Synthetic LXR ligand inhibits the development of atherosclerosis in mice.

Abstract:

:The nuclear receptors LXRalpha and LXRbeta 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.

authors

Joseph SB,McKilligin E,Pei L,Watson MA,Collins AR,Laffitte BA,Chen M,Noh G,Goodman J,Hagger GN,Tran J,Tippin TK,Wang X,Lusis AJ,Hsueh WA,Law RE,Collins JL,Willson TM,Tontonoz P

doi

10.1073/pnas.112059299

keywords:

subject

Has Abstract

pub_date

2002-05-28 00:00:00

pages

7604-9

issue

11

eissn

0027-8424

issn

1091-6490

journal_volume

99

pub_type

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