Activation of SIRT1 protects pancreatic β-cells against palmitate-induced dysfunction

作者：Wu, Ling; Zhou, Libin; Lu, Yan; Zhang, Juan; Jian, Fangfang; Liu, Yun; Li, Fengying; Li, Wenyi; Wang, Xiao^*; Li, Guo

来源：Biochimica et Biophysica Acta-Molecular Basis of Disease, 2012, 1822(11): 1815-1825.

DOI：10.1016/j.bbadis.2012.08.009

• SIRT1
• Palmitate
• beta-cell
• Lipotoxicity
• Insulin transcription

Sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide-dependent histone deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. In pancreatic beta-cells, SIRT1 has been shown to up-regulate insulin secretion in response to glucose stimulation. However, the potential roles of SIRT1 in islet beta-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 24 h. Long-term exposure to 0.4 mmol/L palmitate also decreased SIRT1 expression in cultured INS-1 cells and isolated rat islets, which was prevented by 10 mu mol/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 01 protein (FOXO1)-decreased insulin transcriptional activity. Resveratrol reversed FOXO1 nuclear translocation induced by palmitate. Our findings indicate that SIRT1 protects against palmitate-induced beta-cell dysfunction.

• 出版日期2012-11
• 单位上海市闵行区中心医院; 上海交通大学