Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System.
Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System.
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DOI：
10.1155/2015/280615
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发表时间：
2015
影响因子：
4.3
通讯作者：
Gurzov EN
中科院分区：
文献类型：
--
作者：
Litwak SA;Wali JA;Pappas EG;Saadi H;Stanley WJ;Varanasi LC;Kay TW;Thomas HE;Gurzov EN
由饱和游离脂肪酸（FFA）诱导的胰腺β细胞损失被认为有助于2型糖尿病。先前的研究表明，2型糖尿病患者胰腺中内质网（ER）应激的诱导、泛素化蛋白的增加以及Bcl-2家族的失调。然而，β细胞死亡的确切机制仍然未知。在本研究中，我们证明了FFA棕榈酸酯阻断泛素-蛋白酶体系统（UPS），并通过诱导ER应激和Bcl-2蛋白的失调引起细胞凋亡。我们发现，棕榈酸酯和蛋白酶体抑制剂MG 132诱导β细胞中的ER应激，导致促存活蛋白Bcl-2、Mcl-1和Bcl-XL的表达降低，促死亡蛋白BH 3-only的表达上调。另一方面，萝卜硫素对UPS的药理学激活改善了ER应激，上调了促存活Bcl-2蛋白，并保护β细胞免于FFA诱导的细胞死亡。此外，Bcl-2的转基因过表达在体外保护胰岛免受FFA诱导的细胞死亡，并在体内改善葡萄糖诱导的胰岛素分泌。总之，我们的研究结果表明，靶向UPS和Bcl-2蛋白表达可能是预防2型糖尿病β细胞死亡的有价值的策略。
Pancreatic β-cell loss induced by saturated free fatty acids (FFAs) is believed to contribute to type 2 diabetes. Previous studies have shown induction of endoplasmic reticulum (ER) stress, increased ubiquitinated proteins, and deregulation of the Bcl-2 family in the pancreas of type 2 diabetic patients. However, the precise mechanism of β-cell death remains unknown. In the present study we demonstrate that the FFA palmitate blocks the ubiquitin-proteasome system (UPS) and causes apoptosis through induction of ER stress and deregulation of Bcl-2 proteins. We found that palmitate and the proteasome inhibitor MG132 induced ER stress in β-cells, resulting in decreased expression of the prosurvival proteins Bcl-2, Mcl-1, and Bcl-XL, and upregulation of the prodeath BH3-only protein PUMA. On the other hand, pharmacological activation of the UPS by sulforaphane ameliorated ER stress, upregulated prosurvival Bcl-2 proteins, and protected β-cells from FFA-induced cell death. Furthermore, transgenic overexpression of Bcl-2 protected islets from FFA-induced cell death in vitro and improved glucose-induced insulin secretion in vivo. Together our results suggest that targeting the UPS and Bcl-2 protein expression may be a valuable strategy to prevent β-cell demise in type 2 diabetes.
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影响因子：
7.7
作者：
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