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Structural requirements of ligands for the oxysterol liver X receptors LXRα and LXRβ
Open accessAbstract
LXRα and -β are nuclear receptors that regulate the metabolism of several important lipids, including cholesterol and bile acids. Previously, we have proposed that LXRs regulate these pathways through their interaction with specific, naturally occurring oxysterols, including 22( R )-hydroxycholesterol, 24( S )-hydroxycholesterol, and 24( S ),25-epoxycholesterol. Using a ligand binding assay that incorporates scintillation proximity technology to circumvent many of the problems associated with assaying extremely hydrophobic ligands, we now demonstrate that these oxysterols bind directly to LXRs at concentrations that occur in vivo . To characterize further the structural determinants required for potent LXR ligands, we synthesized and tested a series of related compounds for binding to LXRs and activation of transcription. These studies revealed that position-specific monooxidation of the sterol side chain is requisite for LXR high-affinity binding and activation. Enhanced binding and activation can also be achieved through the use of 24-oxo ligands that act as hydrogen bond acceptors in the side chain. In addition, introduction of an oxygen on the sterol B-ring results in a ligand with LXRα-subtype selectivity. These results support the hypothesis that naturally occurring oxysterols are physiological ligands for LXRs and show that a rational, structure-based approach can be used to design potent LXR ligands for pharmacologic use.
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Cites
Yung-Chi, C., & Prusoff, W. H. (1973) · Biochemical Pharmacology · doi:10.1016/0006-2952(73)90196-2 · Cited by 12,922
The nuclear receptor superfamily: the second decade
Mangelsdorf, D. J., Thummel, C., Beato, M., Herrlich, P., Schütz, G., Umesono, K., Blumberg, B., Kastner, P., Mark, M., Chambon, P., et al. (1995) · Cell · doi:10.1016/0092-8674(95)90199-x · Cited by 6,964
Self-citation9-cis retinoic acid is a high affinity ligand for the retinoid X receptor
Heyman, R. A., Mangelsdorf, D. J., Dyck, J. A., Stein, R. B., Eichele, G., Evans, R. M., & Thaller, C. (1992) · Cell · doi:10.1016/0092-8674(92)90479-v · Cited by 1,780
Self-citationActivation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway
Lehmann, J. M., Kliewer, S. A., Moore, L. B., Smith-Oliver, T. A., Oliver, B. B., Su, J.-L., Sundseth, S. S., Winegar, D. A., Blanchard, D. E., Spencer, T. A., et al. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.6.3137 · Cited by 1,233
Self-citationRussell, D. W., & Setchell, K. D. R. (1992) · Biochemistry · doi:10.1021/bi00135a001 · Cited by 819
Apfel, R., Benbrook, D., Lernhardt, E., Ortiz, M. A., Salbert, G., & Pfahl, M. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.10.7025 · Cited by 372
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SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15593 · Cited by 4,794
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215593 · Cited by 4,092
Targeted Disruption of the Nuclear Receptor FXR/BAR Impairs Bile Acid and Lipid Homeostasis
Sinal, C. J., Tohkin, M., Miyata, M., Ward, J. M., Lambert, G., & Gonzalez, F. J. (2000) · Cell · doi:10.1016/s0092-8674(00)00062-3 · Cited by 1,819
Role of LXRs in control of lipogenesis
Schultz, J. R., Tu, H., Luk, A., Repa, J. J., Medina, J. C., Li, L., Schwendner, S., Wang, S., Thoolen, M., Mangelsdorf, D. J., et al. (2000) · Genes & Development · doi:10.1101/gad.850400 · Cited by 1,499
