Dysregulation of lipid homeostasis is intimately associated with defects in insulin secretion, a key feature of type 2 diabetes. Here, we explore the role of the putative lipid transporter ABCA12 in regulating insulin secretion from β-cells. Mice with β-cell-specific deletion of Abca12 display impaired glucose-stimulated insulin secretion and eventual islet inflammation and β-cell death. ABCA12's action in the pancreas is independent of changes in the abundance of two other cholesterol transporters, ABCA1 and ABCG1, or of changes in cellular cholesterol or ceramide content. Instead, loss of ABCA12 results in defects in the genesis and fusion of insulin secretory granules and increases in the abundance of lipid rafts at the cell membrane. These changes are associated with dysregulation of the small GTPase CDC42 and with decreased actin polymerisation. Our findings establish a new, pleiotropic role for ABCA12 in regulating pancreatic lipid homeostasis and insulin secretion.

中文翻译：

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ABCA12 调节 β 细胞的胰岛素分泌。

脂质体内平衡失调与胰岛素分泌缺陷密切相关，胰岛素分泌缺陷是 2 型糖尿病的一个关键特征。在这里，我们探讨了假定的脂质转运蛋白 ABCA12 在调节 β 细胞分泌胰岛素中的作用。具有 β 细胞特异性 Abca12 缺失的小鼠表现出葡萄糖刺激的胰岛素分泌受损以及最终的胰岛炎症和 β 细胞死亡。ABCA12 在胰腺中的作用与其他两种胆固醇转运蛋白 ABCA1 和 ABCG1 的丰度变化或细胞胆固醇或神经酰胺含量的变化无关。相反，ABCA12 的缺失会导致胰岛素分泌颗粒的生成和融合出现缺陷，并增加细胞膜上脂筏的丰度。这些变化与小 GTPase CDC42 的失调和肌动蛋白聚合减少有关。我们的研究结果确立了 ABCA12 在调节胰腺脂质稳态和胰岛素分泌中的新的多效性作用。