Mirabegron-induced brown fat activation does not exacerbate atherosclerosis in mice with a functional hepatic ApoE-LDLR pathway. (January 2023)

• Record Type: Journal Article
• Authors: Ying, Zhixiong; van Eenige, Robin; Beerepoot, Rosa; Boon, Mariëtte R.; Kloosterhuis, Niels J.; van de Sluis, Bart; Bartelt, Alexander; Rensen, Patrick C.N.; Kooijman, Sander
• Is Part Of: Pharmacological research. Volume 187(2023)
• Publication Date: 2023-01
• Subjects: [14C]CO [14C]cholesteryl oleate -- [3H]TO glycerol tri[3H]oleate -- ACACA acetyl-CoA carboxylase -- APOB apolipoprotein B -- ADRB1 β1-adrenergic receptor -- ADRB2 β2-adrenergic receptor -- ADRB3 β3-adrenergic receptor -- ANGPTL4 angiopoietin-like 4 -- APOE apolipoprotein E -- BAT, DPM brown adipose tissuedisintegrations per minute -- CD36 cluster of differentiation 36 -- CPT1Α carnitine palmitoyltransferase 1 α -- DGAT1 diacylglycerol O-acyltransferase 1 -- DGAT2 diacylglycerol O-acyltransferase 2 -- E3L.CETP APOE* 3-Leiden.CETP -- CETP cholesteryl ester transfer protein -- FA fatty acid -- FASN, GAPDH fatty acid synthaseglyceraldehyde 3-phosphate dehydrogenase -- GPIHBP1 glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 -- HDL high-density lipoprotein -- HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase -- iBAT interscapular brown adipose tissue -- LDL low-density lipoprotein -- LDLR low-density lipoprotein receptor -- LPL lipoprotein lipase -- MTTP microsomal triglyceride transfer protein -- PL phospholipid -- PPARΑ peroxisome proliferator activated receptor α -- sBAT subscapular brown adipose tissue -- SREBF2 sterol regulatory element-binding transcription factor 2 -- sWAT subcutaneous white adipose tissue -- TC total cholesterol -- TG, TRL triglyceridetriglyceride-rich lipoprotein -- UCP1 uncoupling protein 1 -- VLDL very-low-density lipoprotein -- β-AR β-adrenergic receptor; Atherosclerosis -- Brown adipose tissue -- Lipolysis -- Lipoproteins -- VLDL secretion -- White adipose tissue; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106634
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Activation of brown adipose tissue (BAT) with the β3-adrenergic receptor agonist CL316, 243 protects mice from atherosclerosis development, and the presence of metabolically active BAT is associated with cardiometabolic health in humans. In contrast, exposure to cold or treatment with the clinically used β3-adrenergic receptor agonist mirabegron to activate BAT exacerbates atherosclerosis in apolipoprotein E (ApoE)- and low-density lipoprotein receptor (LDLR)-deficient mice, both lacking a functional ApoE-LDLR pathway crucial for lipoprotein remnant clearance. We, therefore, investigated the effects of mirabegron treatment on dyslipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a humanized lipoprotein metabolism model with a functional ApoE-LDLR clearance pathway. Mirabegron activated BAT and induced white adipose tissue (WAT) browning, accompanied by selectively increased fat oxidation and attenuated fat mass gain. Mirabegron increased the uptake of fatty acids derived from triglyceride (TG)-rich lipoproteins by BAT and WAT, which was coupled to increased hepatic uptake of the generated cholesterol-enriched core remnants. Mirabegron also promoted hepatic very low-density lipoprotein (VLDL) production, likely due to an increased flux of fatty acids from WAT to the liver, and resulted in transient elevation in plasma TG levels followed by a substantial decrease in plasma TGs. These effects led to a trend toward lower plasma cholesterol levels and reduced atherosclerosis. We conclude that BAT activation by mirabegron leads to substantial metabolic benefits in APOE*3-Leiden.CETP mice, and mirabegron treatment is certainly not atherogenic. These data underscore the importance of the choice of experimental models when investigating the effect of BAT activation on lipoprotein metabolism and atherosclerosis. Graphical Abstract: ga1