Self-citationMolecular Basis for Feedback Regulation of Bile Acid Synthesis by Nuclear Receptors
Lu, T. T., Makishima, M., Repa, J. J., Schoonjans, K., Kerr, T. A., Auwerx, J., & Mangelsdorf, D. J. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00050-2 · Cited by 1,487
Self-citationA PPARγ-LXR-ABCA1 Pathway in Macrophages Is Involved in Cholesterol Efflux and Atherogenesis
Chawla, A., Boisvert, W. A., Lee, C.-H., Laffitte, B. A., Barak, Y., Joseph, S. B., Liao, D., Nagy, L., Edwards, P. A., Curtiss, L. K., et al. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00164-2 · Cited by 1,347
Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXRα
Venkateswaran, A., Laffitte, B. A., Joseph, S. B., Mak, P. A., Wilpitz, D. C., Edwards, P. A., & Tontonoz, P. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.200367697 · Cited by 1,005
Iqbal, J., & Hussain, M. M. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90899.2008 · Cited by 811
Liver X receptors in lipid signalling and membrane homeostasis
Wang, B., & Tontonoz, P. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0037-x · Cited by 722
Cholesterol metabolism and homeostasis in the brain
Zhang, J., & Liu, Q. (2015) · Protein & Cell · doi:10.1007/s13238-014-0131-3 · Cited by 686
LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes
Laffitte, B. A., Repa, J. J., Joseph, S. B., Wilpitz, D. C., Kast, H. R., Mangelsdorf, D. J., & Tontonoz, P. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.2.507 · Cited by 683
Self-citationLiu, S.-Y., Aliyari, R., Chikere, K., Li, G., Marsden, M. D., Smith, J. K., Pernet, O., Guo, H., Nusbaum, R., Zack, J. A., et al. (2013) · Immunity · doi:10.1016/j.immuni.2012.11.005 · Cited by 678
Liver X receptors in lipid metabolism: opportunities for drug discovery
Hong, C., & Tontonoz, P. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4280 · Cited by 587
Ghisletti, S., Huang, W., Ogawa, S., Pascual, G., Lin, M.-E., Willson, T. M., Rosenfeld, M. G., & Glass, C. K. (2007) · Molecular Cell · doi:10.1016/j.molcel.2006.11.022 · Cited by 561
ATP-Binding Cassette Cholesterol Transporters and Cardiovascular Disease
Oram, J. F., & Vaughan, A. M. (2006) · Circulation Research · doi:10.1161/01.res.0000250171.54048.5c · Cited by 411
PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis
Li, A. C., & Glass, C. K. (2004) · Journal of Lipid Research · doi:10.1194/jlr.r400010-jlr200 · Cited by 357
Lee, G., Elwood, F., McNally, J., Weiszmann, J., Lindstrom, M., Amaral, K., Nakamura, M., Miao, S., Cao, P., Learned, R. M., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200743200 · Cited by 319
Cholesterol in brain disease: Sometimes determinant and frequently implicated
Martín, M. G., Pfrieger, F., & Dotti, C. G. (2014) · The EMBO Reports · doi:10.15252/embr.201439225 · Cited by 304
Oxysterols are allosteric activators of the oncoprotein Smoothened
Nachtergaele, S., Mydock, L. K., Krishnan, K., Rammohan, J., Schlesinger, P. H., Covey, D. F., & Rohatgi, R. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.765 · Cited by 284
Liver X receptors link lipid metabolism and inflammation
Schulman, I. G. (2017) · FEBS Letters · doi:10.1002/1873-3468.12702 · Cited by 244
Edwards (2002) · doi:10.1016/s1537-1891(02)00175-1 · Cited by 233
Characterization of the Human ABCG1 Gene
Kennedy, M. A., Venkateswaran, A., Tarr, P. T., Xenarios, I., Kudoh, J., Shimizu, N., & Edwards, P. A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105863200 · Cited by 217
