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Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development

Author: Berbeé, J.F.P. · Boon, M.R. · Khedoe, P.P.S.J. · Bartelt, A. · Schlein, C. · Worthmann, A. · Kooijman, S. · Hoeke, G. · Mol, I.M. · John, C. · Jung, C. · Vazirpanah, N. · Brouwers, L.P.J. · Gordts, P.L.S.M. · Esko, J.D. · Hiemstra, P.S. · Havekes, L.M. · Scheja, L. · Heeren, J. · Rensen, P.C.N.
Type:article
Date:2015
Source:Nature Communications, 6
Identifier: 524141
doi: doi:10.1038/ncomms7356
Article number: 6356
Keywords: Biology · 5 [2 [[2 (3 chlorophenyl) 2 hydroxyethyl]amino]propyl] 1,3 benzodioxole 2,2 dicarboxylic acid · Apolipoprotein E · Cholesterol · Fatty acid · Low density lipoprotein receptor · Triacylglycerol · Bioenergetics · Fat · Fatty acid · Obesity · Plasma · Rodent · Animal experiment · Animal model · Animal tissue · Atherosclerosis · Beta adrenergic stimulation · Brown adipose tissue · Cholesterol blood level · Cholesterol metabolism · Controlled study · Energy expenditure · Fatty acid transport · Female · Hypercholesterolemia · Lipolysis · Liver clearance · Mouse · Triacylglycerol blood level · Mus · Biomedical Innovation · Healthy Living · Life · MHR - Metabolic Health Research · ELSS - Earth, Life and Social Sciences

Abstract

Brown adipose tissue (BAT) combusts high amounts of fatty acids, thereby lowering plasma triglyceride levels and reducing obesity. However, the precise role of BAT in plasma cholesterol metabolism and atherosclerosis development remains unclear. Here we show that BAT activation by b3-adrenergic receptor stimulation protects from atherosclerosis in hyperlipidemic APOE3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism that unlike hyperlipidemic Apoe-/-and Ldlr-/-mice expresses functional apoE and LDLR. BAT activation increases energy expenditure and decreases plasma triglyceride and cholesterol levels. Mechanistically, we demonstrate that BAT activation enhances the selective uptake of fatty acids from triglyceride-rich lipoproteins into BAT, subsequently accelerating the hepatic clearance of the cholesterol-enriched remnants. These effects depend on a functional hepatic apoE-LDLR clearance pathway as BAT activation in Apoe-/-and Ldlr-/-mice does not attenuate hypercholesterolaemia and atherosclerosis. We conclude that activation of BAT is a powerful therapeutic avenue to ameliorate hyperlipidaemia and protect from atherosclerosis. © 2015 Macmillan Publishers Limited.