Abstract 425: Brown Fat Activation Enhances the Lipid-lowering and Anti-atherogenic Effect of Statin Treatment

Abstract

Introduction: Brown adipose tissue (BAT) produces heat by burning triglyceride (TG)-derived fatty acids. As a result, BAT accelerates the formation and hepatic clearance of cholesterol-enriched lipoprotein remnants via the apoE-LDL receptor (LDLR) pathway, thereby alleviating hypercholesterolemia. Since statins upregulate hepatic LDLR expression, the aim of this study was to investigate whether BAT activation and statin treatment cooperate in lowering hyperlipidemia and atherosclerosis. Methods and Results: APOE*3-Leiden.CETP mice were fed a Western-type diet and treated with the selective β3-AR agonist CL316243 that activates BAT (CL, 20 μg/day; s.c.), atorvastatin (statin, 0.0036% w/w, in diet) or both. BAT activation alone and combined with statin treatment increased energy expenditure (+15%) as a result of increased fat oxidation (+50%). Furthermore, BAT activation decreased the lipid droplet content within BAT (-50%) and induced browning of subcutaneous white adipose tissue. BAT activation alone and combined with statin treatment also lowered plasma TG levels (-60%). In addition, plasma cholesterol was lowered by both BAT activation (-29%) and statin (-31%), but even further by the combination (-44%). The uptake of TG-derived fatty acids from glycerol tri[3H]oleate and [14C]cholesteryl oleate-labeled VLDL-mimicking particles into BAT was enhanced by BAT activation (+234%) and on top of statin (+220%), but not by statin alone. The hepatic uptake of the cholesterol-enriched remnants tended to be increased by BAT activation (+18%) or statin (+22%), and was markedly increased by the combination of BAT activation and statin treatment (+70%). Hepatic cholesterol levels were reduced by statin alone and the combination (-41%). Importantly, atherosclerosis development was decreased by BAT activation (-42%) and statin (-50%) alone and further decreased by the combination (-70%). Conclusions: BAT activation enhances the lipid-lowering and anti-atherogenic effect of statin treatment. We postulate that combining statin treatment with BAT activation is a promising new avenue to combat hyperlipidemia and cardiovascular diseases.