Conditional ablation of HDAC3 in islet beta cells results in glucose intolerance and enhanced susceptibility to STZ-induced diabetes
Chen WB, Gao L, Wang J, Wang YG, Dong Z, Zhao J, Mi QS, Zhou L. Conditional ablation of HDAC3 in islet beta cells results in glucose intolerance and enhanced susceptibility to STZ-induced diabetes. Oncotarget. 2016 Sep 6;7(36):57485-57497.
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.
Medical Subject Headings
Animals; Cell Line; Diabetes Mellitus, Experimental; Female; Gene Deletion; Glucose Intolerance; Glucose Tolerance Test; Histone Deacetylases; Insulin; Insulin Secretion; Islets of Langerhans; Male; Mice; Mice, Knockout; Microscopy, Fluorescence; Pancreas; RNA Interference; RNA, Small Interfering; Streptozocin