title: Genetic modulation of islet β-cell iPLA₂β expression provides evidence for its impact on β-cell apoptosis and autophagy.
abstract: β-cell apoptosis is a significant contributor to β-cell dysfunction in diabetes and ER stress is among the factors that contributes to β-cell death. We previously identified that the Ca²⁺-independent phospholipase A₂β (iPLA₂β), which in islets is localized in β-cells, participates in ER stress-induced β-cell apoptosis. Here, direct assessment of iPLA₂β role was made using β-cell-specific iPLA₂β overexpressing (RIP-iPLA₂β-Tg) and globally iPLA₂β-deficient (iPLA₂β-KO) mice. Islets from Tg, but not KO, express higher islet iPLA₂β and neutral sphingomyelinase, decrease in sphingomyelins, and increase in ceramides, relative to WT group. ER stress induces iPLA₂β, ER stress factors, loss of mitochondrial membrane potential (∆Ψ), caspase-3 activation, and β-cell apoptosis in the WT and these are all amplified in the Tg group. Surprisingly, β-cells apoptosis while reduced in the KO is higher than in the WT group. This, however, was not accompanied by greater caspase-3 activation but with larger loss of ∆Ψ, suggesting that iPLA₂β deficiency impacts mitochondrial membrane integrity and causes apoptosis by a caspase-independent manner. Further, autophagy, as reflected by LC3-II accumulation, is increased in Tg and decreased in KO, relative to WT. Our findings suggest that (1) iPLA₂β impacts upstream (UPR) and downstream (ceramide generation and mitochondrial) pathways in β-cells and (2) both over- or under-expression of iPLA₂β is deleterious to the β-cells. Further, we present for the first time evidence for potential regulation of autophagy by iPLA₂β in islet β-cells. These findings support the hypothesis that iPLA₂β induction under stress, as in diabetes, is a key component to amplifying β-cell death processes.
authors: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Xiaoyong
authors: X
authors: Lei
authors: Robert N
authors: RN
authors: Bone
authors: Tomader
authors: T
authors: Ali
authors: Mary
authors: M
authors: Wohltmann
authors: Ying
authors: Y
authors: Gai
authors: Karen J
authors: KJ
authors: Goodwin
authors: Alan E
authors: AE
authors: Bohrer
authors: John
authors: J
authors: Turk
authors: Sasanka
authors: S
authors: Ramanadham
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D003920:Diabetes Mellitus / Q000201:enzymology / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D054513:Group IV Phospholipases A2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D013108:Sphingomyelin Phosphodiesterase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D002518:Ceramides; D004791:Enzyme Inhibitors; C516390:Pla2g4a protein, mouse; D054513:Group IV Phospholipases A2; D013108:Sphingomyelin Phosphodiesterase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: RIP-iPLA2β-Tg; apoptosis; autophagy; caspase-3; iPLA2β; iPLA2β-KO; mitochondrial membrane potential; β-cell