Cannabinoid type 1 receptor inverse agonism attenuates dyslipidemia and atherosclerosis in APOE∗3-Leiden.CETP mice

Abstract

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 ( R 2 = 0.60). Taken together, inhibition of the endocannabinoid system potently reverses dyslipidemia and prevents atherogenesis, even in the absence of obesity.

ZnO Nanoparticles Induce Dyslipidemia and Atherosclerotic Lesions Leading to Changes in Vascular Contractility and Cannabinoid Receptors Expression as Well as Increased Blood Pressure

“…Activation of the CB 1 receptor, with agonists such as anandamide, induces vasorelaxation [ 33 , 34 ] and a decrease in the blood pressure in normotensive and hypertension models [ 35 , 36 ]. Blockade of the CB 1 receptor decreases the atherosclerosis risk while activation of the CB 2 receptor decreases the progression of the atherosclerosis acting as a cardioprotective agent [ 37 , 38 , 39 , 40 , 41 ]. Furthermore, increased CB 1 receptor expression has been associated with vascular smooth muscle cell proliferation and atherosclerosis [ 42 , 43 ].…”

Serum bile acids associate with liver volume in polycystic liver disease and decrease upon treatment with lanreotide

“…29 Bile acids were analysed as described elsewhere. 30 Briefly, 10 μL of an internal standard solution (500 ng/ mL and 290 μL methanol) was added to 100 μL of serum. Samples were vortexed (5 s) and stored at −20°C for 20 min.…”

Molecular networks underlying cannabinoid signaling in skeletal muscle plasticity

“…Whole‐body CB 1 knockout decreased body weight, adiposity, plasma insulin levels, plasma leptin levels, and generally protected mice from diet‐induced obesity (Cota et al, 2003; Ravinet Trillou et al, 2004). Also, the CB 1 antagonist rimonabant increased energy expenditure, improved the plasma lipid profile, and prevented atherogenesis in dyslipidemic mice (Boon et al, 2014; Van Eenige et al, 2021). It also improved adiposity, BMI, blood lipid profile, and weight loss in patients suffering from metabolic diseases such as type 2 diabetes and obesity (Boesten et al, 2012; Després et al, 2005, 2009; Dibble et al, 2007; Pi‐sunyer et al, 2006).…”