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Journal of Lipid Research, Vol. 46, 2182-2191, October 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Synthetic LXR agonists increase LDL in CETP species

Pieter H. E. Groot¹, Nigel J. Pearce¹, John W. Yates¹, Claire Stocker¹, Charles Sauermelch, Christopher P. Doe, Robert N. Willette, Alan Olzinski, Tambra Peters, Denise d'Epagnier², Kathleen O. Morasco², John A. Krawiec, Christine L. Webb, Karpagam Aravindhan, Beat Jucker, Mark Burgert³, Chun Ma, Joseph P. Marino, Jon L. Collins⁴, Colin H. Macphee, Scott K. Thompson and Michael Jaye⁵

Cardiovascular Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA 19406-0939

Published, JLR Papers in Press, July 16, 2005. DOI 10.1194/jlr.M500116-JLR200

¹ Present address of P. H. E. Groot, N. J. Pearce, J. W. Yates, and C. Stocker: Cardiovascular Center for Excellence in Drug Discovery, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.

² Present address of D. d'Epagnier, and K. O. Morasco: Department of Laboratory Animal Sciences, GlaxoSmithKline, King of Prussia, PA 19406, USA.

³ Present address of M. Burgert: Department of Statistical Sciences, GlaxoSmithKline, King of Prussia, PA 19406, USA.

⁴ Present address of J. L. Collins: Discovery Research, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27707, USA.

⁵ To whom correspondence should be addressed. e-mail: michael.c.jaye{at}gsk.com

Liver X receptor (LXR) nuclear receptors regulate the expression of genes involved in whole body cholesterol trafficking, including absorption, excretion, catabolism, and cellular efflux, and possess both anti-inflammatory and antidiabetic actions. Accordingly, LXR is considered an appealing drug target for multiple indications. Synthetic LXR agonists demonstrated inhibition of atherosclerosis progression in murine genetic models; however, these and other studies indicated that their major undesired side effect is an increase of plasma and hepatic triglycerides. A significant impediment to extrapolating results with LXR agonists from mouse to humans is the absence in mice of cholesteryl ester transfer protein, a known LXR target gene, and the upregulation in mice but not humans of cholesterol 7-hydroxylase. To better predict the human response to LXR agonism, two synthetic LXR agonists were examined in hamsters and cynomolgus monkeys. In contrast to previously published results in mice, neither LXR agonist increased HDL-cholesterol in hamsters, and similar results were obtained in cynomolgus monkeys. Importantly, in both species, LXR agonists increased LDL-cholesterol, an unfavorable effect not apparent from earlier murine studies.

These results reveal additional problems associated with current synthetic LXR agonists and emphasize the importance of profiling compounds in preclinical species with a more human-like LXR response and lipoprotein metabolism.

Abbreviations: ABCG1, ATP binding cassette protein G1; apoE, apolipoprotein E; CETP, cholesteryl ester transfer protein; cyp7a, cholesterol 7-hydroxylase; HDL-C, high density lipoprotein-cholesterol; LXR, liver X receptor; SCD, steroyl coenzyme A desaturase; SREBP, sterol-regulatory element binding protein

Supplementary key words liver X receptor • low density lipoprotein • cholesteryl ester transfer protein • monkey • hamster • triglyceride • atherosclerosis

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