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

Author: Verschuren, L. · Vries de Weij, J. van der · Zadelaar, A.S.M. · Kleemann, R. · Kooistra, T.
Institution: TNO Kwaliteit van Leven
Source:Journal of Lipid Research, 2, 50, 301-311
Identifier: 241636
doi: doi:10.1194/jlr.M800374-JLR200
Keywords: Health · Biomedical Research · Atherosclerosis · Inflammation · Liver-X-receptor · Macrophages · ABC transporter A1 · ABC transporter G1 · apolipoprotein E3 · cell adhesion molecule · chemokine receptor CCR7 · cholesterol · endothelial leukocyte adhesion molecule 1 · Hermes antigen · immunoglobulin enhancer binding protein · intercellular adhesion molecule 1 · lipid · liver X receptor agonist · n (2,2,2 trifluoroethyl) n [4 [2,2,2 trifluoro 1 hydroxy 1 (trifluoromethoxy)ethyl]phenyl]benzenesulfonamide · serum amyloid A · triacylglycerol · ABC transporter · ABCG1 protein, mouse · apolipoprotein E3 (Leidein) · cell receptor · DNA binding protein · fluorinated hydrocarbon · hypocholesterolemic agent · lipoprotein · liver X receptor · n (2,2,2 trifluoroethyl) n [4 (2,2,2 trifluoro 1 hydroxy 1 trifluoromethylethyl)phenyl]benzenesulfonamide · sulfonamide · TO-901317 · animal experiment · animal model · atherosclerosis · cell adhesion · cholesterol blood level · cholesterol diet · controlled study · disease course · drug mechanism · drug potency · endothelium · female · immunohistochemistry · macrophage · monocyte · mouse · nonhuman · priority journal · protein expression · remission · triacylglycerol blood level · animal · drug potentiation · genetics · metabolism · pathology · transgenic mouse · Animals · Anticholesteremic Agents · Antigens, CD44 · Apolipoprotein E3 · Atherosclerosis · ATP-Binding Cassette Transporters · DNA-Binding Proteins · E-Selectin · Female · Hydrocarbons, Fluorinated · Intercellular Adhesion Molecule-1 · Lipoproteins · Mice · Mice, Transgenic · Receptors, Cytoplasmic and Nuclear · Serum Amyloid A Protein · Sulfonamides


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-κB) 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. Copyright © 2009 by the American Society for Biochemistry and Molecular Biology, Inc.