Role of calcium-independent phospholipase A(2)β in human pancreatic islet β-cell apoptosis.
Death of β-cells due to apoptosis is an important contributor to β-cell dysfunction in both type 1 and type 2 diabetes mellitus. Previously, we described participation of the Group VIA Ca(2+)-independent phospholipase A(2) (iPLA(2)β) in apoptosis of insulinoma cells due to ER stress. To examine whether islet β-cells are similarly susceptible to ER stress and undergo iPLA(2)β-mediated apoptosis, we assessed the ER stress response in human pancreatic islets. Here, we report that the iPLA(2)β protein is expressed predominantly in the β-cells of human islets and that thapsigargin-induced ER stress promotes β-cell apoptosis, as reflected by increases in activated caspase-3 in the β-cells. Furthermore, we demonstrate that ER stress is associated with increases in islet iPLA(2)β message, protein, and activity, iPLA(2)β-dependent induction of neutral sphingomyelinase and ceramide accumulation, and subsequent loss of mitochondrial membrane potential. We also observe that basal activated caspase-3 increases with age, raising the possibility that β-cells in older human subjects have a greater susceptibility to undergo apoptotic cell death. These findings reveal for the first time expression of iPLA(2)β protein in human islet β-cells and that induction of iPLA(2)β during ER stress contributes to human islet β-cell apoptosis. We hypothesize that modulation of iPLA(2)β activity might reduce β-cell apoptosis and this would be beneficial in delaying or preventing β-cell dysfunction associated with diabetes.
Dept. of Cell, Developmental, and Integrative Biology, Univ. of Alabama at Birmingham, Birmingham, AL 35294, USA.
Xiaoyong
X
Lei
Sheng
S
Zhang
Alan
A
Bohrer
Suzanne E
SE
Barbour
Sasanka
S
Ramanadham
D000328:Adult; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology*; D007515:Islets of Langerhans / Q000166:cytology / Q000201:enzymology*; D008297:Male; D054512:Phospholipases A2, Calcium-Independent / Q000187:drug effects / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology
D004791:Enzyme Inhibitors; D019284:Thapsigargin; D054512:Phospholipases A2, Calcium-Independent