Group VIA Ca2+-independent phospholipase A2 (iPLA2β) and its role in β-cell programmed cell death

Activation of phospholipases A2 (PLA2s) leads to the generation of biologically active lipid mediators that can affect numerous cellular events. The Group VIA Ca2+-independent PLA2, designated iPLA2β, is active in the absence of Ca2+, activated by ATP, and inhibited by the bromoenol lactone suicide inhibitor (BEL). Over the past 10–15 years, studies using BEL have demonstrated that iPLA2β participates in various biological processes and the recent availability of mice in which iPLA2β expression levels have been genetically-modified are extending these findings. Work in our laboratory suggests that iPLA2β activates a unique signaling cascade that promotes β-cell apoptosis. This pathway involves iPLA2β dependent induction of neutral sphingomyelinase, production of ceramide, and activation of the intrinsic pathway of apoptosis. There is a growing body of literature supporting β-cell apoptosis as a major contributor to the loss of β-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 β-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 Ca2+-independent PLA2 (iPLA2β) followed by a more focused discussion of its participation in β-cell apoptosis. We suggest that iPLA2β-derived products trigger pathways which can lead to β-cell apoptosis during the development of diabetes.