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Atorvastatin accelerates clearance of lipoprotein remnants generated by activated brown fat to further reduce hypercholesterolemia and atherosclerosis

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Author: Hoeke, G. · Wang, Y. · Dam, A.D. van · Mol, M. · Gart, E. · Klop, H.G. · Berg, S.M. van den · Pieterman, E.H. · Princen, H.M.G. · Groen, A.K. · Rensen, P.C.N. · Berbée, J.F.P. · Boon, M.R.
Type:article
Date:2017
Source:Atherosclerosis, 267, 116-126
Identifier: 781835
doi: doi:10.1016/j.atherosclerosis.2017.10.030
Keywords: Biology · Atherosclerosis · Brown adipose tissue · Hypercholesterolemia · Cholesterol metabolism · Lipid and lipoprotein metabolism · 5 [2 [[2 (3 chlorophenyl) 2 hydroxyethyl]amino]propyl] 1,3 benzodioxole 2,2 dicarboxylic acid · Atorvastatin · Cholesterol · Fatty acid · High density lipoprotein cholesterol · Lipoprotein · Proprotein convertase 9 · Triacylglycerol · Animal experiment · Animal model · Animal tissue · Atherosclerosis · Brown adipose tissue · Cholesterol blood level · Controlled study · Drug effect · Drug potentiation · Energy expenditure · Female · Gene expression · Hypercholesterolemia · Lipid composition · Lipid liver level · Lipid metabolism · Lipid oxidation · Lipid transport · Lipoprotein metabolism · Mouse · Nonhuman · Triacylglycerol blood level · Western diet · Biomedical Innovation · Healthy Living · Life · MHR - Metabolic Health Research · EELS - Earth, Environmental and Life Sciences

Abstract

Background and aims Activation of brown adipose tissue (BAT) reduces both hyperlipidemia and atherosclerosis by increasing the uptake of triglyceride-derived fatty acids by BAT, accompanied by formation and clearance of lipoprotein remnants. We tested the hypothesis that the hepatic uptake of lipoprotein remnants generated by BAT activation would be accelerated by concomitant statin treatment, thereby further reducing hypercholesterolemia and atherosclerosis. Methods APOE*3-Leiden.CETP mice were fed a Western-type diet and treated without or with the selective β3-adrenergic receptor (AR) agonist CL316,243 that activates BAT, atorvastatin (statin) or both. Results β3-AR agonism increased energy expenditure as a result of an increased fat oxidation by activated BAT, which was not further enhanced by statin addition. Accordingly, statin treatment neither influenced the increased uptake of triglyceride-derived fatty acids from triglyceride-rich lipoprotein-like particles by BAT nor further lowered plasma triglyceride levels induced by β3-AR agonism. Statin treatment increased the hepatic uptake of the formed cholesterol-enriched remnants generated by β3-AR agonism. Consequently, statin treatment further lowered plasma cholesterol levels. Importantly, statin, in addition to β3-AR agonism, also further reduced the atherosclerotic lesion size as compared to β3-AR agonism alone, without altering lesion severity and composition. Conclusions Statin treatment accelerates the hepatic uptake of remnants generated by BAT activation, thereby increasing the lipid-lowering and anti-atherogenic effects of BAT activation in an additive fashion. We postulate that, in clinical practice, combining statin treatment with BAT activation is a promising new avenue to combat hyperlipidemia and cardiovascular disease.