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

Tomader Ali,Akio Koizumi,Suzanne E. Barbour,Charles E. Chalfant,Xiaoyong Lei,Sasanka Ramanadham

doi:10.3390/molecules26216361

Abstract

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.

Highlights

Diabetes is a consequence of pancreatic islet β-cell dysfunction and/or reduced peripheral insulin sensitivity, and both type 1 and type 2 diabetes (T1D and T2D) are associated with β-cell apoptosis [1,2]
As the changes in sphingolipids described in INS-1 and AK β-cells correlated with increased iPLA2 β, we examined whether they could be reversed by the inactivation of iPLA2 β
We find that both iPLA2 β (Figure 5A) and neutral sphingomyelinase 2 (NSMase2) (Figure 5B) are induced in the presence of thapsigargin (T), in both WTT and AKT cells, relative to WT and AK control cells, respectively

Summary

Introduction

Diabetes is a consequence of pancreatic islet β-cell dysfunction and/or reduced peripheral insulin sensitivity, and both type 1 and type 2 diabetes (T1D and T2D) are associated with β-cell apoptosis [1,2]. In addition to the extrinsic (receptor-mediated) and intrinsic (mitochondrial) apoptotic pathways, ER stress is recognized as an inducer of apoptosis in several disease states, including diabetes [3]. Reports from both experimental models and clinical settings have linked diabetes development with ER stress-induced β-cell apoptosis [4], and studies in our laboratory revealed an important role for the group VIA Ca2+ -independent phospholipase. The cytosol-associated iPLA2 β participates in membrane phospholipid remodeling, signal transduction, cell proliferation, inflammation, and apoptosis [4,8,9]

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