Regulation of Cholesterol Homeostasis by the Liver X Receptors in the Central Nervous System
Whitney, K. D., Watson, M. A., Collins, J. L., Benson, W. G., Stone, T. M., Numerick, M. J., Tippin, T. K., Wilson, J. G., Winegar, D. A., & Kliewer, S. A. (2002) · Molecular Endocrinology · doi:10.1210/mend.16.6.0835 · Cited by 211
Self-citationDeBose-Boyd, R. A., Ou, J., Goldstein, J. L., & Brown, M. S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.4.1477 · Cited by 209
Practical uses for ecdysteroids in mammals including humans: and update
Lafont, R., & Dinan, L. (2003) · Journal of Insect Science · doi:10.1093/jis/3.1.7 · Cited by 196
Practical uses for ecdysteroids in mammals including humans: And update
Lafont, R., & Dinan, L. (2003) · Journal of Insect Science · doi:10.1673/031.003.0701 · Cited by 196
Kirchgessner, T. G., Sleph, P., Ostrowski, J., Lupisella, J., Ryan, C. S., Liu, X., Fernando, G., Grimm, D., Shipkova, P., Zhang, R., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.07.016 · Cited by 172
Panzenboeck, U., Balazs, Z., Sovic, A., Hrzenjak, A., Levak-Frank, S., Wintersperger, A., Malle, E., & Sattler, W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207601200 · Cited by 169
Liang, Y., Lin, S., Beyer, T. P., Zhang, Y., Wu, X., Bales, K. R., DeMattos, R. B., May, P. C., Li, S. D., Jiang, X., et al. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02183.x · Cited by 160
Liver X Receptor (LXR) Regulation of the LXRα Gene in Human Macrophages
Whitney, K. D., Watson, M. A., Goodwin, B., Galardi, C. M., Maglich, J. M., Wilson, J. G., Willson, T. M., Collins, J. L., & Kliewer, S. A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106155200 · Cited by 154
Self-citationFeedback Regulation of Cholesterol Uptake by the LXR–IDOL–LDLR Axis
Zhang, L., Reue, K., Fong, L. G., Young, S. G., & Tontonoz, P. (2012) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.112.250571 · Cited by 137
Kim, H.-J., Fan, X., Gabbi, C., Yakimchuk, K., Parini, P., Warner, M., & Gustafsson, J.-Å. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711599105 · Cited by 136
Liver X receptors (LXR) as therapeutic targets in dyslipidemia
Bełtowski, J. (2008) · Cardiovascular Therapeutics · doi:10.1111/j.1755-5922.2008.00062.x · Cited by 132
Wong, J., Quinn, C. M., & Brown, A. J. (2006) · Biochemical Journal · doi:10.1042/bj20060914 · Cited by 127
Hepatic transcriptional responses to fasting and feeding
Bideyan, L., Nagari, R., & Tontonoz, P. (2021) · Genes & Development · doi:10.1101/gad.348340.121 · Cited by 126
ABCA1: at the nexus of cholesterol, HDL and atherosclerosis
ATTIE, A. (2007) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2007.02.001 · Cited by 126
Zhang-Gandhi, C. X., & Drew, P. D. (2007) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2006.11.007 · Cited by 117
Fan, X., Kim, H.-J., Bouton, D., Warner, M., & Gustafsson, J.-Å. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806974105 · Cited by 103
Ma, L., Wang, L., Nelson, A. T., Han, C., He, S., Henn, M. A., Menon, K., Chen, J. J., Baek, A. E., Vardanyan, A., et al. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.08.020 · Cited by 98
Sphingosine regulates the transcription of CYP17 by binding to steroidogenic factor-1
Urs, A. N., Dammer, E., & Sewer, M. B. (2006) · Endocrinology · doi:10.1210/en.2006-0355 · Cited by 94
