Activation of SIRT1 protects pancreatic ¦Â-cells against palmitate-induced dysfunction

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• 作者：Ling Wu ; Libin Zhou ; Yan Lu ; Juan Zhang ; Fangfang Jian ; Yun Liu ; Fengying Li ; Wenyi Li ; Xiao Wang ; Guo Li
• 关键词：FFA ; free fatty acid ; PDX1 ; pancreatic and duodenal homeobox 1 ; GSIS ; glucose-stimulated insulin secretion ; JNK ; Jun N-terminal kinase ; SIRT1 ; sirtuin 1 ; PGC-1 ; peroxisome proliferator-activated receptor gamma coactivator 1 ; NeuroD ; neurogenic differentia
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：2012
• 出版时间：November, 2012
• 年：2012
• 卷：1822
• 期：11
• 页码：1815-1825
• 全文大小：1335 K

文摘

Sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide-dependent histone deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. In pancreatic ¦Â-cells, SIRT1 has been shown to up-regulate insulin secretion in response to glucose stimulation. However, the potential roles of SIRT1 in islet ¦Â-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 ¦Ìmol/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 ¦Â-cell dysfunction.