PLIN2 is a Key Regulator of the Unfolded Protein Response and Endoplasmic Reticulum Stress Resolution in Pancreatic β Cells.
PLIN2 is a Key Regulator of the Unfolded Protein Response and Endoplasmic Reticulum Stress Resolution in Pancreatic β Cells.
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PLIN2 是胰腺 β 细胞中未折叠蛋白反应和内质网应激消解的关键调节因子。
DOI：
10.1038/srep40855
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发表时间：
2017-01-19
影响因子：
4.6
通讯作者：
Chang BH
中科院分区：
文献类型：
--
作者：
Chen E;Tsai TH;Li L;Saha P;Chan L;Chang BH
进行性胰腺β细胞衰竭是糖耐量受损向显性糖尿病转变的基础;在这种情况下，内质网（ER）应激加速β细胞衰竭。ER应激可由脂毒性和糖尿病对胰岛素需求的增加引起。我们以前报道过脂滴蛋白perilipin 2（PLIN 2）调节肝脏中的脂质稳态。在这里，我们表明PLIN 2调节胰腺β细胞中的未折叠蛋白反应（UPR）和ER应激。当β细胞暴露于脂质负荷或化学ER应激诱导剂时，PLIN 2表达升高。PLIN 2的下调改善了脂肪酸和化学物质诱导的ER应激的作用，而PLIN 2过表达则加剧了它们。携带杂合C96 Y Ins 2突变的糖尿病秋田小鼠在其β细胞中表现出升高的PLIN 2表达和ER应激。秋田小鼠中Plin 2的基因消除导致ER应激的减轻、阻止β细胞凋亡、部分恢复β细胞质量和改善糖尿病。机制实验表明，PLIN 2下调与增强的自噬通量和加速的ER应激消退相关。总之，我们已经确定了PLIN 2在调节自噬、ER应激缓解和β细胞凋亡和存活中的关键作用。
Progressive pancreatic β cell failure underlies the transition of impaired glucose tolerance to overt diabetes; endoplasmic reticulum (ER) stress expedites β cell failure in this situation. ER stress can be elicited by lipotoxicity and an increased demand for insulin in diabetes. We previously reported that the lipid droplet protein perilipin 2 (PLIN2) modulates lipid homeostasis in the liver. Here, we show that PLIN2 modulates the unfolded protein response (UPR) and ER stress in pancreatic β cells. PLIN2 expression goes up when β cells are exposed to a lipid load or to chemical ER stress inducers. Downregulation of PLIN2 ameliorates the effects of fatty acid- and chemical-induced ER stress, whereas PLIN2 overexpression exacerbates them. Diabetic Akita mice, which carry a heterozygous C96Y Ins2 mutation, exhibit elevated PLIN2 expression and ER stress in their β cells. Genetic ablation of Plin2 in Akita mice leads to mitigation of ER stress, forestalling β cell apoptosis, partially restoring β cell mass, and ameliorating diabetes. Mechanistic experiments showed that PLIN2 downregulation is associated with enhanced autophagic flux and accelerated ER stress resolution. In sum, we have identified a crucial role for PLIN2 in modulating autophagy, ER stress resolution, and β cell apoptosis and survival.