Alterations in β-Cell Sphingolipid Profile Associated with ER Stress and iPLA2β: Another Contributor to β-Cell Apoptosis in Type 1 Diabetes

Type 1 diabetes (T1D) development, in part, is due to ER stress-induced β-cell apoptosis. Activation of the Ca2+-independent phospholipase A2 beta (iPLA2β) leads to the generation of pro-inflammatory eicosanoids, which contribute to β-cell death and T1D. ER stress induces iPLA2β-mediated generation...

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Published in:Molecules (Basel, Switzerland) Switzerland), 2021-10, Vol.26 (21), p.6361
Main Authors: Ali, Tomader, Lei, Xiaoyong, Barbour, Suzanne E., Koizumi, Akio, Chalfant, Charles E., Ramanadham, Sasanka
Format: Article
Language:English
Subjects:
Apoptosis
Beta cells
Calcium ions
Cell activation
Cell death
Cell growth
Diabetes
Diabetes mellitus
Diabetes mellitus (insulin dependent)
Eicosanoids
Inactivation
Inflammation
Lipids
Macrophages
Phospholipase A2
Signal transduction
Sphingolipids
Sphingomyelin phosphodiesterase
Stress
Survival
Variance analysis
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Summary:Type 1 diabetes (T1D) development, in part, is due to ER stress-induced β-cell apoptosis. Activation of the Ca2+-independent phospholipase A2 beta (iPLA2β) leads to the generation of pro-inflammatory eicosanoids, which contribute to β-cell death and T1D. ER stress induces iPLA2β-mediated generation of pro-apoptotic ceramides via neutral sphingomyelinase (NSMase). To gain a better understanding of the impact of iPLA2β on sphingolipids (SLs), we characterized their profile in β-cells undergoing ER stress. ESI/MS/MS analyses followed by ANOVA/Student’s t-test were used to assess differences in sphingolipids molecular species in Vector (V) control and iPLA2β-overexpressing (OE) INS-1 and Akita (AK, spontaneous model of ER stress) and WT-littermate (AK-WT) β-cells. As expected, iPLA2β induction was greater in the OE and AK cells in comparison with V and WT cells. We report here that ER stress led to elevations in pro-apoptotic and decreases in pro-survival sphingolipids and that the inactivation of iPLA2β restores the sphingolipid species toward those that promote cell survival. In view of our recent finding that the SL profile in macrophages—the initiators of autoimmune responses leading to T1D—is not significantly altered during T1D development, we posit that the iPLA2β-mediated shift in the β-cell sphingolipid profile is an important contributor to β-cell death associated with T1D.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules26216361