Research Department, Imperial College London Diabetes Center, Abu Dhabi 51133, United Arab Emirates.
Department of Cell, Developmental, and Integrative Biology and Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Molecules. 2021 Oct 21;26(21):6361. doi: 10.3390/molecules26216361.
Type 1 diabetes (T1D) development, in part, is due to ER stress-induced β-cell apoptosis. Activation of the Ca-independent phospholipase A beta (iPLAβ) leads to the generation of pro-inflammatory eicosanoids, which contribute to β-cell death and T1D. ER stress induces iPLAβ-mediated generation of pro-apoptotic ceramides via neutral sphingomyelinase (NSMase). To gain a better understanding of the impact of iPLAβ on sphingolipids (SLs), we characterized their profile in β-cells undergoing ER stress. ESI/MS/MS analyses followed by ANOVA/Student's -test were used to assess differences in sphingolipids molecular species in Vector (V) control and iPLAβ-overexpressing (OE) INS-1 and Akita (AK, spontaneous model of ER stress) and WT-littermate (AK-WT) β-cells. As expected, iPLAβ 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 iPLAβ 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 iPLAβ-mediated shift in the β-cell sphingolipid profile is an important contributor to β-cell death associated with T1D.
1 型糖尿病（T1D）的发生部分归因于内质网应激诱导的β细胞凋亡。钙非依赖性磷脂酶 Aβ（iPLAβ）的激活导致促炎类花生酸的产生，这有助于β细胞死亡和 T1D。内质网应激通过中性鞘磷脂酶（NSMase）诱导 iPLAβ介导的促凋亡神经酰胺的产生。为了更好地了解 iPLAβ对鞘脂（SL）的影响，我们对经历内质网应激的β细胞中 SL 的特征进行了研究。采用 ESI/MS/MS 分析，然后进行方差分析/Student's -test，以评估 Vector（V）对照和 iPLAβ过表达（OE）INS-1和 Akita（AK，内质网应激的自发模型）以及 WT 同窝仔（AK-WT）β细胞中鞘脂分子种类的差异。正如预期的那样，与 V 和 WT 细胞相比，OE 和 AK 细胞中的 iPLAβ诱导更高。我们在此报告，内质网应激导致促凋亡的 SL 升高和促生存的 SL 降低，而 iPLAβ失活可使 SL 种类恢复到促进细胞生存的状态。鉴于我们最近的发现，即导致 T1D 的自身免疫反应起始细胞——巨噬细胞中的 SL 谱在 T1D 发展过程中没有明显改变，我们假设 iPLAβ介导的β细胞 SL 谱变化是与 T1D 相关的β细胞死亡的重要原因。
