Synthetic LXR agonists elevate LDL in CETP species

doi:10.1194/jlr.M500116-JLR200

HOME

HELP

FEEDBACK

SUBSCRIPTIONS

Synthetic LXR agonists elevate LDL in CETP species

Pieter H. E. Groot, Nigel J. Pearce, John W. Yates, Claire Stocker, Charles Sauermelch, Christopher P. Doe, Robert N. Willette, Alan Olzinski, Tambra Peters, Denise d'Epagnier, Kathleen O. Morasco, John A. Krawiec, Christine L. Webb, Karpagam Aravindham, Beat M. Jucker, Mark Burgert, Chun Ma, Joseph P. Marino, Jon L. Collins, Colin H. Macphee, Scott K. Thompson, and Michael Jaye

Department of Vascular Biology and Thrombosis, GlaxoSmithKline, Cardiovascular Center for Excellence in Drug Discovery, King of Prussia, PA 19406-0939

Corresponding Author: michael.c.jaye{at}gsk.com

Liver X receptor (LXR) nuclear receptors regulate expression of genes involved in whole body cholesterol trafficking, including absorption, excretion, catabolism and cellular efflux and possess both anti-inflammatory and anti-diabetic actions. Accordingly, LXR is considered an appealing drug target for multiple indications, including coronary artery disease. Indeed, structurally distinct synthetic LXR agonists were shown to inhibit atherogenesis in murine genetic models. However, these and other studies of synthetic LXR agonists in mice also revealed that LXRs can dramatically elevate plasma and/or hepatic triglycerides, considered to be a major liability. Furthermore, a significant impediment to extrapolating results with LXR agonists from mice to humans is the absence in mice of cholesteryl ester transfer protein (CETP), a known LXR target gene, and the upregulation in mice but not humans of cholesterol 7alpha-hydroxylase (cyp7a). To identify more suitable animal models, two synthetic LXR agonists were examined in hamsters and cynomolgus monkeys, both CETP species. In contrast to previously published results in mice, none of the LXR agonists elevated HDL-C, neither in hamsters nor in cynomogous monkeys. In various hamster tissues, expression of LXR target genes including steroyl-CoA desaturase-1 (SCD-1) increased dose-dependently as did plasma levels of the SCD-1 product, oleic acid. Importantly, in both species the LXR agonists elevated LDL-C, a liability not apparent from earlier murine studies. These results reveal additional liabilities associated with current synthetic LXR agonists and emphasize the importance of profiling compounds in preclinical species which possess a more human-like lipoprotein metabolism.

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

This article has been cited by other articles:

C. A. Phelan, J. M. Weaver, D. J. Steger, S. Joshi, J. T. Maslany, J. L. Collins, W. J. Zuercher, T. M. Willson, M. Walker, M. Jaye, et al.
Selective Partial Agonism of Liver X Receptor {alpha} Is Related to Differential Corepressor Recruitment
Mol. Endocrinol., October 1, 2008; 22(10): 2241 - 2249.
[Abstract] [Full Text] [PDF]

P. Kotokorpi, E. Ellis, P. Parini, L.-M. Nilsson, S. Strom, K. R. Steffensen, J.-A. Gustafsson, and A. Mode
Physiological Differences between Human and Rat Primary Hepatocytes in Response to Liver X Receptor Activation by 3-[3-[N-(2-Chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic Acid Hydrochloride (GW3965)
Mol. Pharmacol., October 1, 2007; 72(4): 947 - 955.
[Abstract] [Full Text] [PDF]

E. M. Quinet, D. A. Savio, A. R. Halpern, L. Chen, G. U. Schuster, J.-A. Gustafsson, M. D. Basso, and P. Nambi
Liver X Receptor (LXR)-beta Regulation in LXR{alpha}-Deficient Mice: Implications for Therapeutic Targeting
Mol. Pharmacol., October 1, 2006; 70(4): 1340 - 1349.
[Abstract] [Full Text] [PDF]

M. Cuchel and D. J. Rader
Macrophage Reverse Cholesterol Transport: Key to the Regression of Atherosclerosis?
Circulation, May 30, 2006; 113(21): 2548 - 2555.
[Full Text] [PDF]

D. Duffy and D. J. Rader
Emerging Therapies Targeting High-Density Lipoprotein Metabolism and Reverse Cholesterol Transport
Circulation, February 28, 2006; 113(8): 1140 - 1150.
[Full Text] [PDF]

S. U. Naik, X. Wang, J. S. Da Silva, M. Jaye, C. H. Macphee, M. P. Reilly, J. T. Billheimer, G. H. Rothblat, and D. J. Rader
Pharmacological Activation of Liver X Receptors Promotes Reverse Cholesterol Transport In Vivo
Circulation, January 3, 2006; 113(1): 90 - 97.
[Abstract] [Full Text] [PDF]

All ASBMB Journals	Journal of Biological Chemistry
Molecular and Cellular Proteomics	ASBMB Today

				P. Kotokorpi, E. Ellis, P. Parini, L.-M. Nilsson, S. Strom, K. R. Steffensen, J.-A. Gustafsson, and A. Mode Physiological Differences between Human and Rat Primary Hepatocytes in Response to Liver X Receptor Activation by 3-[3-[N-(2-Chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic Acid Hydrochloride (GW3965) Mol. Pharmacol., October 1, 2007; 72(4): 947 - 955. [Abstract] [Full Text] [PDF]

				E. M. Quinet, D. A. Savio, A. R. Halpern, L. Chen, G. U. Schuster, J.-A. Gustafsson, M. D. Basso, and P. Nambi Liver X Receptor (LXR)-beta Regulation in LXR{alpha}-Deficient Mice: Implications for Therapeutic Targeting Mol. Pharmacol., October 1, 2006; 70(4): 1340 - 1349. [Abstract] [Full Text] [PDF]

				M. Cuchel and D. J. Rader Macrophage Reverse Cholesterol Transport: Key to the Regression of Atherosclerosis? Circulation, May 30, 2006; 113(21): 2548 - 2555. [Full Text] [PDF]

				D. Duffy and D. J. Rader Emerging Therapies Targeting High-Density Lipoprotein Metabolism and Reverse Cholesterol Transport Circulation, February 28, 2006; 113(8): 1140 - 1150. [Full Text] [PDF]

				S. U. Naik, X. Wang, J. S. Da Silva, M. Jaye, C. H. Macphee, M. P. Reilly, J. T. Billheimer, G. H. Rothblat, and D. J. Rader Pharmacological Activation of Liver X Receptors Promotes Reverse Cholesterol Transport In Vivo Circulation, January 3, 2006; 113(1): 90 - 97. [Abstract] [Full Text] [PDF]