title: Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development.
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.
authors.affiliation: 1] Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands [2] Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Jimmy F P
authors.initials: JF
authors.lastname: Berbée
authors.affiliation: 1] Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands [2] Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Mariëtte R
authors.initials: MR
authors.lastname: Boon
authors.affiliation: 1] Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands [2] Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands [3] Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: P Padmini S J
authors.initials: PP
authors.lastname: Khedoe
authors.affiliation: 1] Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg 20246, Germany [2] Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bartelt
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg 20246, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schlein
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg 20246, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Worthmann
authors.affiliation: 1] Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands [2] Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Kooijman
authors.affiliation: 1] Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands [2] Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Geerte
authors.initials: G
authors.lastname: Hoeke
authors.affiliation: 1] Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands [2] Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Mol
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg 20246, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: John
authors.affiliation: Diagnostic and Interventional Radiology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg 20246, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Jung
authors.affiliation: 1] Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands [2] Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Nadia
authors.initials: N
authors.lastname: Vazirpanah
authors.affiliation: 1] Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands [2] Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Linda P J
authors.initials: LP
authors.lastname: Brouwers
authors.affiliation: Department of Cellular and Molecular Medicine, University of California-San Diego, La Jolla, California 92093, USA.
authors.forename: Philip L S M
authors.initials: PL
authors.lastname: Gordts
authors.affiliation: Department of Cellular and Molecular Medicine, University of California-San Diego, La Jolla, California 92093, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
authors.affiliation: 1] Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands [2] Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands [3] Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands [4] Netherlands Organization for Applied Scientific Research-Metabolic Health Research, Gaubius Laboratory, Zernikedreef 9, Leiden 2333 CK, The Netherlands.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg 20246, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Scheja
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg 20246, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Heeren
authors.affiliation: 1] Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands [2] Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
mesh_terms: D000064:Acclimatization / Q000502:physiology*; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D050197:Atherosclerosis / Q000517:prevention & control*; D002153:Calorimetry, Indirect; D002784:Cholesterol / Q000097:blood; D003080:Cold Temperature; D005260:Female; D006937:Hypercholesterolemia / Q000628:therapy*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood
chemical_list: D001057:Apolipoproteins E; D022702:Receptors, Adrenergic, beta-3; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol