Oncotarget

Research Perspective: Pathology:

Conditional ablation of HDAC3 in islet beta cells results in glucose intolerance and enhanced susceptibility to STZ-induced diabetes

Wen-Bin Chen, Ling Gao, Jie Wang, Yan-Gang Wang, Zheng Dong, Jiajun Zhao, Qing-Sheng Mi and Li Zhou _

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Oncotarget. 2016; 7:57485-57497. https://doi.org/10.18632/oncotarget.11295

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Abstract

Wen-Bin Chen1,2,3, Ling Gao2, Jie Wang1,3,4, Yan-Gang Wang4, Zheng Dong5, Jiajun Zhao6, Qing-Sheng Mi1,3,7 and Li Zhou1,3,7

1 Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI, USA

2 Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China

3 Department of Dermatology, Henry Ford Health System, Detroit, MI, USA

4 Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, China

5 Department of Cellular Biology and Anatomy, Augusta University, GA, USA

6 Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China

7 Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA

Correspondence to:

Qing-Sheng Mi, email:

Jiajun Zhao, email:

Li Zhou, email:

Keywords: HDAC3; knockout; autoimmune diabetes; glucose tolerance; insulin; Pathology Section

Received: April 15, 2016 Accepted: August 10, 2016 Published: August 15, 2016

Abstract

Histone deacetylases (HDACs) are enzymes that regulate gene expression by modifying chromatin structure through removal of acetyl groups from target histones or non-histone proteins. Previous in vitro studies suggest that HDACs may be novel pharmacological targets in immune-mediated islet β-cell destruction. However, the role of specific HDAC in islet β-cell development and function remain unclear. Here, we generated a conditional islet β-cells specific HDAC3 deletion mouse model to determine the consequences of HDAC3 depletion on islet β-cell differentiation, maintenance and function. Islet morphology, insulin secretion, glucose tolerance, and multiple low-dose streptozotocin (STZ)-induced diabetes incidence were evaluated and compared between HDAC3 knockout and wild type littermate controls. Mice with β-cell-specific HDAC3 deletion displayed decreased pancreatic insulin content, disrupted glucose-stimulated insulin secretion, with intermittent spontaneous diabetes and dramatically enhanced susceptibility to STZ-induced diabetes. Furthermore, islet β-cell line, MIN6 cells with siRNA-mediated HDAC3 silence, showed decreased insulin gene transcription, which was mediated, at least partially, through the upregulation of suppressors of cytokine signaling 3 (SOCS3). These results indicate the critical role of HDAC3 in normal β-cell differentiation, maintenance and function.


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