Loss of both ABCA1 and ABCG1 results in increased disturbances in islet sterol homeostasis, inflammation, and impaired β-cell function.
Loss of both ABCA1 and ABCG1 results in increased disturbances in islet sterol homeostasis, inflammation, and impaired β-cell function.
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作者：
Kruit JK;Wijesekara N;Westwell-Roper C;Vanmierlo T;de Haan W;Bhattacharjee A;Tang R;Wellington CL;LütJohann D;Johnson JD;Brunham LR;Verchere CB;Hayden MR
细胞胆固醇稳态对于正常β细胞功能是重要的。由于ATP结合盒（ABC）转运蛋白ABCA 1功能降低而导致胆固醇转运中断，导致胰岛素分泌受损。缺乏β细胞ABCA 1的小鼠具有增加的ABCG 1的胰岛表达，ABCG 1是另一种与β细胞功能有关的胆固醇转运蛋白。为了确定ABCA 1和ABCG 1在β细胞中是否具有互补作用，产生缺乏ABCG 1和β细胞ABCA 1的小鼠，并评估葡萄糖耐量、胰岛固醇水平和β细胞功能。与单独β细胞中ABCG 1缺失或ABCA 1缺失相比，ABCG 1和β细胞ABCA 1两者的缺乏导致空腹血糖水平升高和葡萄糖耐量更大的损害。此外，葡萄糖刺激的胰岛素分泌减少，甾醇积累增加，胰岛缺乏两个转运蛋白相比，那些单独从敲除小鼠与每个基因。ABCA 1和ABCG 1的联合缺乏也导致显著的胰岛炎症，如白细胞介素-1 β表达增加和巨噬细胞浸润所示。因此，ABCA 1和ABCG 1两者的缺乏比任一转运蛋白单独缺乏诱导更大的β细胞功能缺陷。这些数据表明，ABCA 1和ABCG 1各自通过维持体内胰岛胆固醇稳态对β细胞功能做出互补和重要的贡献。
Cellular cholesterol homeostasis is important for normal β-cell function. Disruption of cholesterol transport by decreased function of the ATP-binding cassette (ABC) transporter ABCA1 results in impaired insulin secretion. Mice lacking β-cell ABCA1 have increased islet expression of ABCG1, another cholesterol transporter implicated in β-cell function. To determine whether ABCA1 and ABCG1 have complementary roles in β-cells, mice lacking ABCG1 and β-cell ABCA1 were generated and glucose tolerance, islet sterol levels, and β-cell function were assessed. Lack of both ABCG1 and β-cell ABCA1 resulted in increased fasting glucose levels and a greater impairment in glucose tolerance compared with either ABCG1 deletion or loss of ABCA1 in β-cells alone. In addition, glucose-stimulated insulin secretion was decreased and sterol accumulation increased in islets lacking both transporters compared with those isolated from knockout mice with each gene alone. Combined deficiency of ABCA1 and ABCG1 also resulted in significant islet inflammation as indicated by increased expression of interleukin-1β and macrophage infiltration. Thus, lack of both ABCA1 and ABCG1 induces greater defects in β-cell function than deficiency of either transporter individually. These data suggest that ABCA1 and ABCG1 each make complimentary and important contributions to β-cell function by maintaining islet cholesterol homeostasis in vivo.
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