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Papers In Press, published online ahead of print December 1, 2009
J. Lipid Res., doi:10.1194/jlr.M900037-JLR200

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Journal of Lipid Research, Vol. 50, 2358-2370, December 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

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

Elaine M. Quinet^*, Michael D. Basso^*, Anita R. Halpern^*, David W. Yates, Robert J. Steffan, Valerie Clerin^*, Christine Resmini^*, James C. Keith^*, Thomas J. Berrodin^*, Irene Feingold^**, Wenyan Zhong, Helen B. Hartman^*, Mark J. Evans^*, Stephen J. Gardell^*, Elizabeth DiBlasio-Smith, William M. Mounts, Edward R. LaVallie, Jay Wrobel, Ponnal Nambi^* and George P. Vlasuk^1,2,*

^* Department of Cardiovascular/Metabolic Diseases and Nuclear Receptor Biology, Wyeth Research, Collegeville, PA and Cambridge, MA
Department of Bioresources, Wyeth Research Pearl River, NY
Chemical Sciences, Wyeth Research, Collegeville, PA
^** Department of Biotransformation, Wyeth Research, Collegeville, PA
Department of Biological Technologies, Wyeth Research, Cambridge, MA

² To whom correspondence should be addressed. e-mail: gvlasuk{at}sirtrispharma.com

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.

Supplementary key words cynomolgus monkey • dyslipidemia • fibroblast growth factor 19 • hypertriglyceridemia

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; apo, apolipoprotein; CETP, cholesteryl ester transfer protein; FGF, fibroblast growth factor; FXR, farnesoid X receptor; HFHC, high-fat, high-cholesterol; INSIG, insulin induced gene 1; LBD, ligand binding domain; LDLc, LDL cholesterol; LXR, liver X receptor; PLTP, phospholipid transfer protein; RCT, reverse cholesterol transport; SCD1, stearoyl CoA desaturase-1; SHP, small heterodimer partner; SREBP, sterol-response element binding protein; TG, triglyceride

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