Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins

Abstract

The endocannabinoid (EC) system regulates food intake and energy metabolism. Cannabinoid receptor type 1 (CB1) antagonists show promise in the treatment of obesity and its metabolic consequences. Although the reduction in adiposity resulting from therapy with CB1 antagonists may not account fully for the concomitant improvements in dyslipidemia, direct effects of overactive EC signaling on plasma lipoprotein metabolism have not been documented. The present study used a chemical approach to evaluate the direct effects of increased EC signaling in mice by inducing acute elevations of endogenously produced cannabinoids through pharmacological inhibition of their enzymatic hydrolysis by isopropyl dodecylfluorophosphonate (IDFP). Acute IDFP treatment increased plasma levels of triglyceride (TG) (2.0-to 3.1-fold) and cholesterol (1.3-to 1.4-fold) in conjunction with an accumulation in plasma of apolipoprotein (apo)E-depleted TG-rich lipoproteins. These changes did not occur in either CB1-null or apoE-null mice, were prevented by pretreatment with CB1 antagonists, and were not associated with reduced hepatic apoE gene expression. Although IDFP treatment increased hepatic mRNA levels of lipogenic genes (Srebp1 and Fas), there was no effect on TG secretion into plasma. Instead, IDFP treatment impaired clearance of an intravenously administered TG emulsion, despite increased postheparin lipoprotein lipase activity. Therefore, overactive EC signaling elicits an increase in plasma triglyceride levels associated with reduced plasma TG clearance and an accumulation in plasma of apoE-depleted TG-rich lipoproteins. These findings suggest a role of CB1 activation in the pathogenesis of obesity-related hypertriglyceridemia and underscore the potential efficacy of CB1 antagonists in treating metabolic disease.2-arachidonoylglycerol ͉ hypertriglyceridemia ͉ monoaylglycerol lipase ͉ organophosphorus ͉ cannabinoid receptor O besity elicits a cluster of interrelated disorders, termed the ''metabolic syndrome,'' that increases the risk of cardiovascular disease (1). Epidemiological and genetic data indicate that dysregulation of the endocannabinoid (EC) system increases adiposity in humans (2-4). Pharmacological or genetic ablation of the cannabinoid type 1 receptor (CB1) in normal mice and in diet-induced and genetic mouse models of obesity results in a transient hypophagic response mediated through the hypothalamus, but there also are prolonged effects on weight loss, adiposity, and normalization of metabolic parameters, including plasma lipids (5-11). These effects suggest that the improvement in adiposity-related measures with CB1 inactivation is not limited to reduced food intake, a major known effect of CB1 inactivation (5, 11). CB1 activation in liver increases de novo lipogenesis and decreases fatty acid oxidation (12, 13). High-fat diet or chronic ethanol treatment increases cannabinoid signaling tone via increased hepatic CB1 receptor density and EC levels leading to CB1-mediated hepatic steatosis (12, 13). These observations...

Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma

“…Diets rich in -3 PUFAs dampened the infl ammatory response and reduced ectopic triacylglycerol accumulation in the obese Zucker rat, an effect attributed, at least in part, to the accompanying reduction in membrane phospholipid AA ester substrate for proinfl ammatory molecules and AEA/AG ( 47 ). Although appropriate caution should be exercised in extrapolating these fi ndings in a genetic rat model of obesity and related metabolic dysfunction (i.e., type-2 diabetes) to ours in healthy mice, the aggregate data of Batetta et al ( 47 ) and the present study suggest that dietary -3 supplementation may shift AA availability in vivo to modulate endocannabinoid tone for therapeutic benefi t. This suggestion is reinforced by the positive correlations observed between plasma AG and triacylglycerol levels in abdominally obese men ( 57 ) and in mice whose plasma AG had been pharmacologically elevated ( 58 ). Whether brain or circulating triacylglycerol levels are modifi ed by our dietary DHAenrichment regime remains to be explored.…”

Estimation of reference intervals of five endocannabinoids and endocannabinoid related compounds in human plasma by two dimensional-LC/MS/MS

“…The most striking result, however, derives from the strong correlation observed in males and, to a lesser extent, in females, between MAGs and triglycerides, which parallels a very similar correlation found in obese patients of both genders ( 9,28,29 ). In an intriguing paper by Ruby et al ( 47 ) an artifi cial increase of 2AG plasma levels in mice caused an increase in triglycerides, independently of adiposity or food intake, by modulating the dislocation of ApoE among circulating lipoproteins. These fi ndings may suggest that a strong link between 2AG and triglycerides exists independently of a condition of obesity or overweight and might represent an early trigger for the development of lipid and lipoprotein metabolism alteration.…”

Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

“…Although the exact role of the endocannabinoid system in the control of mood and anxiety-like behaviors is not clear, CB 1 R in the prefrontal cortex, amygdala, and the mesolimbic dopaminergic reward pathway have been linked to the control of these behaviors (14). On the other hand, CB 1 Rs are also present in peripheral tissues including the liver (15)(16)(17), skeletal muscle (18,19), endocrine pancreas (20,21), and fat (16,22,23), where their activation contributes to obesity-related metabolic and hormonal abnormalities (24)(25)(26). This suggests that selective targeting of peripheral CB 1 R may result in an improved hormonal-metabolic profile in obesity without the untoward behavioral effects observed following treatment with brain-penetrant CB 1 R antagonists.…”