Fielding PE, and Fielding CJ (2004) Role of p160 coactivator complex in the activation of liver X receptor. Arterioscler Thromb Vasc Biol 24: 703-708

  • ↵15. in J, Yang R, Tarr PT, Wu PH, Handschin C, Li S, Yang W, Pei L, Uldry M, Tontonoz P, et al. (2005) Hyperlipidemic effects of dietary saturated fats mediated through PGC-1β coactivation of SREBP. Cell 120: 261-273

  • ↵16. berkofler H, Schraml E, Krempler F, and Patsch W (2003) Potentiation of liver X receptor transcriptional activity by peroxisome-proliferator-activated receptor gamma co-activator 1 α. Biochem J 371: 89-96

  • ↵17. ong C, Hiipakka RA, and Liao S (2001) Auto-oxidized cholesterol sulfates are antagonistic ligands of liver X receptors: implications for the development and treatment of atherosclerosis. Steroids 66: 473-479

  • ↵18. nno A, Takada I, Takezawa S, Oishi H, Baba A, Shimizu T, Tokita A, Yanagisawa J, and Kato S (2005) TRRAP as a hepatic coactivator of LXR and FXR function. Biochem Biophys Res Commun 327: 933-938

  • ↵19. u X, Li S, Wu J, Xia C, and Lala DS (2003) Liver X receptors interact with corepressors to regulate gene expression. Mol Endocrinol 17: 1019-1026

  • ↵20. ostet P, Luo Y, Wang N, and Tall AR. (2000) Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem 275: 28240-28245

  • ↵21. epa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, and Mangelsdorf DJ (2000) Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289: 1524-1529

  • ↵22. ennedy MA, Venkateswaran A, Tarr PT, Xenarios I, Kudoh J, Shimizu N, and Edwards PA (2001) Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein. J Biol Chem 276: 39438-39447

  • ↵23. enkateswaran A, Repa JJ, Lobaccaro JM, Bronson A, Mangelsdorf DJ, and Edwards PA (2000) Human white/murine ABC8 MRNA levels are highly induced in lipid-loaded macrophages: a transcriptional role for specific oxysterols. J Biol Chem 275: 14700-14707

  • ↵24. epa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, and Mangelsdorf DJ (2000) Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes Dev 14: 2819-2830

  • ↵25. ak PA, Laffitte BA, Desrumaux C, Joseph SB, Curtiss LK, Mangelsdorf DJ, Tontonoz P and Edwards PA (2002) Regulated expression of the apolipoprotein E/C-I/C-IV/C-II gene cluster in murine and human macrophages: a critical role for nuclear liver X receptors α and β. J Biol Chem 277: 31900-31908

  • ↵26. affitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, and Tontonoz P (2001) LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci USA 98: 507-512

  • ↵27. ummasti S, Laffitte BA, Watson MA, Galardi C, Chao LC, Ramamurthy L, Moore JT, and Tontonoz P (2004) Liver X receptors are regulators of adipocyte gene expression but not differentiation: identification of ApoD as a direct target. J Lipid Res 45: 616-625

  • ↵28. hang Y, Repa JJ, Gauthier K, and Mangelsdorf DJ (2001) Regulation of lipoprotein lipase by the oxysterol receptors, LXRα and LXRβ. J Biol Chem 276: 43018-43024

  • ↵29. ao G, Beyer TP, Yang XP, Schmidt RJ, Zhang Y, Bensch WR, Kauffman RF, Gao H, Ryan TP, Liang Y, et al. (2002) Phospholipid transfer protein is regulated by liver X receptors in vivo. J Biol Chem 277: 39561-39565

  • ↵30. affitte BA, Joseph SB, Chen M, Castrillo A, Repa J, Wilpitz D, Mangelsdorf D, and Tontonoz P (2003) The phospholipid transfer protein gene is a liver X receptor target expressed by macrophages in atherosclerotic lesions. Mol Cell Biol 23: 2182-2191

  • ↵31. oseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, Collins JL, Osborne TF, and Tontonoz P (2002) Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem 277: 11019-11025

  • ↵32. alen KT, Ulven SM, Bamberg K, Gustafsson JA, and Nebb HI (2003) Expression of the insulin-responsive glucose transporter GLUT4 in adipocytes is dependent on liver X receptor α. J Biol Chem 278: 48283-48291

  • ↵33. eet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, and Mangelsdorf DJ (1998) Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR α. Cell 93: 693-704

  • ↵34. chuster GU, Parini P, Wang L, Alberti S, Steffensen KR, Hansson GK, Angelin B, and Gustafsson JA (2002) Accumulation of foam cells in liver X receptor-deficient mice. Circulation 106: 1147-1153

  • ↵35. alaany NY, Gauthier KC, Zavacki AM, Mammen PP, Kitazume T, Peterson JA, Horton JD, Garry DJ, Bianco AC, and Mangelsdorf DJ (2005) LXRs regulate the balance between fat storage and oxidation. Cell Metab 1: 231-244