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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Overactive Endocannabinoid Signaling Impairs Apolipoprotein E-mediated Clearance Of Triglyceride-rich Lipoproteins
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Overactive Endocannabinoid Signaling Impairs Apolipoprotein E-mediated Clearance Of Triglyceride-rich Lipoproteins

机译：过度激活的内源性大麻素信号会破坏载脂蛋白E介导的富含甘油三酸酯的脂蛋白的清除

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摘要

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 over-active 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 lipo-genic 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 post-heparin 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.
机译：内源性大麻素（EC）系统调节食物摄入量和能量代谢。大麻素1型受体（CB1）拮抗剂在治疗肥胖及其代谢后果方面显示出希望。尽管使用CB1拮抗剂治疗导致的肥胖减少可能无法完全解释血脂异常的伴随改善，但尚未见过活跃的EC信号传导对血浆脂蛋白代谢的直接影响。本研究使用化学方法，通过药理学抑制十二烷基氟膦酸异丙酯（IDFP）的酶促水解，诱导内源性大麻素的急性升高，从而评估增加的EC信号转导在小鼠中的直接作用。急性IDFP治疗会增加血浆中甘油三酯（TG）（2.0至3.1倍）和胆固醇（1.3至1.4倍）的水平，同时贫血中富含载脂蛋白（apo）E的富含TG的脂蛋白。这些变化在CB1无效或apoE无效的小鼠中均未发生，可以通过用CB1拮抗剂进行预处理来预防，并且与减少的肝apoE基因表达无关。尽管IDFP处理增加了脂肪基因（Srebp1和Fas）的肝mRNA水平，但对TG分泌到血浆中没有影响。取而代之的是，尽管肝素后脂蛋白脂肪酶活性增加，但IDFP治疗会损害静脉内施用的TG乳剂的清除率。因此，过度活跃的EC信号引发血浆甘油三酯水平升高，与血浆TG清除率降低和apoE耗尽的富含TG的脂蛋白在血浆中的积累有关。这些发现表明CB1激活在肥胖相关的高甘油三酯血症的发病机理中的作用，并强调了CB1拮抗剂在治疗代谢疾病中的潜在功效。

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