Sean B. Joseph1, Elaine McKilligin1, Liming Pei1, Michael A. Watson1, Alan R. Collins1, Bryan Laffitte1, Mingyi Chen1, Grace Noh1, Joanne Goodman1, Graham N. Hagger1, Jonathan Tran1, Tim K. Tippin1, Xuping Wang1, Aldons J. Lusis1, Willa A. Hsueh1, Ronald E. Law1, Jon L. Collins1, Timothy M. Willson1, Peter Tontonoz1
1Howard Hughes Medical Institute and the Departments of Pathology and Laboratory Medicine, Medicine, Human Genetics, and Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095-1662; Atherosclerosis Department, Cardiovascular and Urology CEDD, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom; and Nuclear Receptor Discovery Research and Biometabolism Research Support, GlaxoSmithKline, Research Triangle Park, NC 27709-3398
Tóm tắt
The nuclear receptors LXRα and LXRβ have been implicated in the control of cholesterol and fatty acid metabolism in multiple cell types. Activation of these receptors stimulates cholesterol efflux in macrophages, promotes bile acid synthesis in liver, and inhibits intestinal cholesterol absorption, actions that would collectively be expected to reduce atherosclerotic risk. However, synthetic LXR ligands have also been shown to induce lipogenesis and hypertriglyceridemia in mice, raising questions as to the net effects of these compounds on the development of cardiovascular disease. We demonstrate here that the nonsteroidal LXR agonist GW3965 has potent antiatherogenic activity in two different murine models. In LDLR
−/−
mice, GW3965 reduced lesion area by 53% in males and 34% in females. A similar reduction of 47% was observed in male apoE
−/−
mice. Long-term (12-week) treatment with LXR agonist had differential effects on plasma lipid profiles in LDLR
−/−
and apoE
−/−
mice. GW3965 induced expression of ATP-binding cassettes A1 and G1 in modified low-density lipoprotein-loaded macrophages
in vitro
as well as in the aortas of hyperlipidemic mice, suggesting that direct actions of LXR ligands on vascular gene expression are likely to contribute to their antiatherogenic effects. These observations provide direct evidence for an atheroprotective effect of LXR agonists and support their further evaluation as potential modulators of human cardiovascular disease.
