Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes
Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes
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DOI：
10.1007/s00125-006-0590-z
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发表时间：
2007-04-01
期刊：
影响因子：
8.2
通讯作者：
Biden, T. J.
中科院分区：
文献类型：
--
作者：
Laybutt, D. R.;Preston, A. M.;Biden, T. J.
脂质供应增加导致β细胞死亡，这可能导致2型糖尿病中β细胞质量减少。我们研究了内质网（ER）应激是否是脂质诱导的β细胞凋亡所必需的，以及ER应激是否存在于糖尿病动物模型和2型糖尿病患者的胰岛中，在暴露于高脂的胰岛素分泌MIN 6细胞中，在分离自db/db小鼠的胰岛和2型糖尿病患者的胰腺切片中，评估了ER应激相关基因的表达。过量生产的ER伴侣蛋白热休克70 kDa蛋白5（HSPA 5，以前称为免疫球蛋白重链结合蛋白[BIP]）进行评估是否衰减的ER应力影响脂质诱导apoptosis.We证明，促凋亡脂肪酸棕榈酸酯触发一个全面的ER应激反应在MIN 6细胞，这是几乎没有使用非凋亡脂肪酸油酸酯。转录激活因子4（Atf 4）、DNA损伤诱导转录物3（Ddit 3，以前称为C/EBP同源蛋白[Chop]）和DnaJ同源物（HSP 40）C3（Dnajc 3，以前称为p58）的mRNA水平的时间依赖性增加与棕榈酸酯处理的MIN 6细胞中的凋亡增加相关，但与油酸酯处理的MIN 6细胞中的凋亡无关。MIN 6细胞中HSPA 5的过度产生对ER应激的减弱显著地保护脂质诱导的凋亡。在db/db小鼠胰岛中，多种ER应激标志基因也上调。还观察到X盒结合蛋白1（Xbp 1）mRNA的加工（激活）增加，证实了ER应激的存在。最后，我们观察到2型糖尿病受试者胰腺切片中HSPA 5、DDIT 3、DNAJC 3和BCL 2相关X蛋白的胰岛蛋白产量增加，我们的结果提供了证据表明ER应激发生在2型糖尿病中，并且是潜在β细胞衰竭所必需的。
Increased lipid supply causes beta cell death, which may contribute to reduced beta cell mass in type 2 diabetes. We investigated whether endoplasmic reticulum (ER) stress is necessary for lipid-induced apoptosis in beta cells and also whether ER stress is present in islets of an animal model of diabetes and of humans with type 2 diabetes.Expression of genes involved in ER stress was evaluated in insulin-secreting MIN6 cells exposed to elevated lipids, in islets isolated from db/db mice and in pancreas sections of humans with type 2 diabetes. Overproduction of the ER chaperone heat shock 70 kDa protein 5 (HSPA5, previously known as immunoglobulin heavy chain binding protein [BIP]) was performed to assess whether attenuation of ER stress affected lipid-induced apoptosis.We demonstrated that the pro-apoptotic fatty acid palmitate triggers a comprehensive ER stress response in MIN6 cells, which was virtually absent using non-apoptotic fatty acid oleate. Time-dependent increases in mRNA levels for activating transcription factor 4 (Atf4), DNA-damage inducible transcript 3 (Ddit3, previously known as C/EBP homologous protein [Chop]) and DnaJ homologue (HSP40) C3 (Dnajc3, previously known as p58) correlated with increased apoptosis in palmitate- but not in oleate-treated MIN6 cells. Attenuation of ER stress by overproduction of HSPA5 in MIN6 cells significantly protected against lipid-induced apoptosis. In islets of db/db mice, a variety of marker genes of ER stress were also upregulated. Increased processing (activation) of X-box binding protein 1 (Xbp1) mRNA was also observed, confirming the existence of ER stress. Finally, we observed increased islet protein production of HSPA5, DDIT3, DNAJC3 and BCL2-associated X protein in human pancreas sections of type 2 diabetes subjects.Our results provide evidence that ER stress occurs in type 2 diabetes and is required for aspects of the underlying beta cell failure.