A link between endoplasmic reticulum stress-induced β-cell apoptosis and the group VIA Ca2+-independent phospholipase A₂ (iPLA₂β)

摘要

Endoplasmic reticulum (ER) stress is becoming recognized as an important contributing factor in various diseases, including diabetes mellitus. Prolonged ER stress can cause β-cell apoptosis; however, the underlying mechanism(s) that contribute to this process are not well understood. Early reports suggested that arachidonic acid metabolites and a Ca2+-independent phospholipase A₂ (iPLA₂) activity play a role in β-cell apoptosis. The PLA₂ family of enzymes catalyse the hydrolysis of the sn-2 substituent (i.e. arachidonic acid) of membrane phospholipids. In light of our findings that the pancreatic islet β-cells are enriched in arachidonate-containing phospholipids and express the group VIA iPLA₂β, we considered the possibility that iPLA₂β participates in ER stress-induced β-cell apoptosis. Our work revealed a novel mechanism, involving ceramide generation and triggering of mitochondrial abnormalities, by which iPLA₂β participates in the β-cell apoptosis process. Here, we review our evidence linking ER stress, β-cell apoptosis and iPLA₂β. Continued studies in this area will increase our understanding of the contribution of iPLA₂β to the evolution of diabetes mellitus and will further our knowledge of factors that influence β-cell health in diabetes mellitus and identify potential targets for future therapeutic interventions to prevent β-cell death.