An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic β cells
An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic β cells
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DOI：
10.1172/jci41280
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发表时间：
2010-07-01
影响因子：
15.9
通讯作者：
Hedrick, Catherine C.
中科院分区：
文献类型：
--
作者：
Sturek, Jeffrey M.;Castle, J. David;Hedrick, Catherine C.
胆固醇是细胞膜的重要组成部分，并且细胞胆固醇水平和分布在哺乳动物中受到严格调节。最近的证据已经揭示了胰腺β细胞特异性胆固醇稳态在胰岛素分泌以及糖尿病中的β细胞功能障碍和对噻唑烷二酮（TZD）（其为抗糖尿病药物）的代谢应答中的关键作用。ATP结合盒转运蛋白G1（ABCG 1）已被证明在胆固醇流出中发挥作用，但其在β细胞中的作用目前尚不清楚。在其他细胞类型中，ABCG1表达在糖尿病中下调，并被TZD上调。在这里，我们已经证明了ABCG 1在β细胞中的细胞内作用。ABCG1表达的丧失在体内和体外均损害胰岛素分泌，但对细胞胆固醇含量或外排没有影响。亚细胞定位研究表明，ABCG 1蛋白的大部分存在于胰岛素颗粒中。ABCG1的缺失导致颗粒形态改变和颗粒胆固醇水平降低。外源性胆固醇的管理恢复颗粒形态和胆固醇含量和挽救ABCG 1缺陷胰岛的胰岛素分泌。这些发现表明，ABCG 1主要用于调节小鼠β细胞中的亚细胞胆固醇分布。此外，糖尿病小鼠胰岛ABCG 1表达降低，并通过TZDs恢复，暗示胰岛ABCG 1表达的调节在糖尿病发病机制和治疗中的作用。
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.