Sirtuin-3 (SIRT3) protects pancreatic β-cells from endoplasmic reticulum (ER) stress-induced apoptosis and dysfunction

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• 作者：Hao-Hao Zhang ; Xiao-Jun Ma ; Li-Na Wu ; Yan-Yan Zhao…
• 刊名：Molecular and Cellular Biochemistry
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：420
• 期：1-2
• 页码：95-106
• 全文大小：2,771 KB
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Biochemistry
  Medical Biochemistry
  Oncology
  Cardiology
  
• 出版者：Springer Netherlands
• ISSN：1573-4919
• 卷排序：420

文摘

Insufficient insulin produced by pancreatic β-cells in the control of blood sugar is a central feature of the etiology of diabetes. Reports have shown that endoplasmic reticulum (ER) stress is fundamentally involved in β-cell dysfunction. In this study, we hypothesized that NAD-dependent deacetylase sirtuin-3 (SIRT3), an important regulator of cell metabolism, protects pancreatic β-cells from ER stress-mediated apoptosis. To validate our hypothesis, a rat diabetic model was established by a high-fat diet (HFD). We found that SIRT3 expression was markedly decreased in NIT1 and INS1 cells incubated with palmitate. Palmitate treatment significantly decreased β-cell viability and insulin secretion, and promoted malondialdehyde (MDA) formation. However, SIRT3 overexpression in NIT1 and INS1 cells reversed these effects, resulting in higher insulin secretion, decreased β-cell apoptosis, and downregulation of the expression of ER stress-associated genes. Moreover, SIRT3 overexpression also inhibited calcium influx and the hyperacetylation of glucose-regulated protein of 78 kDa (GRP78). SIRT3 knockdown effectively enhanced the upregulation of phospho-extracellular regulated protein kinases (pERK), inositol-requiring enzyme-1 (IRE1), activating transcription factor 6 (ATF6), and C/EBP homologous protein (CHOP) induced by palmitate, and promoted palmitate-induced β-cell apoptosis and dysfunction. Taken together, our results suggest that SIRT3 is an integral regulator of ER function and that its depletion might result in the hyperacetylation of critical ER proteins that protect against islet lipotoxicity under conditions of nutrient excess.KeywordsSirtuin-3Pancreatic β-cellsEndoplasmic reticulum stressAcetylationApoptosis