Department of Medicine, Mass Spectrometry Resource and Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
Biochimie. 2010 Jun;92(6):627-37. doi: 10.1016/j.biochi.2010.01.005. Epub 2010 Jan 18.
Activation of phospholipases A(2) (PLA(2)s) leads to the generation of biologically active lipid mediators that can affect numerous cellular events. The Group VIA Ca(2+)-independent PLA(2), designated iPLA(2)beta, is active in the absence of Ca(2+), activated by ATP, and inhibited by the bromoenol lactone suicide inhibitor (BEL). Over the past 10-15 years, studies using BEL have demonstrated that iPLA(2)beta participates in various biological processes and the recent availability of mice in which iPLA(2)beta expression levels have been genetically-modified are extending these findings. Work in our laboratory suggests that iPLA(2)beta activates a unique signaling cascade that promotes beta-cell apoptosis. This pathway involves iPLA(2)beta dependent induction of neutral sphingomyelinase, production of ceramide, and activation of the intrinsic pathway of apoptosis. There is a growing body of literature supporting beta-cell apoptosis as a major contributor to the loss of beta-cell mass associated with the onset and progression of Type 1 and Type 2 diabetes mellitus. This underscores a need to gain a better understanding of the molecular mechanisms underlying beta-cell apoptosis so that improved treatments can be developed to prevent or delay the onset and progression of diabetes mellitus. Herein, we offer a general review of Group VIA Ca(2+)-independent PLA(2) (iPLA(2)beta) followed by a more focused discussion of its participation in beta-cell apoptosis. We suggest that iPLA(2)beta-derived products trigger pathways which can lead to beta-cell apoptosis during the development of diabetes.
磷脂酶 A(2)（PLA(2)s）的激活导致生物活性脂质介质的产生，这些介质可以影响许多细胞事件。VIA 组钙离子非依赖性 PLA(2)，称为 iPLA(2)beta，在没有钙离子的情况下活跃，被 ATP 激活，并被溴烯醇内酯自杀抑制剂（BEL）抑制。在过去的 10-15 年中，使用 BEL 的研究表明，iPLA(2)beta 参与了各种生物学过程，而最近可以对 iPLA(2)beta 表达水平进行基因修饰的小鼠的出现正在扩展这些发现。我们实验室的工作表明，iPLA(2)beta 激活了一个独特的信号级联，促进了β细胞凋亡。这条途径涉及 iPLA(2)beta 依赖性诱导中性鞘磷脂酶、产生神经酰胺和激活细胞凋亡的内在途径。越来越多的文献支持β细胞凋亡是与 1 型和 2 型糖尿病的发病和进展相关的β细胞数量减少的主要原因。这强调了需要更好地了解β细胞凋亡的分子机制，以便开发出更好的治疗方法来预防或延迟糖尿病的发病和进展。在此，我们提供了对 VIA 组钙离子非依赖性 PLA(2)（iPLA(2)beta）的一般性综述，然后更集中地讨论了它在β细胞凋亡中的参与。我们认为，iPLA(2)beta 衍生的产物触发了在糖尿病发展过程中可能导致β细胞凋亡的途径。
