Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development

Jimmy F. P. Berbée, Mariëtte R Boon, P. Padmini S. J. Khedoe, Alexander Bartelt, Christian Schlein, Anna Worthmann, Sander Kooijman, Geerte Hoeke, Isabel M. Mol, Clara John, Caroline Jung, Nadia Vazirpanah, Linda P.J. Brouwers, Philip L.S.M. Gordts, Jeffrey D. Esko, Pieter S. Hiemstra, Louis M. Havekes, Ludger Scheja, Joerg Heeren () and Patrick C.N. Rensen ()
Additional contact information
Jimmy F. P. Berbée: Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
Mariëtte R Boon: Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
P. Padmini S. J. Khedoe: Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
Alexander Bartelt: University Medical Center Hamburg-Eppendorf, Martinistraße 52
Christian Schlein: University Medical Center Hamburg-Eppendorf, Martinistraße 52
Anna Worthmann: University Medical Center Hamburg-Eppendorf, Martinistraße 52
Sander Kooijman: Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
Geerte Hoeke: Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
Isabel M. Mol: Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
Clara John: University Medical Center Hamburg-Eppendorf, Martinistraße 52
Caroline Jung: Diagnostic and Interventional Radiology, University Medical Center Hamburg-Eppendorf, Martinistraße 52
Nadia Vazirpanah: Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
Linda P.J. Brouwers: Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
Philip L.S.M. Gordts: University of California–San Diego, La Jolla, California 92093, USA
Jeffrey D. Esko: University of California–San Diego, La Jolla, California 92093, USA
Pieter S. Hiemstra: Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
Louis M. Havekes: Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
Ludger Scheja: University Medical Center Hamburg-Eppendorf, Martinistraße 52
Joerg Heeren: University Medical Center Hamburg-Eppendorf, Martinistraße 52
Patrick C.N. Rensen: Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7356

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