Title
Atorvastatin accelerates clearance of lipoprotein remnants generated by activated brown fat to further reduce hypercholesterolemia and atherosclerosis
Author
Hoeke, G.
Wang, Y.
van Dam, A.D.
Mol, M.
Gart, E.
Klop, H.G.
van den Berg, S.M.
Pieterman, E.H.
Princen, H.M.G.
Groen, A.K.
Rensen, P.C.N.
Berbée, J.F.P.
Boon, M.R.
Publication year
2017
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.
Subject
Life
MHR - Metabolic Health Research
EELS - Earth, Environmental and Life Sciences
Biomedical Innovation
Biology
Healthy Living
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
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DOI
https://doi.org/10.1016/j.atherosclerosis.2017.10.030
TNO identifier
781835
Source
Atherosclerosis, 267, 116-126
Document type
article