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

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Abstract

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.

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Abbreviations

SIRT3:

Sirtuin-3

HFD:

High-fat diet

ER:

Endoplasmic reticulum

GRP78:

Glucose-regulated protein of 78 kDa

T1D:

Type 1 diabetes

T2D:

Type 2 diabetes

GD:

Gestational diabetes

UPR:

Unfolded protein response

MDA:

Malondialdehyde

TBA:

Thiobarbituric acid

CHOP, C/EBP:

Homologous protein

GSIS:

Glucose-stimulated insulin secretion

IRE1:

Inositol-requiring enzyme-1

ATF6:

Activating transcription factor 6

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Acknowledgments

This work was supported by National Natural Science Foundation of China (81300656). This work was also supported by National Natural Science Foundation of China grant (81300685).

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Authors and Affiliations

  1. Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, 40 Daxue Road, Zhengzhou, 450052, China

    Hao-Hao Zhang, Xiao-Jun Ma, Li-Na Wu, Yan-Yan Zhao, Peng-Yu Zhang, Ying-Hui Zhang, Ming-Wei Shao, Fei Liu & Gui-Jun Qin

  2. Division of Vasculitis, Guancheng Traditional Chinese Medical Hospital, Shangdu Road, Zhengzhou, 450016, China

    Fei Li

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  1. Hao-Hao Zhang
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Correspondence to Gui-Jun Qin.

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Zhang, HH., Ma, XJ., Wu, LN. et al. Sirtuin-3 (SIRT3) protects pancreatic β-cells from endoplasmic reticulum (ER) stress-induced apoptosis and dysfunction. Mol Cell Biochem 420, 95–106 (2016). https://doi.org/10.1007/s11010-016-2771-5

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