Wu Ling, Zhou Libin, Lu Yan, Zhang Juan, Jian Fangfang, Liu Yun, Li Fengying, Li Wenyi, Wang Xiao, Li Guo
Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Biochim Biophys Acta. 2012 Nov;1822(11):1815-25. doi: 10.1016/j.bbadis.2012.08.009. Epub 2012 Aug 19.
Sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide-dependent histone deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. In pancreatic β-cells, SIRT1 has been shown to up-regulate insulin secretion in response to glucose stimulation. However, the potential roles of SIRT1 in islet β-cells against lipotoxicity remain poorly understood. Here, we demonstrated that SIRT1 mRNA and protein expressions were markedly reduced in the islets isolated from rats infused with 20% Intralipid for 24h. Long-term exposure to 0.4mmol/L palmitate also decreased SIRT1 expression in cultured INS-1 cells and isolated rat islets, which was prevented by 10μmol/L resveratrol, a SIRT1 agonist. In addition, resveratrol improved glucose-stimulated insulin secretion decreased by palmitate, which was abrogated by EX527, a specific SIRT1 inhibitor. Furthermore, inhibition of SIRT1 activity by EX527 or a knockdown of SIRT1 suppressed insulin promoter activity, along with decreased insulin, v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), and NK6 homeodomain 1 (NKX6.1) mRNA expressions. Activation of SIRT1 by resveratrol or overexpression of SIRT1 antagonized palmitate-inhibited insulin transcriptional activity. SIRT1 overexpression exerted an additive effect on pancreatic and duodenal homeobox 1 (PDX1)-stimulated insulin promoter activity and abolished forkhead box O1 protein (FOXO1)-decreased insulin transcriptional activity. Resveratrol reversed FOXO1 nuclear translocation induced by palmitate. Our findings indicate that SIRT1 protects against palmitate-induced β-cell dysfunction.
沉默调节蛋白1（SIRT1）是一种烟酰胺腺嘌呤二核苷酸依赖性组蛋白脱乙酰酶，是响应营养物质可利用性时能量稳态的重要调节因子。在胰腺β细胞中，SIRT1已被证明可响应葡萄糖刺激上调胰岛素分泌。然而，SIRT1在胰岛β细胞抵抗脂毒性方面的潜在作用仍知之甚少。在此，我们证明，从输注20%脂肪乳24小时的大鼠分离的胰岛中，SIRT1 mRNA和蛋白表达显著降低。长期暴露于0.4mmol/L棕榈酸酯也会降低培养的INS-1细胞和分离的大鼠胰岛中SIRT1的表达，而10μmol/L白藜芦醇（一种SIRT1激动剂）可预防这种情况。此外，白藜芦醇改善了棕榈酸酯降低的葡萄糖刺激的胰岛素分泌，而特异性SIRT1抑制剂EX527可消除这种作用。此外，EX527抑制SIRT1活性或敲低SIRT1会抑制胰岛素启动子活性，同时降低胰岛素、v-maf肌腱膜纤维肉瘤癌基因同源物A（MafA）和NK6同源异型盒1（NKX6.1）mRNA的表达。白藜芦醇激活SIRT1或过表达SIRT1可拮抗棕榈酸酯抑制的胰岛素转录活性。SIRT1过表达对胰腺和十二指肠同源盒1（PDX1）刺激的胰岛素启动子活性具有累加效应，并消除叉头框O1蛋白（FOXO1）降低的胰岛素转录活性。白藜芦醇逆转了棕榈酸酯诱导的FOXO1核转位。我们的研究结果表明，SIRT1可保护细胞免受棕榈酸酯诱导的β细胞功能障碍。
