Cannabinoid type 1 receptor inverse agonism attenuates dyslipidemia and atherosclerosis in APOE∗3-Leiden.CETP mice
Pharmacological blockade of the cannabinoid type 1 receptor, a G protein-coupled receptor expressed in the central nervous system and various peripheral tissues, reverses diet-induced obesity and dyslipidemia through the reduction of food intake and altered nutrient partitioning. This strategy is be...
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Format: | Article |
Language: | English |
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Elsevier
2021-01-01
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Series: | Journal of Lipid Research |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227521000523 |
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doaj-9dc750d1ebc14d54b6be276bd11ac14f |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Robin van Eenige Zhixiong Ying Lauren Tambyrajah Amanda C.M. Pronk Niek Blomberg Martin Giera Yanan Wang Tamer Coskun Mario van der Stelt Patrick C.N. Rensen Sander Kooijman |
spellingShingle |
Robin van Eenige Zhixiong Ying Lauren Tambyrajah Amanda C.M. Pronk Niek Blomberg Martin Giera Yanan Wang Tamer Coskun Mario van der Stelt Patrick C.N. Rensen Sander Kooijman Cannabinoid type 1 receptor inverse agonism attenuates dyslipidemia and atherosclerosis in APOE∗3-Leiden.CETP mice Journal of Lipid Research adipose tissue atherosclerosis bile acids and salts/metabolism cannabinoid receptor type 1 cardiovascular disease drug therapy |
author_facet |
Robin van Eenige Zhixiong Ying Lauren Tambyrajah Amanda C.M. Pronk Niek Blomberg Martin Giera Yanan Wang Tamer Coskun Mario van der Stelt Patrick C.N. Rensen Sander Kooijman |
author_sort |
Robin van Eenige |
title |
Cannabinoid type 1 receptor inverse agonism attenuates dyslipidemia and atherosclerosis in APOE∗3-Leiden.CETP mice |
title_short |
Cannabinoid type 1 receptor inverse agonism attenuates dyslipidemia and atherosclerosis in APOE∗3-Leiden.CETP mice |
title_full |
Cannabinoid type 1 receptor inverse agonism attenuates dyslipidemia and atherosclerosis in APOE∗3-Leiden.CETP mice |
title_fullStr |
Cannabinoid type 1 receptor inverse agonism attenuates dyslipidemia and atherosclerosis in APOE∗3-Leiden.CETP mice |
title_full_unstemmed |
Cannabinoid type 1 receptor inverse agonism attenuates dyslipidemia and atherosclerosis in APOE∗3-Leiden.CETP mice |
title_sort |
cannabinoid type 1 receptor inverse agonism attenuates dyslipidemia and atherosclerosis in apoe∗3-leiden.cetp mice |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2021-01-01 |
description |
Pharmacological blockade of the cannabinoid type 1 receptor, a G protein-coupled receptor expressed in the central nervous system and various peripheral tissues, reverses diet-induced obesity and dyslipidemia through the reduction of food intake and altered nutrient partitioning. This strategy is being explored for a number of therapeutic applications; however, its potency for the treatment of atherosclerotic cardiovascular disease via improvements in lipid metabolism remains unclear. Therefore, here, we aimed to investigate whether inhibition of the endocannabinoid system can attenuate atherosclerosis development through improvement of dyslipidemia. Lean, dyslipidemic female APOE∗3-Leiden.CETP transgenic mice were fed a Western-type diet supplemented with or without the cannabinoid type 1 receptor inverse agonist rimonabant (20 mg·kg body weight−1 day−1) for up to 20 weeks. Plasma lipids and bile acids were determined, and atherosclerotic lesions were scored in the aortic valve region. Rimonabant lowered plasma levels of triglyceride (TG) (−56%) and non-HDL-C (−19%) and increased HDL-C (+57%). These effects were explained by decreased VLDL-TG production (−52%) and accelerated VLDL-TG turnover accompanied by pronounced browning of white adipose tissue. In addition, rimonabant attenuated reverse cholesterol transport (−30%), increased plasma bile acid levels (+160%), and increased hepatic cholesterol accumulation (+88%). Importantly, rimonabant markedly lowered atherosclerotic lesion size (−64%), which coincided with decreased lesion severity (28% vs. 56% severe lesions) and which strongly correlated with non-HDL-C exposure (R2 = 0.60). Taken together, inhibition of the endocannabinoid system potently reverses dyslipidemia and prevents atherogenesis, even in the absence of obesity. |
topic |
adipose tissue atherosclerosis bile acids and salts/metabolism cannabinoid receptor type 1 cardiovascular disease drug therapy |
url |
http://www.sciencedirect.com/science/article/pii/S0022227521000523 |
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doaj-9dc750d1ebc14d54b6be276bd11ac14f2021-04-22T14:03:29ZengElsevierJournal of Lipid Research0022-22752021-01-0162100070Cannabinoid type 1 receptor inverse agonism attenuates dyslipidemia and atherosclerosis in APOE∗3-Leiden.CETP miceRobin van Eenige0Zhixiong Ying1Lauren Tambyrajah2Amanda C.M. Pronk3Niek Blomberg4Martin Giera5Yanan Wang6Tamer Coskun7Mario van der Stelt8Patrick C.N. Rensen9Sander Kooijman10Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The NetherlandsCenter for Proteomics & Metabolomics, Leiden University Medical Center, Leiden, The NetherlandsCenter for Proteomics & Metabolomics, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands; Center for Immunological and Metabolic Diseases, MED-X institute, and Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, ChinaDepartment of Diabetes/Endocrine, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USADepartment of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, The NetherlandsDepartment of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands; Center for Immunological and Metabolic Diseases, MED-X institute, and Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; For correspondence: Patrick C. N. RensenDepartment of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The NetherlandsPharmacological blockade of the cannabinoid type 1 receptor, a G protein-coupled receptor expressed in the central nervous system and various peripheral tissues, reverses diet-induced obesity and dyslipidemia through the reduction of food intake and altered nutrient partitioning. This strategy is being explored for a number of therapeutic applications; however, its potency for the treatment of atherosclerotic cardiovascular disease via improvements in lipid metabolism remains unclear. Therefore, here, we aimed to investigate whether inhibition of the endocannabinoid system can attenuate atherosclerosis development through improvement of dyslipidemia. Lean, dyslipidemic female APOE∗3-Leiden.CETP transgenic mice were fed a Western-type diet supplemented with or without the cannabinoid type 1 receptor inverse agonist rimonabant (20 mg·kg body weight−1 day−1) for up to 20 weeks. Plasma lipids and bile acids were determined, and atherosclerotic lesions were scored in the aortic valve region. Rimonabant lowered plasma levels of triglyceride (TG) (−56%) and non-HDL-C (−19%) and increased HDL-C (+57%). These effects were explained by decreased VLDL-TG production (−52%) and accelerated VLDL-TG turnover accompanied by pronounced browning of white adipose tissue. In addition, rimonabant attenuated reverse cholesterol transport (−30%), increased plasma bile acid levels (+160%), and increased hepatic cholesterol accumulation (+88%). Importantly, rimonabant markedly lowered atherosclerotic lesion size (−64%), which coincided with decreased lesion severity (28% vs. 56% severe lesions) and which strongly correlated with non-HDL-C exposure (R2 = 0.60). Taken together, inhibition of the endocannabinoid system potently reverses dyslipidemia and prevents atherogenesis, even in the absence of obesity.http://www.sciencedirect.com/science/article/pii/S0022227521000523adipose tissueatherosclerosisbile acids and salts/metabolismcannabinoid receptor type 1cardiovascular diseasedrug therapy |