VAMP7 Regulates Autophagy to Maintain Mitochondrial Homeostasis and to Control Insulin Secretion in Pancreatic β-Cells
VAMP7 Regulates Autophagy to Maintain Mitochondrial Homeostasis and to Control Insulin Secretion in Pancreatic β-Cells
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DOI：
10.2337/db15-1207
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发表时间：
2016-06-01
期刊：
影响因子：
7.7
通讯作者：
Nagamatsu, Shinya
中科院分区：
文献类型：
--
作者：
Aoyagi, Kyota;Ohara-Imaizumi, Mica;Nagamatsu, Shinya
VAMP7是一种SNARE蛋白，在细胞内转运过程中介导特定的膜融合，最近被报道调节自噬小体的形成。然而，它在胰岛β细胞中的功能在很大程度上是未知的。为了阐明VAMP7在β细胞中的生理作用，我们产生了胰腺β细胞特异性VAMP7基因敲除(VAMP7(FLOX/Y)；Cre)小鼠。VAMP7缺失可抑制葡萄糖刺激的ATP合成和胰岛素分泌，但VAMP7不定位于胰岛素颗粒。VAMP7缺陷的β细胞表现出自噬小体形成缺陷和线粒体减少！功能。P62/SQSTM1是缺陷自噬的标志蛋白，在VAMP7缺陷的β细胞中选择性地积聚在线粒体上。这些发现表明，通过自噬降解的功能障碍的线粒体的积累导致VAMP7(FLOX/Y)；Creβ细胞中葡萄糖刺激的ATP产生和胰岛素分泌的损害。以高脂饲料喂养VAMP7(FLOX/Y)；CRE小鼠加剧线粒体功能障碍，进一步减少ATP产生和胰岛素分泌，从而诱导葡萄糖耐量减低。此外，我们发现，在喂食高脂饮食的野生型小鼠和糖尿病模型db/db小鼠中，VAMP7的表达上调。因此，我们的数据表明，VAMP7调节自噬，以维持线粒体质量和胰岛素分泌，以应对病理性应激。
VAMP7 is a SNARE protein that mediates specific membrane fusions in intracellular trafficking and was recently reported to regulate autophagosome formation. However, its function in pancreatic beta-cells is largely unknown. To elucidate the physiological role of VAMP7 in beta-cells, we generated pancreatic beta-cell-specific VAMP7 knockout (Vamp7(flox/Y);Cre) mice. VAMP7 deletion impaired glucose-stimulated ATP production and insulin secretion, though VAMP7 was not localized to insulin granules. VAMP7-deficient beta-cells showed defective autophagosome formation and reduced mitochondria! function. p62/SQSTM1, a marker protein for defective autophagy, was selectively accumulated on mitochondria in VAMP7-deficient beta-cells. These findings suggest that accumulation of dysfunctional mitochondria that are degraded by autophagy caused impairment of glucose-stimulated ATP production and insulin secretion in Vamp7(flox/Y);Cre beta-cells. Feeding a high-fat diet to Vamp7(flox/Y);Cre mice exacerbated mitochondrial dysfunction, further decreased ATP production and insulin secretion, and consequently induced glucose intolerance. Moreover, we found upregulated VAMP7 expression in wild-type mice fed a high-fat diet and in db/db mice, a model for diabetes. Thus our data indicate that VAMP7 regulates autophagy to maintain mitochondrial quality and insulin secretion in response to pathological stress in beta-cells.