Geerte Hoeke1, Yanan Wang2, Andrea D van Dam3, Isabel M Mol3, Eveline Gart4, Henk G Klop3, Susan M van den Berg5, Elsbet H Pieterman4, Hans M G Princen4, Albert K Groen6, Patrick C N Rensen3, Jimmy F P Berbée3, Mariëtte R Boon3. 1. Dept. of Medicine, Div. of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: g.hoeke@lumc.nl. 2. Dept. of Medicine, Div. of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands; Dept. of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands. 3. Dept. of Medicine, Div. of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. 4. The Netherlands Organization of Applied Scientific Research (TNO) - Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands. 5. Dept. of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, Amsterdam, The Netherlands. 6. Dept. of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands; Dept. of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Abstract
BACKGROUND AND AIMS: Activation of brown adipose tissue (BAT) reduces both hyperlipidemia and atherosclerosis by increasing the uptake of triglyceride-derived fatty acids by BAT, accompanied by formation and clearance of lipoprotein remnants. We tested the hypothesis that the hepatic uptake of lipoprotein remnants generated by BAT activation would be accelerated by concomitant statin treatment, thereby further reducing hypercholesterolemia and atherosclerosis. METHODS: APOE*3-Leiden.CETP mice were fed a Western-type diet and treated without or with the selective β3-adrenergic receptor (AR) agonist CL316,243 that activates BAT, atorvastatin (statin) or both. RESULTS: β3-AR agonism increased energy expenditure as a result of an increased fat oxidation by activated BAT, which was not further enhanced by statin addition. Accordingly, statin treatment neither influenced the increased uptake of triglyceride-derived fatty acids from triglyceride-rich lipoprotein-like particles by BAT nor further lowered plasma triglyceride levels induced by β3-AR agonism. Statin treatment increased the hepatic uptake of the formed cholesterol-enriched remnants generated by β3-AR agonism. Consequently, statin treatment further lowered plasma cholesterol levels. Importantly, statin, in addition to β3-AR agonism, also further reduced the atherosclerotic lesion size as compared to β3-AR agonism alone, without altering lesion severity and composition. CONCLUSIONS: Statin treatment accelerates the hepatic uptake of remnants generated by BAT activation, thereby increasing the lipid-lowering and anti-atherogenic effects of BAT activation in an additive fashion. We postulate that, in clinical practice, combining statin treatment with BAT activation is a promising new avenue to combat hyperlipidemia and cardiovascular disease.
BACKGROUND AND AIMS: Activation of brown adipose tissue (BAT) reduces both hyperlipidemia and atherosclerosis by increasing the uptake of triglyceride-derived fatty acids by BAT, accompanied by formation and clearance of lipoprotein remnants. We tested the hypothesis that the hepatic uptake of lipoprotein remnants generated by BAT activation would be accelerated by concomitant statin treatment, thereby further reducing hypercholesterolemia and atherosclerosis. METHODS: APOE*3-Leiden.CETP mice were fed a Western-type diet and treated without or with the selective β3-adrenergic receptor (AR) agonist CL316,243 that activates BAT, atorvastatin (statin) or both. RESULTS: β3-AR agonism increased energy expenditure as a result of an increased fat oxidation by activated BAT, which was not further enhanced by statin addition. Accordingly, statin treatment neither influenced the increased uptake of triglyceride-derived fatty acids from triglyceride-rich lipoprotein-like particles by BAT nor further lowered plasma triglyceride levels induced by β3-AR agonism. Statin treatment increased the hepatic uptake of the formed cholesterol-enriched remnants generated by β3-AR agonism. Consequently, statin treatment further lowered plasma cholesterol levels. Importantly, statin, in addition to β3-AR agonism, also further reduced the atherosclerotic lesion size as compared to β3-AR agonism alone, without altering lesion severity and composition. CONCLUSIONS: Statin treatment accelerates the hepatic uptake of remnants generated by BAT activation, thereby increasing the lipid-lowering and anti-atherogenic effects of BAT activation in an additive fashion. We postulate that, in clinical practice, combining statin treatment with BAT activation is a promising new avenue to combat hyperlipidemia and cardiovascular disease.
Authors: André C Carpentier; Denis P Blondin; Kirsi A Virtanen; Denis Richard; François Haman; Éric E Turcotte Journal: Front Endocrinol (Lausanne) Date: 2018-08-07 Impact factor: 5.555
Authors: Enchen Zhou; Geerte Hoeke; Zhuang Li; Arthur C Eibergen; Amber W Schonk; Martijn Koehorst; Renze Boverhof; Rick Havinga; Folkert Kuipers; Tamer Coskun; Mariëtte R Boon; Albert K Groen; Patrick C N Rensen; Jimmy F P Berbée; Yanan Wang Journal: Cardiovasc Res Date: 2020-08-01 Impact factor: 10.787