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 β3-adrenergic receptor stimulation protects from atherosclerosis in hyperlipidemic APOE*3-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.
Highlights
Brown adipose tissue (BAT) combusts high amounts of fatty acids, thereby lowering plasma triglyceride levels and reducing obesity
Apoe À / À mice predominantly display an accumulation of cholesterolenriched very-low-density lipoprotein (VLDL) remnants and very low high-density lipoprotein (HDL) levels[22,23], Ldlr À / À mice are characterized by high levels of remnant lipoproteins and LDL-cholesterol (LDL-C) without significant changes in HDL levels[24]
It is likely to be that the enhanced clearance of plasma TGs on BAT activation may require efficient clearance of cholesterol-enriched lipoprotein remnants by the liver, a pathway that is considered to be crucially dependent on a functional apoE-low-density lipoprotein receptor (LDLR) axis[21]
Summary
Brown adipose tissue (BAT) combusts high amounts of fatty acids, thereby lowering plasma triglyceride levels and reducing obesity. 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 À / À and Ldlr À/ À mice does not attenuate hypercholesterolaemia and atherosclerosis. It is likely to be that the enhanced clearance of plasma TGs on BAT activation may require efficient clearance of cholesterol-enriched lipoprotein remnants by the liver, a pathway that is considered to be crucially dependent on a functional apoE-LDLR axis[21]
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