Yang, M., Liu, W., Pellicane, C., Sahyoun, C., Joseph, B. K., Gallo-Ebert, C., Donigan, M., Pandya, D., Giordano, C., Bata, A., et al. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m041335 · Cited by 93
On the formation and possible biological role of 25-hydroxycholesterol
Diczfalusy, U. (2013) · Biochimie · doi:10.1016/j.biochi.2012.06.016 · Cited by 87
Cook, I. T., Duniec-Dmuchowski, Z., Kocarek, T. A., Runge-Morris, M., & Falany, C. N. (2009) · Drug Metabolism and Disposition · doi:10.1124/dmd.108.025759 · Cited by 86
Töröcsik, D., Szanto, A., & Nagy, L. (2009) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2009.02.002 · Cited by 82
Janowski, B. A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.202471599 · Cited by 79
Self-citationLXRα Enhances Lipid Synthesis in SZ95 Sebocytes
Hong, I., Lee, M.-H., Na, T.-Y., Zouboulis, C. C., & Lee, M.-O. (2008) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5701134 · Cited by 77
Scotti, E., Hong, C., Yoshinaga, Y., Tu, Y., Hu, Y., Zelcer, N., Boyadjian, R., de Jong, P. J., Young, S. G., Fong, L. G., et al. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.01469-10 · Cited by 77
Cashikar, A. G., Toral-Rios, D., Timm, D., Romero, J., Strickland, M., Long, J. M., Han, X., Holtzman, D. M., & Paul, S. M. (2023) · Journal of Lipid Research · doi:10.1016/j.jlr.2023.100350 · Cited by 72
Cholesterol metabolism: from lipidomics to immunology
Griffiths, W. J., & Wang, Y. (2022) · Journal of Lipid Research · doi:10.1016/j.jlr.2021.100165 · Cited by 68
Liver X receptors: Emerging therapeutic targets for Alzheimer's disease
Sodhi, R. K., & Singh, N. (2013) · Pharmacological Research · doi:10.1016/j.phrs.2013.03.008 · Cited by 61
Fujiyoshi, M., Ohtsuki, S., Hori, S., Tachikawa, M., & Terasaki, T. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04240.x · Cited by 56
Ali, Z., Heverin, M., Olin, M., Acimovic, J., Lövgren-Sandblom, A., Shafaati, M., Båvner, A., Meiner, V., Leitersdorf, E., & Björkhem, I. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m034124 · Cited by 54
Cholesterol: From Feeding to Gene Regulation
Martini, C., & Pallottini, V. (2007) · Genes & Nutrition · doi:10.1007/s12263-007-0049-y · Cited by 53
Pascual-García, M., Rué, L., León, T., Julve, J., Carbó, J. M., Matalonga, J., Auer, H., Celada, A., Escolà-Gil, J. C., Steffensen, K. R., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1201393 · Cited by 51
Wassif, C. A., Yu, J., Cui, J., Porter, F. D., & Javitt, N. B. (2003) · Steroids · doi:10.1016/s0039-128x(03)00090-4 · Cited by 44
Liu, Y., Han, X., Bian, Z., Peng, Y., You, Z., Wang, Q., Chen, X., Qiu, D., & Ma, X. (2012) · Digestive Diseases and Sciences · doi:10.1007/s10620-011-1902-9 · Cited by 35
Birolini, G., Valenza, M., Di Paolo, E., Vezzoli, E., Talpo, F., Maniezzi, C., Caccia, C., Leoni, V., Taroni, F., Bocchi, V. D., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.202012519 · Cited by 27
Leitch, E. K., Elumalai, N., Fridén-Saxin, M., Dahl, G., Wan, P., Clarkson, P., Valeur, E., Pairaudeau, G., Boyd, H., & Tavassoli, A. (2018) · Chemical Science · doi:10.1039/c8sc01186a · Cited by 25
Metadata
- Authors
- Janowski, B. A., Grogan, M. J., Jones, S. A., Wisely, G. B., Kliewer, S. A., Corey, E. J., & Mangelsdorf, D. J.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 1999-01-05
- Volume
- 96
- Issue
- 1
- Pages
- 266-271
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2088436733
- Cited by
- 942
- References
- 6
- FWCI
- 35.03
- Type
- journal article
- Language
- en
- Open access
- green
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