Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development

• Published in: Nature communications Vol. 6; no. 1; p. 6356
• Main Authors: Berbée, Jimmy F. P., Boon, Mariëtte R, Khedoe, P. Padmini S. J., Bartelt, Alexander, Schlein, Christian, Worthmann, Anna, Kooijman, Sander, Hoeke, Geerte, Mol, Isabel M., John, Clara, Jung, Caroline, Vazirpanah, Nadia, Brouwers, Linda P.J., Gordts, Philip L.S.M., Esko, Jeffrey D., Hiemstra, Pieter S., Havekes, Louis M., Scheja, Ludger, Heeren, Joerg, Rensen, Patrick C.N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.03.2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 631/443/319/1642; 631/443/319/2723; 64/110; 692/308; 692/699/75/593/2100; 82/51; Acclimatization - physiology; Adipose tissue; Adipose Tissue, Brown - metabolism; Animals; Apolipoproteins E - metabolism; Atherosclerosis - prevention & control; Calorimetry, Indirect; Cholesterol; Cholesterol - blood; Cold Temperature; Fatty acids; Female; Humanities and Social Sciences; Hypercholesterolemia - therapy; Liver - metabolism; Male; Mice; Mice, Knockout; multidisciplinary; Receptors, Adrenergic, beta-3 - metabolism; Receptors, LDL - metabolism; Regression Analysis; Reverse Transcriptase Polymerase Chain Reaction; Science; Science (multidisciplinary); Triglycerides - blood
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7356

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. Brown adipose tissue (BAT) produces heat by burning lipid triglycerides. Here, Berbée et al . show that pharmacological BAT activation protects hyperlipidemic mice from atherosclerosis, provided mice retain the metabolic capacity to clear cholesterol-enriched lipoprotein remnants by the liver.