Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, 950 West 28th Ave, Vancouver, BC, Canada V5Z 4H4.
Diabetologia. 2010 Jun;53(6):1110-9. doi: 10.1007/s00125-010-1691-2. Epub 2010 Mar 13.
AIMS/HYPOTHESIS: Cellular cholesterol accumulation is an emerging mechanism for beta cell dysfunction in type 2 diabetes. Absence of the cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) results in increased islet cholesterol and impaired insulin secretion, indicating that impaired cholesterol efflux leads to beta cell dysfunction. In this study, we aimed to determine the role of the LDL receptor (LDLr) in islet cholesterol uptake and to assess the contributions of cholesterol uptake compared with efflux to islet cholesterol levels.
Islet cholesterol and beta cell function were assessed in mice lacking LDLr (Ldlr(-/-)), or apolipoprotein E (Apoe(-/-)), as well as in mice with beta-cell-specific deficiency of Abca1 crossed to Ldlr(-/-) mice.
Hypercholesterolaemia resulted in increased islet cholesterol levels and decreased beta cell function in Apoe(-/-) mice but not in Ldlr(-/-) mice, suggesting that the LDL receptor is required for cholesterol uptake leading to cholesterol-induced beta cell dysfunction. Interestingly, when wild-type islets with functional LDL receptors were transplanted into diabetic, hypercholesterolaemic mice, islet graft function was normal compared with Ldlr(-/-) islets, suggesting that compensatory mechanisms can maintain islet cholesterol homeostasis in a hypercholesterolaemic environment. Indeed, transplanted wild-type islets had increased Abca1 expression. However, lack of the Ldlr did not protect Abca1(-/-) mice from islet cholesterol accumulation, suggesting that cholesterol efflux is the critical regulator of cholesterol levels in islets.
CONCLUSIONS/INTERPRETATION: Our data indicate that islet cholesterol levels and beta cell function are strongly influenced by LDLr-mediated uptake of cholesterol into beta cells. Cholesterol efflux mediated by ABCA1, however, can compensate in hypercholesterolaemia to regulate islet cholesterol levels in vivo.
目的/假设：细胞胆固醇积累是 2 型糖尿病中β细胞功能障碍的一个新出现的机制。胆固醇转运体 ATP 结合盒转运体 A1（ABCA1）的缺失导致胰岛胆固醇增加和胰岛素分泌受损，表明胆固醇外排受损导致β细胞功能障碍。在这项研究中，我们旨在确定 LDL 受体（LDLr）在胰岛胆固醇摄取中的作用，并评估与外排相比胆固醇摄取对胰岛胆固醇水平的贡献。
在缺乏 LDLr（Ldlr(-/-)）或载脂蛋白 E（Apoe(-/-)）的小鼠中评估胰岛胆固醇和β细胞功能，以及在与 Ldlr(-/-)小鼠交叉的β细胞特异性缺乏 Abca1 的小鼠中评估。
高胆固醇血症导致 Apoe(-/-)小鼠胰岛胆固醇水平升高和β细胞功能下降，但在 Ldlr(-/-)小鼠中则不然，这表明 LDL 受体是导致胆固醇诱导的β细胞功能障碍的胆固醇摄取所必需的。有趣的是，当具有功能性 LDL 受体的野生型胰岛被移植到糖尿病、高胆固醇血症的小鼠中时，与 Ldlr(-/-)胰岛相比，胰岛移植物功能正常，这表明补偿机制可以维持高胆固醇血症环境中的胰岛胆固醇稳态。事实上，移植的野生型胰岛表达增加了 Abca1。然而，缺乏 Ldlr 并不能保护 Abca1(-/-)小鼠免受胰岛胆固醇积累，这表明胆固醇外排是调节胰岛胆固醇水平的关键调节剂。
结论/解释：我们的数据表明，LDLr 介导的胆固醇进入β细胞摄取强烈影响胰岛胆固醇水平和β细胞功能。然而，ABCA1 介导的胆固醇外排可以在高胆固醇血症中代偿，以调节体内胰岛胆固醇水平。
