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.