Inhibition of Histone Deacetylase 3 Protects Beta Cells from Cytokine-Induced Apoptosis

Chou, Danny Hung‐Chieh; Holson, Edward B.; Wagner, Florence F.; Tang, Alicia J.; Maglathlin, Rebecca L.; Lewis, Timothy A.; Schreiber, Stuart L.; Wagner, Bridget K.

doi:10.1016/j.chembiol.2012.05.010

Cited by 88 publications

(69 citation statements)

References 15 publications

(19 reference statements)

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“…Inhibition of HDACs has also been shown to have important functions in preventing β -cell inflammatory damage, improving insulin resistance, promoting β -cell development, proliferation, differentiation and function, and positively having an impact on late diabetic microvascular complications [121]. Both pharmacological and genetic inhibition of HDAC3 has been shown to protect β -cells against cytokine-induced apoptosis and restores glucose-stimulated insulin secretion [128]. In addition, oral administration of ITF2357, a class I and II HDACI, improved islet function, reduced iNOS (inducible NOS) levels and apoptosis [129].…”

Section: Hdacs and Metabolic Disordersmentioning

confidence: 99%

Histone deacetylases as targets for treatment of multiple diseases

2013

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HDACs (histone deacetylases) are a group of enzymes that deacetylate histones as well as non-histone proteins. They are known as modulators of gene transcription and are associated with proliferation and differentiation of a variety of cell types and the pathogenesis of some diseases. Recently, HDACs have come to be considered crucial targets in various diseases, including cancer, interstitial fibrosis, autoimmune and inflammatory diseases, and metabolic disorders. Pharmacological inhibitors of HDACs have been used or tested to treat those diseases. In the present review, we will examine the application of HDAC inhibitors in a variety of diseases with the focus on their effects of anti-cancer, fibrosis, anti-inflammatory, immunomodulatory activity and regulating metabolic disorders.

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Section: Hdacs and Metabolic Disordersmentioning

confidence: 99%

Histone deacetylases as targets for treatment of multiple diseases

2013

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“…Class I HDACs are ubiquitously expressed and have been implicated in regulation of metabolic gene signatures [7]. In the past several years, multiple studies of siRNA knockdown and pharmacological inhibition of HDAC3 have suggested a role for HDAC3 in β-cells, with loss of HDAC3 function protecting β-cells from cytokine-induced apoptosis and helping to maintain proper glucose-stimulated insulin secretion [8], [9], [10], [11], [12]. Furthermore, an HDAC3-specific inhibitor was reported to improve glucose homeostasis and insulin secretion in a diabetic rat model [11].…”

Section: Introductionmentioning

confidence: 99%

Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion

Remsberg

Ediger

et al. 2017

Molecular Metabolism

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ObjectiveHistone deacetylases are epigenetic regulators known to control gene transcription in various tissues. A member of this family, histone deacetylase 3 (HDAC3), has been shown to regulate metabolic genes. Cell culture studies with HDAC-specific inhibitors and siRNA suggest that HDAC3 plays a role in pancreatic β-cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in β-cells of adult mice.MethodsAn HDAC3 β-cell specific knockout was generated in adult MIP-CreERT transgenic mice using the Cre-loxP system. Induction of HDAC3 deletion was initiated at 8 weeks of age with administration of tamoxifen in corn oil (2 mg/day for 5 days). Mice were assayed for glucose tolerance, glucose-stimulated insulin secretion, and islet function 2 weeks after induction of the knockout. Transcriptional functions of HDAC3 were assessed by ChIP-seq as well as RNA-seq comparing control and β-cell knockout islets.ResultsHDAC3 β-cell specific knockout (HDAC3βKO) did not increase total pancreatic insulin content or β-cell mass. However, HDAC3βKO mice demonstrated markedly improved glucose tolerance. This improved glucose metabolism coincided with increased basal and glucose-stimulated insulin secretion in vivo as well as in isolated islets. Cistromic and transcriptomic analyses of pancreatic islets revealed that HDAC3 regulates multiple genes that contribute to glucose-stimulated insulin secretion.ConclusionsHDAC3 plays an important role in regulating insulin secretion in vivo, and therapeutic intervention may improve glucose homeostasis.

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“…[29][30][31][32][33][34][35] CI-994 has also been pursued as a treatment for neurodegenerative diseases and for diseases outside of the brain. 36,37 For example, it was recently reported that CI-994 inhibition of HDACs may have potential as for the treatment of memory/cognition and anxiety disorders (Tsai, et al submitted) CI-994 is a class I HDACs inhibitor, selective for HDAC1, 2 and 3 with varying potency. 39 Thus, a tritium-labeled version could provide a map of HDAC1-3 and be used to associate this class with disease, to develop class B max of 13.6 picomol·mg −1 protein and K d 9.6 nM.…”

Section: Resultsmentioning

confidence: 99%