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Papers In Press, published online ahead of print February 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800374-JLR200

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Journal of Lipid Research, Vol. 50, 301-311, February 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms

Lars Verschuren^*,, Jitske de Vries-van der Weij^*,, Susanne Zadelaar^*, Robert Kleemann^* and Teake Kooistra^1,*

^* Netherlands Organisation for Applied Scientific Research (TNO) Quality of Life, Biosciences, Leiden, The Netherlands
Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

The online version of this article (available at http://www.jlr.org) contains supplementary Materials and Methods and a supplementary table.

The Dutch Heart Foundation (NHS; grant 2002B102 to L.V.), the Center for Medical Systems Biology CMSB (grant 115 to J.d.V.-v.d.W), the Dutch Organization for Scientific Research (NWO; grant VENI 016. 036.061 to R.K.), the European Nutrigenomics Organisation NuGO (CT-2004-505944; grants to S.Z, R.K., and T.K.) a Network of Excellence funded by the European Commission's Research Directorate General (Sixth Framework Programme for Research and Technological Development) and TNO Research Program NISB (to R.K. and T.K..

Published, JLR Papers in Press, August 30, 2008.

¹ To whom correspondence should be addressed. e-mail: Teake.Kooistra{at}tno.nl

The aim of this study was to define the anti-atherosclerotic role of liver-X-receptors (LXRs) under lesion progressive and lesion regressive conditions, to establish a temporal line of events, and to gain insights into the mechanisms underlying the anti-atherogenic potency of LXRs. We used apoE*3Leiden (E3L) mice to comprehensively and time-dependently dissect how T0901317, an LXR-agonist, inhibits initiation and progression of atherosclerotic lesions and regresses existing lipid- and macrophage-rich lesions. T0901317 suppresses lesion evolution and promotes lesion regression regarding lesion number, area, and severity. Quantitative plasma and vessel wall analyses corroborated by immunohistochemical evaluation of the aortic lesions revealed that under progressive (high-cholesterol diet) as well as regressive (cholesterol-free diet) conditions T0901317: i) significantly increases plasma triglyceride and total cholesterol levels; ii) does not affect the systemic inflammation marker, Serum amyloid A (SAA); iii) suppresses endothelial monocyte adhesion; and iv) induces the expression of the cholesterol efflux-related genes apolipoprotein E (apoE), ATP binding cassette (ABC) transporters ABCA1 and ABCG1. Furthermore, under progressive conditions, T0901317 suppresses the vascular inflammatory status (NF-B) and the vascular expression of adhesion molecules [E-selectin, intercellular adhesion molecule (ICAM)-1, and CD44], lowers lesional macrophage accumulation, and blocks lesion evolution at the transition from lesional stage II to III. Under regressive conditions, T0901317 induces lesional macrophage disappearance and increases the expression of the chemokine receptor CCR7, a factor functionally required for regression. The LXR-agonist T0901317 retards vascular lesion development and promotes lesion regression at several levels. The findings support that vascular LXR is a potential anti-atherosclerotic target.

Supplementary key words atherosclerosis • liver-X-receptor • inflammation • macrophages

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