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Sirt1通过抑制胰腺β细胞中的UCP2来调节胰岛素分泌。

Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells.

作者信息

Bordone Laura, Motta Maria Carla, Picard Frederic, Robinson Ashley, Jhala Ulupi S, Apfeld Javier, McDonagh Thomas, Lemieux Madeleine, McBurney Michael, Szilvasi Akos, Easlon Erin J, Lin Su-Ju, Guarente Leonard

机构信息

Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

出版信息

PLoS Biol. 2006 Feb;4(2):e31. doi: 10.1371/journal.pbio.0040031. Epub 2005 Dec 27.

DOI:10.1371/journal.pbio.0040031
PMID:16366736
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1318478/
Abstract

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 beta cells. Sirt1 represses the uncoupling protein (UCP) gene UCP2 by binding directly to the UCP2 promoter. In beta 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 beta cells to affect insulin secretion.

摘要

Sir2和胰岛素/胰岛素样生长因子-1是影响低等生物衰老的主要途径。在秀丽隐杆线虫中，已有报道称Sir2与胰岛素/胰岛素样生长因子-1途径之间可能存在遗传联系。在此，我们研究哺乳动物中的这种联系。我们发现，Sirt1正向调节胰腺β细胞中的胰岛素分泌。Sirt1通过直接结合解偶联蛋白（UCP）基因UCP2的启动子来抑制该基因。在通过小干扰RNA降低Sirt1水平的β细胞系中，UCP2水平升高，胰岛素分泌减少。UCP2的上调与葡萄糖刺激后细胞内ATP水平无法升高有关。敲低UCP2可恢复Sirt1水平降低的细胞分泌胰岛素的能力，表明UCP2导致了葡萄糖刺激的胰岛素分泌缺陷。禁食可诱导小鼠胰腺中UCP2的表达，这可能是通过胰腺中烟酰胺腺嘌呤二核苷酸（烟酸的一种衍生物）水平降低以及Sirt1下调来实现的。Sirt1基因敲除小鼠表现出UCP2的组成性高表达。我们的研究结果表明，Sirt1在β细胞中调节UCP2，从而影响胰岛素分泌。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/c2bdbde5d805/pbio.0040031.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/7e5dc87ba062/pbio.0040031.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/e1f0141fe914/pbio.0040031.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/f0f897fca9f5/pbio.0040031.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/4bbcdc4f2368/pbio.0040031.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/a7200815d500/pbio.0040031.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/5efb005964cc/pbio.0040031.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/a2ada78c3c41/pbio.0040031.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/c2bdbde5d805/pbio.0040031.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/7e5dc87ba062/pbio.0040031.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/e1f0141fe914/pbio.0040031.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/f0f897fca9f5/pbio.0040031.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/4bbcdc4f2368/pbio.0040031.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/a7200815d500/pbio.0040031.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/5efb005964cc/pbio.0040031.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/a2ada78c3c41/pbio.0040031.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df8/1363697/c2bdbde5d805/pbio.0040031.g008.jpg

相似文献

[1]
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[10]
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