Selective inhibition of eukaryotic translation initiation factor 2α dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic β-cell dysfunction and apoptosis
Journal of Biological Chemistry, cilt.282, sa.6, ss.3989-3997, 2007 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 282 Sayı: 6
- Basım Tarihi: 2007
- Doi Numarası: 10.1074/jbc.m607627200
- Dergi Adı: Journal of Biological Chemistry
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
- Sayfa Sayıları: ss.3989-3997
- İstanbul Yeni Yüzyıl Üniversitesi Adresli: Hayır
Özet
Free fatty acids cause pancreatic β-cell apoptosis and may contribute to β-cell loss in type 2 diabetes via the induction of endoplasmic reticulum stress. Reductions in eukaryotic translation initiation factor (eIF) 2α phosphorylation trigger β-cell failure and diabetes. Salubrinal selectively inhibits eIF2α dephosphorylation, protects other cells against endoplasmic reticulum stress-mediated apoptosis, and has been proposed as a β-cell protector. Unexpectedly, salubrinal induced apoptosis in primary β-cells, and it potentiated the deleterious effects of oleate and palmitate. Salubrinal induced a marked eIF2α phosphorylation and potentiated the inhibitory effects of free fatty acids on protein synthesis and insulin release. The synergistic activation of the PERK-eIF2α 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 eIF2α phosphorylation is poorly tolerated by β-cells and exacerbates free fatty acid-induced apoptosis. This modifies the present paradigm regarding the beneficial role of eIF2α phosphorylation in β-cells and must be taken into consideration when designing therapies to protect β-cells in type 2 diabetes. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.