TABLE 7

LXRβ

Receptor Nomenclature NR1H2
Receptor code 4.1.1:OXY:1:H2
Other names LXR-b, UNR, OR-1, NER, NER1, RIP15
Molecular information Hs: 461aa, P55055, chr. 19q13.31
Rn: 446aa, Q62755, chr. 1q222
Mm: 446aa, Q60644, chr. 7 B33
DNA binding
   Structure RXR partner
   HRE core sequence AGGTCANNNNAGGTCA (DR-1, DR-4)
Partners RXR (physical)3; SHP (physical, functional)4
Agonists Acetyl-podocarpic dimmer (1 nM), GW3965 (30 nM), T0901317 (50 nM), 27-hydroxycholesterol (71 nM), 22(R)-hydroxycholesterol (3 μM), 24(S)-hydroxycholesterol (3 μM), 24(S),25-epoxycholesterol (3 μM),* paxilline (4 μM), [EC50]5–11; F(3)methylAA (7 nM) [Kd]12
Antagonists
Coactivator NCOA1, p30013
Corepressor NCOR1, NCOR214
Biologically important isoforms
Tissue distribution Ubiquitous {Rn} [Northern blot]2,15
Functional assay
Main target genes Activated: ABCA1 {Hs},16,17 ABCG1 {Hs},18,19 SREBP1c {Hs},20 APOCI/IV/II {Hs},21 APOE {Hs},22 CETP {Hs},23 Cyp7A {Mm},9 FAS {Hs},24 GLUT4 {Hs}25
Mutant phenotype Alterations in adipocyte growth, glucose homeostasis, and β -cell function (normal resistance to dietary cholesterol, unlike the LXRα knockout) {Mm} [knockout]26,27
Human disease

  • aa, amino acids; chr., chromosome; HRE, hormone response element; UNR, ubiquitously expressed nuclear receptor; APOC, apolipoprotein C; APOE, apolipoprotein E; CETP, cholesteryl ester transfer protein; FAS, fatty acid synthase

  • ↵* Radioligand

  • ↵1. Shinar DM, Endo N, Rutledge SJ, Vogel R, Rodan GA, and Schmidt A (1994) NER, a new member of the gene family encoding the human steroid hormone nuclear receptor. Gene 147: 273-276

  • ↵2. Song C, Kokontis JM, Hiipakka RA, and Liao S (1994) Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors. Proc Natl Acad Sci USA 91: 10809-10813

  • ↵3. Seol W, Choi HS, and Moore DD (1995) Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors. Mol Endocrinol 9: 72-85

  • ↵4. Brendel 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. Bramlett 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

  • ↵6. Collins 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

  • ↵7. Fu 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

  • ↵8. Janowski BA, Willy PJ, Devi TR, Falck JR, and Mangelsdorf DJ (1996) An oxysterol signalling pathway mediated by the nuclear receptor LXR α. Nature (Lond) 383: 728-371

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

  • ↵10. Schultz 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

  • ↵11. Sparrow 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. Menke 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

  • ↵13. Huuskonen 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

  • ↵14. Hu 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

  • ↵15. Lu TT, Repa JJ, and Mangelsdorf DJ (2001) Orphan nuclear receptors as elixirs and fixers of sterol metabolism. J Biol Chem 276: 37735-37738

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

  • ↵17. Repa 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 (Wash DC) 289: 1524-1529

  • ↵18. Kennedy 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

  • ↵19. Venkateswaran 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

  • ↵20. Repa 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

  • ↵21. Mak 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

  • ↵22. Laffitte 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

  • ↵23. Luo 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

  • ↵24. Joseph 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

  • ↵25. Dalen 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

  • ↵26. Alberti S, Schuster G, Parini P, Feltkamp D, Diczfalusy U, Rudling M, Angelin B, Bjorkhem I, Pettersson S, and Gustafsson JA (2001) Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRβ -deficient mice. J Clin Investig 107: 565-573

  • ↵27. Gerin I, Dolinsky VW, Shackman JG, Kennedy RT, Chiang SH, Burant CF, Steffensen KR, Gustafsson JA, and MacDougald OA (2005) LXRβ is required for adipocyte growth, glucose homeostasis, and β cell function. J Biol Chem 280: 23024-23031