Inhibition of Monoacylglycerol Lipase Activity Decreases Glucose-Stimulated Insulin Secretion in INS-1 (832/13) Cells and Rat Islets.
Inhibition of Monoacylglycerol Lipase Activity Decreases Glucose-Stimulated Insulin Secretion in INS-1 (832/13) Cells and Rat Islets.
复制标题
DOI：
10.1371/journal.pone.0149008
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Deeney JT
中科院分区：
文献类型：
--
作者：
Berdan CA;Erion KA;Burritt NE;Corkey BE;Deeney JT
来自脂解和膜磷脂的脂质信号在葡萄糖刺激的胰岛素分泌(GSIS)中起着重要作用，但确切的次级信号仍不清楚。以前的报道已经证明，外源性添加的单酰甘油对培养的β细胞和胰岛的胰岛素分泌具有刺激作用。在这份报告中，我们确定了通过抑制单酰甘油脂肪酶活性来增加β-细胞内MAG的效果，单酰甘油脂肪酶催化三酰甘油分解的最后一步，即MAG水解为甘油和游离脂肪酸(FA)。为了确定MGL在GSIS中的作用，我们使用了三种不同的药理学药物(JZL184、MJN110和URB602)。三者均抑制GSIS和去极化诱导的INS-1胰岛素分泌(832/13)。JZL184显著抑制GSIS和去极化诱导的大鼠胰岛胰岛素分泌。JZL184可显著降低INS-1细胞的脂解作用，增加单甘油和双甘油的含量。对GSIS动力学的分析表明，在分泌的持续阶段，抑制作用更强。在钙离子对葡萄糖和去极化的反应中也观察到了类似的模式，但程度较小，这表明仅改变钙离子的处理不能解释胰岛素分泌的减少。此外，MGL抑制后，INS-1细胞在基础和刺激葡萄糖条件下的长链辅酶A(LC-CoA)显著减少。我们的数据暗示了MGL在胰岛素分泌中的重要作用。
Lipid signals derived from lipolysis and membrane phospholipids play an important role in glucose-stimulated insulin secretion (GSIS), though the exact secondary signals remain unclear. Previous reports have documented a stimulatory role of exogenously added mono-acyl-glycerol (MAG) on insulin secretion from cultured β-cells and islets. In this report we have determined effects of increasing intracellular MAG in the β-cell by inhibiting mono-acyl-glycerol lipase (MGL) activity, which catalyzes the final step in triacylglycerol breakdown, namely the hydrolysis of MAG to glycerol and free fatty acid (FA). To determine the role of MGL in GSIS, we used three different pharmacological agents (JZL184, MJN110 and URB602). All three inhibited GSIS and depolarization-induced insulin secretion in INS-1 (832/13). JZL184 significantly inhibited both GSIS and depolarization-induced insulin secretion in rat islets. JZL184 significantly decreased lipolysis and increased both mono- and diacyglycerol species in INS-1 cells. Analysis of the kinetics of GSIS showed that inhibition was greater during the sustained phase of secretion. A similar pattern was observed in the response of Ca2+ to glucose and depolarization but to a lesser degree suggesting that altered Ca2+ handling alone could not explain the reduction in insulin secretion. In addition, a significant reduction in long chain-CoA (LC-CoA) was observed in INS-1 cells at both basal and stimulatory glucose following inhibition of MGL. Our data implicate an important role for MGL in insulin secretion.