Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice
Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice
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DOI：
10.1016/j.cmet.2006.06.009
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发表时间：
2006-08-01
期刊：
影响因子：
29
通讯作者：
Yamada, Nobuhiro
中科院分区：
文献类型：
--
作者：
Kato, Toyonori;Shimano, Hitoshi;Yamada, Nobuhiro
嗜颗粒蛋白是胰岛素囊泡与质膜对接机制的重要组成部分。在这里，我们发现嗜颗粒蛋白启动子是SREBP-1c（一种控制脂肪酸合成的转录因子）和MafA（一种β细胞分化因子）的靶标。在腺病毒介导的嗜颗粒蛋白过表达的胰岛中，钾刺激胰岛素分泌（KSIS）被抑制，而在嗜颗粒蛋白被敲低的胰岛中，KSIS被增强。在β细胞特异性SREBP-1c转基因小鼠的胰岛中，以及在几种糖尿病小鼠模型和棕榈酸处理的正常胰岛中，SREBP-1c和嗜颗粒蛋白被激活，并伴有胰岛素分泌的相应减少。敲低或敲除介导的粒细胞或SREBP-1c消融恢复了这些胰岛的KSIS。总的来说，我们的数据提供了证据，证明SREBP-1c/嗜颗粒蛋白途径的激活是糖尿病胰岛素分泌受损的潜在机制，有助于β细胞脂肪毒性。
Granuphilin is a crucial component of the docking machinery of insulin-containing vesicles to the plasma membrane. Here, we show that the granuphilin promoter is a target of SREBP-1c, a transcription factor that controls fatty acid synthesis, and MafA, a beta cell differentiation factor. Potassium-stimulated insulin secretion (KSIS) was suppressed in islets with adenoviral-mediated overexpression of granuphilin and enhanced in islets with knockdown of granuphilin (in which granuphilin had been knocked down). SREBP-1c and granuphilin were activated in islets from beta cell-specific SREBP-1c transgenic mice, as well as in several diabetic mouse models and normal islets treated with palmitate, accompanied by a corresponding reduction in insulin secretion. Knockdown- or knockout-mediated ablation of granuphilin or SREBP-1c restored KSIS in these islets. Collectively, our data provide evidence that activation of the SREBP-1c/granuphilin pathway is a potential mechanism for impaired insulin secretion in diabetes, contributing to beta cell lipotoxicity.