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Journal of Lipid Research, Vol. 47, 1037-1044, May 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

A 15-ketosterol is a liver X receptor ligand that suppresses sterol-responsive element binding protein-2 activity¹

Robert J. Schmidt^*, James V. Ficorilli^*, Youyan Zhang^*, Kelli S. Bramlett^*, Thomas P. Beyer^*, Kristen Borchert^*, Michele S. Dowless^*, Keith A. Houck^*, Thomas P. Burris^*, Patrick I. Eacho^*, Guosheng Liang^*, Li-wei Guo, William K. Wilson, Laura F. Michael^* and Guoqing Cao^*,2

^* Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN 46285
Department of Biochemistry and Cell Biology, Rice University, Houston, TX 77005

¹ This work is dedicated to the memory of George J. Schroepfer, Jr., a pioneer in the development of oxysterols as antihypercholesterolemic agents. Dr. Schroepfer showed that the 15-ketosterol lowers LDL- and raises HDL-cholesterol in primates, but his many efforts in the 1980s to elucidate the mechanisms of action were doomed because the regulation of cholesterol metabolism was only partially understood. Dr. Schroepfer followed subsequent developments in genomics and proteomics and demonstrated that oxysterols activate LXR [Forman et al. (1997) Proc. Natl. Acad. Sci. 94, 10588]. He also tested the 15-ketosterol, but did not publish the results before his untimely death on December 11, 1998, just as the "promised land" was coming into view. Soon afterwards, (a) the big picture of cholesterol homeostasis was recognized as the sum of many processes, notably involving LXR, ABC transporters, and SREBP, and (b) Guoqing Cao (Lilly Research Laboratories) contacted Schroepfer's laboratory to initiate a collaboration on the 15-ketosterol. William K. Wilson (Rice University) helped facilitate the collaboration between Rice and Lilly as an obvious extension of research plans laid out by G. J. Schroepfer, Jr. This collaboration was inspired by the vision and perseverance of Dr. Schroepfer, to whom we are grateful.

Published, JLR Papers in Press, January 13, 2006.

² To whom correspondence should be addressed. e-mail: guoqing_cao{at}lilly

Hypercholesterolemia is a major risk factor for coronary artery disease. Oxysterols are known to inhibit cholesterol biosynthesis and have been explored as potential antihypercholesterolemic agents. The ability of 3ß-hydroxy-5-cholest-8(14)-en-15-one (15-ketosterol) to lower non-HDL cholesterol has been demonstrated in rodent and primate models, but the mechanisms of action remain poorly understood. Here we show in a coactivator recruitment assay and cotransfection assays that the 15-ketosterol is a partial agonist for liver X receptor- and -ß (LXR and LXRß). The binding affinity for the LXRs was comparable to those of native oxysterols. In a macrophage cell line of human origin, the 15-ketosterol elevated ATP binding cassette transporter ABCA1 mRNA in a concentration-dependent fashion with a potency similar to those of other oxysterols. We further found that in human embryonic kidney HEK 293 cells, the 15-ketosterol suppressed sterol-responsive element binding protein processing activity and thus inhibited mRNA expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, LDL receptor, and PCSK9. Our data thus provide a molecular basis for the hypocholesterolemic activity of the 15-ketosterol and further suggest its potential antiatherosclerotic benefit as an LXR agonist.

Supplementary key words hypercholesterolemia • statin • scintillation proximity assay

Abbreviations: LDLR, LDL receptor; LXR, liver X receptor; SPA, scintillation proximity assay; SREBP, sterol-responsive element binding protein

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