The endoplasmic reticulum stress/autophagy pathway is involved in cholesterol-induced pancreatic β-cell injury.
The endoplasmic reticulum stress/autophagy pathway is involved in cholesterol-induced pancreatic β-cell injury.
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DOI：
10.1038/srep44746
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发表时间：
2017-03-15
影响因子：
4.6
通讯作者：
Zhou JQ
中科院分区：
文献类型：
--
作者：
Kong FJ;Wu JH;Sun SY;Zhou JQ
脂毒性与2型糖尿病的胰腺β细胞功能障碍有关，但确切的机制仍不清楚。本研究探讨内质网（ER）应激途径在胆固醇诱导的脂毒性中的作用。两种不同的胰岛素瘤细胞系用胆固醇加或不加抑制剂处理。胆固醇可上调内质网应激相关蛋白GRP 78、转录激活因子ATF 4和C/EBP同源蛋白CHOP以及真核起始因子2α的磷酸化水平。胆固醇还上调微管相关蛋白1轻链3（LC 3）-II，并刺激自噬空泡和LC 3-II聚集体的形成。胆固醇诱导的自噬和细胞损伤抑制预处理与ER应激抑制剂4-苯基丁酸（4-PBA）。自噬抑制剂E-64 d/胃蛋白酶抑制剂A预处理增加了ER应激诱导的细胞损伤，如细胞凋亡增加和胰岛素分泌减少所示。这些结果表明，胆固醇处理诱导细胞凋亡和功能障碍，并通过激活ER应激途径增强自噬。更重要的是，胆固醇诱导的自噬可以保护β细胞免受ER应激相关的细胞损伤。
Lipotoxicity has been implicated in pancreatic β-cell dysfunction in type 2 diabetes, but the exact mechanisms remain unknown. The current study explored the role of the endoplasmic reticulum (ER) stress pathway in cholesterol-induced lipotoxicity. Two different insulinoma cell lines were treated with cholesterol with or without inhibitors. ER stress-associated proteins glucose-regulated protein (GRP) 78, activating transcription factor (ATF) 4 and C/EBP homologous protein (CHOP), as was phosphorylation of eukaryotic initiation factor (EIF) 2α, were all up-regulated by cholesterol. Cholesterol also up-regulated microtubule-associated protein 1 light chain 3 (LC3)-II and stimulated the formation of autophagic vacuoles and LC3-II aggregates. Cholesterol-induced autophagy and cell injuries were suppressed by pretreatment with the ER stress inhibitor 4-phenylbutyrate (4-PBA). Pretreatment with autophagy inhibitors E-64d/pepstatin A increased ER stress-induced cell injuries as indicated by increased cell apoptosis and decreased insulin secretion. These results suggest that cholesterol treatment induces apoptosis and dysfunction of β-cells, and enhances autophagy through activation of the ER stress pathway. More importantly, autophagy induced by cholesterol may protect β-cells against ER stress-associated cell damages.