Alterations in β-Cell Sphingolipid Profile Associated with ER Stress and iPLA<sub>2</sub>β: 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 Ca<sup>2+</sup>-independent phospholipase A<sub>2</sub> beta (iPLA<sub>2</sub>β) leads to the generation of pro-inflammatory eicosanoids, which contribute t...

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Autores principales: Tomader Ali, Xiaoyong Lei, Suzanne E. Barbour, Akio Koizumi, Charles E. Chalfant, Sasanka Ramanadham
Formato: article
Lenguaje:EN
Publicado: MDPI AG 2021
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Acceso en línea:https://doaj.org/article/e36a69fd56814486a980de5987a4cd9a
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Sumario:Type 1 diabetes (T1D) development, in part, is due to ER stress-induced β-cell apoptosis. Activation of the Ca<sup>2+</sup>-independent phospholipase A<sub>2</sub> beta (iPLA<sub>2</sub>β) leads to the generation of pro-inflammatory eicosanoids, which contribute to β-cell death and T1D. ER stress induces iPLA<sub>2</sub>β-mediated generation of pro-apoptotic ceramides via neutral sphingomyelinase (NSMase). To gain a better understanding of the impact of iPLA<sub>2</sub>β on sphingolipids (SLs), we characterized their profile in β-cells undergoing ER stress. ESI/MS/MS analyses followed by ANOVA/Student’s <i>t</i>-test were used to assess differences in sphingolipids molecular species in Vector (V) control and iPLA<sub>2</sub>β-overexpressing (OE) INS-1 and Akita (AK, spontaneous model of ER stress) and WT-littermate (AK-WT) β-cells. As expected, iPLA<sub>2</sub>β 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 iPLA<sub>2</sub>β 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 iPLA<sub>2</sub>β-mediated shift in the β-cell sphingolipid profile is an important contributor to β-cell death associated with T1D.