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Bax and Bak jointly control survival and dampen the early unfolded protein response in pancreatic β-cells under glucolipotoxic stress.
Scientific Reports ( IF 3.8 ) Pub Date : 2020-07-03 , DOI: 10.1038/s41598-020-67755-3
Sarah A White 1, 2 , Lisa S Zhang 1, 2 , Daniel J Pasula 1, 2 , Yu Hsuan Carol Yang 2 , Dan S Luciani 1, 2, 3
Affiliation  

ER stress and apoptosis contribute to the loss of pancreatic β-cells under pro-diabetic conditions of glucolipotoxicity. Although activation of canonical intrinsic apoptosis is known to require pro-apoptotic Bcl-2 family proteins Bax and Bak, their individual and combined involvement in glucolipotoxic β-cell death are not known. It has also remained an open question if Bax and Bak in β-cells have non-apoptotic roles in mitochondrial function and ER stress signaling, as suggested in other cell types. Using mice with individual or combined β-cell deletion of Bax and Bak, we demonstrated that glucolipotoxic β-cell death in vitro occurs by both non-apoptotic and apoptotic mechanisms, and the apoptosis could be triggered by either Bax or Bak alone. In contrast, they had non-redundant roles in mediating staurosporine-induced apoptosis. We further established that Bax and Bak do not affect normal glucose-stimulated β-cell Ca2+ responses, insulin secretion, or in vivo glucose tolerance. Finally, our experiments revealed that combined deletion of Bax and Bak amplified the unfolded protein response in islets during the early stages of chemical- or glucolipotoxicity-induced ER stress. These findings shed new light on roles of the core apoptosis machinery in β-cell survival and stress signals of importance for the pathobiology of diabetes.



中文翻译:

Bax和Bak共同控制生存,并抑制在糖脂毒性胁迫下胰腺β细胞早期未折叠的蛋白质反应。

在糖尿病性糖脂毒性条件下,内质网应激和细胞凋亡有助于胰腺β细胞的丢失。尽管已知经典内在凋亡的激活需要促凋亡的Bcl-2家族蛋白Bax和Bak,但它们各自和联合参与糖脂毒性β细胞死亡尚不清楚。正如其他细胞类型所暗示的那样,β细胞中的Bax和Bak在线粒体功能和ER应激信号传导中是否具有非凋亡作用,仍然是一个悬而未决的问题。使用具有Bax和Bak的单个或组合β细胞缺失的小鼠,我们证明了体外的糖脂毒性β细胞死亡是通过非凋亡和凋亡机制发生的,并且凋亡可能由单独的Bax或Bak触发。相反,它们在介导星形孢菌素诱导的细胞凋亡中具有非冗余作用。2+反应,胰岛素分泌或体内葡萄糖耐量。最后,我们的实验表明,在化学或糖脂毒性诱导的ER应激早期,Bax和Bak的联合缺失会放大胰岛中未折叠的蛋白质反应。这些发现为核心凋亡机制在β细胞存活中的作用和对糖尿病病理生物学重要的应激信号提供了新的启示。

更新日期:2020-07-03
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