Synthetic LXR ligand inhibits the development of atherosclerosis in mice

Sean B. Joseph, Elaine McKilligin, Liming Pei, Michael A. Watson, Alan R. Collins, Bryan A. Laffitte, Mingyi Chen, Grace Noh, Joanne Goodman, Graham N. Hagger, Jonathan Tran, Tim K. Tippin, Xuping Wang, Aldons J. Lusis, Willa A. Hsueh, Ronald E. Law, Jon L. Collins, Timothy M. Willson, Peter Tontonoz

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)7604-7609
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number11
DOIs
StatePublished - May 28 2002

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Atherosclerosis
Ligands
Cholesterol
Apolipoproteins E
Cardiovascular Diseases
Macrophages
Lipogenesis
Hypertriglyceridemia
Intestinal Absorption
Cytoplasmic and Nuclear Receptors
Bile Acids and Salts
LDL Lipoproteins
Blood Vessels
Aorta
Fatty Acids
Adenosine Triphosphate
Lipids
Gene Expression
Liver
GW 3965

ASJC Scopus subject areas

  • General

Cite this

Joseph, S. B., McKilligin, E., Pei, L., Watson, M. A., Collins, A. R., Laffitte, B. A., ... Tontonoz, P. (2002). Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proceedings of the National Academy of Sciences of the United States of America, 99(11), 7604-7609. https://doi.org/10.1073/pnas.112059299

Synthetic LXR ligand inhibits the development of atherosclerosis in mice. / Joseph, Sean B.; McKilligin, Elaine; Pei, Liming; Watson, Michael A.; Collins, Alan R.; Laffitte, Bryan A.; Chen, Mingyi; Noh, Grace; Goodman, Joanne; Hagger, Graham N.; Tran, Jonathan; Tippin, Tim K.; Wang, Xuping; Lusis, Aldons J.; Hsueh, Willa A.; Law, Ronald E.; Collins, Jon L.; Willson, Timothy M.; Tontonoz, Peter.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 11, 28.05.2002, p. 7604-7609.

Research output: Contribution to journalArticle

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 2002, 'Synthetic LXR ligand inhibits the development of atherosclerosis in mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 11, pp. 7604-7609. https://doi.org/10.1073/pnas.112059299
Joseph, Sean B. ; McKilligin, Elaine ; Pei, Liming ; Watson, Michael A. ; Collins, Alan R. ; Laffitte, Bryan A. ; Chen, Mingyi ; Noh, Grace ; Goodman, Joanne ; Hagger, Graham N. ; Tran, Jonathan ; Tippin, Tim K. ; Wang, Xuping ; Lusis, Aldons J. ; Hsueh, Willa A. ; Law, Ronald E. ; Collins, Jon L. ; Willson, Timothy M. ; Tontonoz, Peter. / Synthetic LXR ligand inhibits the development of atherosclerosis in mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2002 ; Vol. 99, No. 11. pp. 7604-7609.
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