Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE-/- mice.
Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE-/- mice.
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DOI：
10.18632/oncotarget.16529
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发表时间：
2017-05-16
期刊：
影响因子：
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通讯作者：
Kratky D
中科院分区：
文献类型：
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作者：
Vujic N;Korbelius M;Leopold C;Duta-Mare M;Rainer S;Schlager S;Goeritzer M;Kolb D;Eichmann TO;Diwoky C;Zimmer A;Zimmermann R;Lass A;Radovic B;Kratky D
单酸甘油酯脂肪酶 (MGL) 将单酸甘油酯 (MG) 水解为甘油和脂肪酸。在各种 MG 物种中，MGL 还能降解 2-花生四烯酰甘油 (2-AG)，这是最丰富的内源性大麻素和大麻素受体 (CBR) 1 和 2 的有效激活剂。MGL 敲除 (−/−) 小鼠表现出明显的 2-AG 积累，但由于 CB1R 脱敏而缺乏中枢大麻模拟作用。我们之前已经表明，MGL 会影响载脂蛋白 E (ApoE)−/− 小鼠的斑块稳定性，这是一种已建立的血脂异常和动脉粥样硬化动物模型。在当前的研究中，我们研究了 MGL 缺乏对 ApoE/MGL 双敲除 (DKO) 小鼠脂质和能量代谢的功能影响。 MGL 缺乏会导致胆固醇通过胆道途径消除增加，从而影响肝脏胆固醇代谢。此外，DKO 小鼠表现出脂质引发的胃排空延迟，但对总体甘油三酯和胆固醇吸收没有重大影响。观察到的 DKO 小鼠表型可能不是 CB1R 信号传导增强的结果，而是依赖于替代信号传导途径的激活。我们得出的结论是，MGL 缺乏会导致复杂的代谢变化，包括胆固醇代谢和独立于内源性大麻素系统的肠道转运调节。
Monoglyceride lipase (MGL) hydrolyzes monoglycerides (MGs) to glycerol and fatty acids. Among various MG species MGL also degrades 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid and potent activator of cannabinoid receptors (CBR) 1 and 2. MGL-knockout (−/−) mice exhibit pronounced 2-AG accumulation, but lack central cannabimimetic effects due to CB1R desensitization. We have previously shown that MGL affects plaque stability in apolipoprotein E (ApoE)−/− mice, an established animal model for dyslipidemia and atherosclerosis. In the current study, we investigated functional consequences of MGL deficiency on lipid and energy metabolism in ApoE/MGL double knockout (DKO) mice. MGL deficiency affected hepatic cholesterol metabolism by causing increased cholesterol elimination via the biliary pathway. Moreover, DKO mice exhibit lipid-triggered delay in gastric emptying without major effects on overall triglyceride and cholesterol absorption. The observed phenotype of DKO mice is likely not a consequence of potentiated CB1R signaling but rather dependent on the activation of alternative signaling pathways. We conclude that MGL deficiency causes complex metabolic changes including cholesterol metabolism and regulation of gut transit independent of the endocannabinoid system.