LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse[S]

• Published in: Journal of lipid research Vol. 50; no. 12; pp. 2358 - 2370
• Main Authors: Quinet, Elaine M., Basso, Michael D., Halpern, Anita R., Yates, David W., Steffan, Robert J., Clerin, Valerie, Resmini, Christine, Keith, James C., Berrodin, Thomas J., Feingold, Irene, Zhong, Wenyan, Hartman, Helen B., Evans, Mark J., Gardell, Stephen J., DiBlasio-Smith, Elizabeth, Mounts, William M., LaVallie, Edward R., Wrobel, Jay, Nambi, Ponnal, Vlasuk, George P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2009; American Society for Biochemistry and Molecular Biology; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Animals; Atherosclerosis - drug therapy; Atherosclerosis - metabolism; Caco-2 Cells; Cholesterol, LDL - drug effects; Cholesterol, LDL - metabolism; Cricetinae; cynomolgus monkey; Disease Models, Animal; dyslipidemia; fibroblast growth factor 19; Humans; hypertriglyceridemia; Indazoles - blood; Indazoles - chemistry; Indazoles - pharmacology; Ligands; Lipid Metabolism - drug effects; Liver - enzymology; Liver - metabolism; Liver X Receptors; Macaca fascicularis - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Orphan Nuclear Receptors - agonists; Orphan Nuclear Receptors - metabolism; hypertriglyceridemia; cynomolgus monkey; dyslipidemia; fibroblast growth factor 19
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M900037-JLR200

Liver X receptors (LXRs) are ligand-activated transcription factors that coordinate regulation of gene expression involved in several cellular functions but most notably cholesterol homeostasis encompassing cholesterol transport, catabolism, and absorption. WAY-252623 (LXR-623) is a highly selective and orally bioavailable synthetic modulator of LXR, which demonstrated efficacy for reducing lesion progression in the murine LDLR−/− atherosclerosis model with no associated increase in hepatic lipogenesis either in this model or Syrian hamsters. In nonhuman primates with normal lipid levels, WAY-252623 significantly reduced total (50–55%) and LDL-cholesterol (LDLc) (70–77%) in a time- and dose-dependent manner as well as increased expression of the target genes ABCA1/G1 in peripheral blood cells. Statistically significant decreases in LDLc were noted as early as day 7, reached a maximum by day 28, and exceeded reductions observed for simvastatin alone (20 mg/kg). Transient increases in circulating triglycerides and liver enzymes reverted to baseline levels over the course of the study. Complementary microarray analysis of duodenum and liver gene expression revealed differential activation of LXR target genes and suggested no direct activation of hepatic lipogenesis.