A novel histone deacetylase inhibitor prevents IL‐1β induced metabolic dysfunction in pancreatic β‐cells

Abstract

The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) has recently been shown to inhibit deleterious effects of cytokines on β‐cells, but it is unable to protect β‐cells from death due to its own cytotoxicity. Herein, we investigated novel HDAC inhibitors for their cytoprotective effects against IL‐1β‐induced damage to isolated β‐cells. We report that three novel compounds (THS‐73–44, THS‐72–5 and THS‐78–5) significantly inhibited HDAC activity and increased the acetylation of histone H4 in isolated β‐cells. Further, these compounds exerted no toxic effects on metabolic cell viability in these cells. However, among the three compounds tested, only THS‐78–5 protected against IL‐1β‐mediated loss in β‐cell viability. THS‐78–5 was also able to attenuate IL‐1β‐induced inducible nitric oxide synthase expression and subsequent NO release. Our data also indicate that the cytoprotective properties of THS‐78–5 against IL‐1β‐mediated effects may, in part, be due to inhibition of IL‐1β‐induced transactivation of nuclear factor κB (NF‐κB) in these cells. Together, we provide evidence for a novel HDAC inhibitor with a significant potential to prevent IL‐1β‐mediated effects on isolated β‐cells. Potential implications of these findings in the development of novel therapeutics to prevent deleterious effects of cytokines and the onset of autoimmune diabetes are discussed.

Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines

“…We recently reported that the KDAC inhibitors SAHA and trichostatin A markedly reduced cytokine-induced beta cell functional failure and death in vitro, a finding confirmed by others [12,25,42]. Here we show that ITF2357 abrogated beta cell toxicity as measured by iNOS levels, nitric oxide formation, cleavage of caspase-3 and apoptosis, and reduced cytokine-mediated suppression of accumulated insulin release, in line with the previous studies.…”

Recent Advances in the Development of Polyamine Analogues as Antitumor Agents

“…These compounds further exerted no toxic effects on metabolic cell viability in these cells. However, among the three compounds tested only 94 protected against IL-1β-mediated loss in β-cell viability 160. Remarkably, compound 94 differs from 96 , which does not protect against this loss in β-cell viability, by a single carbon in the linker chain region.…”

Lysine acetylation in obesity, diabetes and metabolic disease

“…Immune stimuli together with the induction of lipotoxicity induce β‐cell apoptosis and dysfunction in pancreatic islets 49 . KDAC inhibitors promote β‐cell function including development, proliferation and differentiation in animal models of diabetes and insulin resistance 49 , 50 , 51 . In isolated β‐cells, KDAC inhibitors increased the acetylation of histone H4 and inhibited KDAC activity without any toxic responses 50 .…”

“…KDAC inhibitors promote β‐cell function including development, proliferation and differentiation in animal models of diabetes and insulin resistance 49 , 50 , 51 . In isolated β‐cells, KDAC inhibitors increased the acetylation of histone H4 and inhibited KDAC activity without any toxic responses 50 . In IL‐1β induced β‐cell dysfunction, KDAC inhibitors attenuated increased expression of inducible NO synthase and NO release, attributed to preventing IL‐1β activation of NFκB.…”

“…In IL‐1β induced β‐cell dysfunction, KDAC inhibitors attenuated increased expression of inducible NO synthase and NO release, attributed to preventing IL‐1β activation of NFκB. 50 Class III KDACs, the sirtuins, also control pancreatic β‐cell function 52 . Overexpression of SIRT1 in vitro in rat pancreatic β‐cells protected against cytokine‐induced toxicity by preventing NFκB activation 53 .…”