title: Activation of SIRT1 protects pancreatic β-cells against palmitate-induced dysfunction.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ling
authors.initials: L
authors.lastname: Wu
authors.forename: Libin
authors.initials: L
authors.lastname: Zhou
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: Fangfang
authors.initials: F
authors.lastname: Jian
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Fengying
authors.initials: F
authors.lastname: Li
authors.forename: Wenyi
authors.initials: W
authors.lastname: Li
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: Guo
authors.initials: G
authors.lastname: Li
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D037181:Lectins, C-Type / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D000071161:Forkhead Box Protein O1
chemical_list: D002227:Carbazoles; D051858:Forkhead Transcription Factors; D005947:Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D010168:Palmitates; D000077185:Resveratrol; D056564:Sirtuin 1; D013267:Stilbenes; D015534:Trans-Activators; C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; C094696:Klrg1 protein, rat; C491327:Nkx6-1 protein, rat; C084010:pancreatic and duodenal homeobox 1 protein; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C488368:Sirt1 protein, rat