Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells.
Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells.
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DOI：
10.1371/journal.pbio.0040031
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发表时间：
2006-02
期刊：
影响因子：
9.8
通讯作者：
Guarente L
中科院分区：
文献类型：
--
作者：
Bordone L;Motta MC;Picard F;Robinson A;Jhala US;Apfeld J;McDonagh T;Lemieux M;McBurney M;Szilvasi A;Easlon EJ;Lin SJ;Guarente L
Sir 2和胰岛素/IGF-1是影响低等生物衰老的主要途径。在秀丽隐杆线虫中，已经报道了Sir 2和胰岛素/IGF-1途径之间可能的遗传联系。在这里，我们调查了哺乳动物中的这种联系。我们发现Sirt 1正调控胰腺β细胞的胰岛素分泌。Sirt 1通过直接结合UCP 2启动子来抑制解偶联蛋白（UCP）基因UCP 2。在SiRNA降低Sirt 1的β细胞系中，UCP 2水平升高，胰岛素分泌减弱。UCP 2的上调与葡萄糖刺激后细胞未能增加ATP水平有关。UCP 2的敲除恢复了Sirt 1减少的细胞分泌胰岛素的能力，表明UCP 2导致葡萄糖刺激的胰岛素分泌缺陷。食物剥夺诱导小鼠胰腺中的UCP 2，这可能通过胰腺中NAD（烟酸的衍生物）水平的降低和Sirt 1的下调而发生。Sirt 1基因敲除小鼠表现出组成型高UCP 2表达。我们的研究结果表明，Sirt 1调节β细胞中的UCP 2，从而影响胰岛素分泌。Sirt 1被证明可以调节胰腺β细胞中代谢解耦基因UCP 2的表达，这突出了Sirt 1在协调胰岛素释放以响应不断变化的饮食条件中的可能作用。
Sir2 and insulin/IGF-1 are the major pathways that impinge upon aging in lower organisms. In Caenorhabditis elegans a possible genetic link between Sir2 and the insulin/IGF-1 pathway has been reported. Here we investigate such a link in mammals. We show that Sirt1 positively regulates insulin secretion in pancreatic β cells. Sirt1 represses the uncoupling protein (UCP) gene UCP2 by binding directly to the UCP2 promoter. In β cell lines in which Sirt1 is reduced by SiRNA, UCP2 levels are elevated and insulin secretion is blunted. The up-regulation of UCP2 is associated with a failure of cells to increase ATP levels after glucose stimulation. Knockdown of UCP2 restores the ability to secrete insulin in cells with reduced Sirt1, showing that UCP2 causes the defect in glucose-stimulated insulin secretion. Food deprivation induces UCP2 in mouse pancreas, which may occur via a reduction in NAD (a derivative of niacin) levels in the pancreas and down-regulation of Sirt1. Sirt1 knockout mice display constitutively high UCP2 expression. Our findings show that Sirt1 regulates UCP2 in β cells to affect insulin secretion. Sirt1 is shown to regulate the expression of the metabolic decoupling gene UCP2 in pancreatic β cells, highlighting a possible role for Sirt1 in coordinating insulin release in response to changing dietary conditions.