Selective inhibition of eukaryotic translation initiation factor 2α dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic β-cell dysfunction and apoptosis
Selective inhibition of eukaryotic translation initiation factor 2α dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic β-cell dysfunction and apoptosis
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DOI：
10.1074/jbc.m607627200
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发表时间：
2007-02-09
影响因子：
4.8
通讯作者：
Eizirik, Decio L.
中科院分区：
文献类型：
--
作者：
Cnop, Miriam;Ladriere, Laurence;Eizirik, Decio L.
游离脂肪酸引起胰腺β细胞凋亡，并可能通过诱导内质网应激导致2型糖尿病中β细胞丢失。真核生物翻译起始因子（eIF）2 α磷酸化的减少触发P细胞衰竭和糖尿病。Salubrinal选择性抑制eIF 2 α去磷酸化，保护其他细胞免受内质网应激介导的凋亡，并已被提议作为β细胞保护剂。出乎意料的是，salubrinal诱导原代β细胞凋亡，并加强了油酸酯和棕榈酸酯的有害作用。Salubrinal诱导显著的eIF 2 α磷酸化，并增强游离脂肪酸对蛋白质合成和胰岛素释放的抑制作用。内质网应激反应的PERK-eIF 2 α分支的协同激活，而不是IRE 1和激活转录因子-6途径的协同激活，导致激活转录因子-4和促凋亡转录因子CHOP的显著诱导。我们的研究结果表明，过度eIF 2 α磷酸化是由β细胞耐受性差，加剧游离脂肪酸诱导的细胞凋亡。这改变了目前关于eIF 2 α磷酸化在β细胞中的有益作用的范例，并且在设计保护2型糖尿病中β细胞的疗法时必须考虑到这一点。
Free fatty acids cause pancreatic beta-cell apoptosis and may contribute to beta-cell loss in type 2 diabetes via the induction of endoplasmic reticulum stress. Reductions in eukaryotic translation initiation factor (eIF) 2 alpha phosphorylation trigger P-cell failure and diabetes. Salubrinal selectively inhibits eIF2 alpha dephosphorylation, protects other cells against endoplasmic reticulum stress-mediated apoptosis, and has been proposed as a beta-cell protector. Unexpectedly, salubrinal induced apoptosis in primary beta-cells, and it potentiated the deleterious effects of oleate and palmitate. Salubrinal induced a marked eIF2 alpha phosphorylation and potentiated the inhibitory effects of free fatty acids on protein synthesis and insulin release. The synergistic activation of the PERK-eIF2 alpha branch of the endoplasmic reticulum stress response, but not of the IRE1 and activating transcription factor-6 pathways, led to a marked induction of activating transcription factor-4 and the pro-apoptotic transcription factor CHOP. Our findings demonstrate that excessive eIF2 alpha phosphorylation is poorly tolerated by beta-cells and exacerbates free fatty acid-induced apoptosis. This modifies the present paradigm regarding the beneficial role of eIF2 alpha phosphorylation in beta-cells and must be taken into consideration when designing therapies to protect beta-cells in type 2 diabetes.