Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
J Clin Invest. 2010 Jul;120(7):2575-89. doi: 10.1172/JCI41280. Epub 2010 Jun 7.
Cholesterol is a critical component of cell membranes, and cellular cholesterol levels and distribution are tightly regulated in mammals. Recent evidence has revealed a critical role for pancreatic beta cell-specific cholesterol homeostasis in insulin secretion as well as in beta cell dysfunction in diabetes and the metabolic response to thiazolidinediones (TZDs), which are antidiabetic drugs. The ATP-binding cassette transporter G1 (ABCG1) has been shown to play a role in cholesterol efflux, but its role in beta cells is currently unknown. In other cell types, ABCG1 expression is downregulated in diabetes and upregulated by TZDs. Here we have demonstrated an intracellular role for ABCG1 in beta cells. Loss of ABCG1 expression impaired insulin secretion both in vivo and in vitro, but it had no effect on cellular cholesterol content or efflux. Subcellular localization studies showed the bulk of ABCG1 protein to be present in insulin granules. Loss of ABCG1 led to altered granule morphology and reduced granule cholesterol levels. Administration of exogenous cholesterol restored granule morphology and cholesterol content and rescued insulin secretion in ABCG1-deficient islets. These findings suggest that ABCG1 acts primarily to regulate subcellular cholesterol distribution in mouse beta cells. Furthermore, islet ABCG1 expression was reduced in diabetic mice and restored by TZDs, implicating a role for regulation of islet ABCG1 expression in diabetes pathogenesis and treatment.
胆固醇是细胞膜的重要组成部分，哺乳动物细胞内的胆固醇水平和分布受到严格调控。最近的证据表明，胰腺β细胞特异性胆固醇稳态在胰岛素分泌以及糖尿病和噻唑烷二酮（TZDs）代谢反应中的β细胞功能障碍中起着关键作用，TZDs 是一种抗糖尿病药物。ATP 结合盒转运蛋白 G1（ABCG1）已被证明在胆固醇外排中发挥作用，但它在β细胞中的作用尚不清楚。在其他细胞类型中，ABCG1 的表达在糖尿病中下调，在 TZDs 中上调。在这里，我们证明了 ABCG1 在β细胞中的细胞内作用。ABCG1 表达缺失会损害体内和体外的胰岛素分泌，但对细胞内胆固醇含量或外排没有影响。亚细胞定位研究表明，ABCG1 蛋白的大部分存在于胰岛素颗粒中。ABCG1 缺失会导致颗粒形态改变和颗粒内胆固醇水平降低。外源性胆固醇的给药恢复了 ABCG1 缺陷胰岛的颗粒形态和胆固醇含量，并挽救了胰岛素分泌。这些发现表明，ABCG1 主要作用是调节小鼠β细胞内的细胞内胆固醇分布。此外，糖尿病小鼠胰岛中的 ABCG1 表达减少，TZDs 可使其恢复，这表明调节胰岛 ABCG1 表达在糖尿病发病机制和治疗中起作用。
