Departments of Medical Genetics, Centre for Molecular Medicine, and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Diabetes. 2011 Dec;60(12):3186-96. doi: 10.2337/db11-0081. Epub 2011 Oct 12.
The ATP-binding cassette transporter A1 (ABCA1) is essential for normal insulin secretion from β-cells. The aim of this study was to elucidate the mechanisms underlying the impaired insulin secretion in islets lacking β-cell ABCA1.
Calcium imaging, patch clamp, and membrane capacitance were used to assess the effect of ABCA1 deficiency on calcium flux, ion channel function, and exocytosis in islet cells. Electron microscopy was used to analyze β-cell ultrastructure. The quantity and distribution of proteins involved in insulin-granule exocytosis were also investigated.
We show that a lack of β-cell ABCA1 results in impaired depolarization-induced exocytotic fusion of insulin granules. We observed disturbances in membrane microdomain organization and Golgi and insulin granule morphology in β-cells as well as elevated fasting plasma proinsulin levels in mice in the absence of β-cell ABCA1. Acute cholesterol depletion rescued the exocytotic defect in β-cells lacking ABCA1, indicating that elevated islet cholesterol accumulation directly impairs granule fusion and insulin secretion.
Our data highlight a crucial role of ABCA1 and cellular cholesterol in β-cells that is necessary for regulated insulin granule fusion events. These data suggest that abnormalities of cholesterol metabolism may contribute to the impaired β-cell function in diabetes.
三磷酸腺苷结合盒转运体 A1（ABCA1）对于β细胞正常胰岛素分泌至关重要。本研究旨在阐明胰岛细胞中缺乏 ABCA1 时胰岛素分泌受损的机制。
使用钙成像、膜片钳和膜电容来评估 ABCA1 缺乏对胰岛细胞中钙流、离子通道功能和胞吐作用的影响。电子显微镜用于分析β细胞的超微结构。还研究了参与胰岛素颗粒胞吐作用的蛋白质的数量和分布。
我们发现β细胞 ABCA1 的缺乏导致胰岛素颗粒去极化诱导的胞吐融合受损。我们观察到β细胞中膜微区组织、高尔基体和胰岛素颗粒形态的紊乱，以及缺乏β细胞 ABCA1 的小鼠空腹血浆胰岛素原水平升高。急性胆固醇耗竭可挽救缺乏 ABCA1 的β细胞中的胞吐缺陷，表明胰岛胆固醇积累的增加直接损害颗粒融合和胰岛素分泌。
我们的数据强调了 ABCA1 和细胞胆固醇在β细胞中的关键作用，这对于调节胰岛素颗粒融合事件是必需的。这些数据表明，胆固醇代谢异常可能导致糖尿病中β细胞功能受损。
