The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
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
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The nuclear receptor superfamily: the second decade
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Self-citation9-cis retinoic acid is a high affinity ligand for the retinoid X receptor
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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
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Cited by
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
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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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