Histone deacetylase inhibitors: Future therapeutics for insulin resistance and type 2 diabetes

Sharma, Saurabh; Taliyan, Rajeev

doi:10.1016/j.phrs.2016.09.009

Cited by 87 publications

(48 citation statements)

References 86 publications

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“…To address this issue, our study showed HDAC3 as a potential, more specific target for WAT browning. Many studies have also concluded HDAC3 as an emerging target for inflammation, insulin-resistance, and type 2 diabetes [31,46,47,48,49,50] which are closely related to obesity. Future study might be directed to the capability of the HDAC3 inhibitor to induce browning of WAT, as our study highly suggested, especially in humans.…”

Section: Discussionmentioning

confidence: 99%

β-adrenergic Receptor Stimulation Revealed a Novel Regulatory Pathway via Suppressing Histone Deacetylase 3 to Induce Uncoupling Protein 1 Expression in Mice Beige Adipocyte

Yuliana

Jheng

Kawarasaki

et al. 2018

IJMS

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Browning of adipose tissue has been prescribed as a potential way to treat obesity, marked by the upregulation of uncoupling protein 1 (Ucp1). Several reports have suggested that histone deacetylase (HDAC) might regulate Ucp1 by remodelling chromatin structure, although the mechanism remains unclear. Herein, we investigate the effect of β-adrenergic receptor (β-AR) activation on the chromatin state of beige adipocyte. β-AR-stimulated Ucp1 expression via cold (in vivo) and isoproterenol (in vitro) resulted in acetylation of histone activation mark H3K27. H3K27 acetylation was also seen within Ucp1 promoter upon isoproterenol addition, favouring open chromatin for Ucp1 transcriptional activation. This result was found to be associated with the downregulation of class I HDAC mRNA, particularly Hdac3 and Hdac8. Further investigation showed that although HDAC8 activity decreased, Ucp1 expression was not altered when HDAC8 was activated or inhibited. In contrast, HDAC3 mRNA and protein levels were simultaneously downregulated upon isoproterenol addition, resulting in reduced recruitment of HDAC3 to the Ucp1 enhancer region, causing an increased H3K27 acetylation for Ucp1 upregulation. The importance of HDAC3 inhibition was confirmed through the enhanced Ucp1 expression when the cells were treated with HDAC3 inhibitor. This study highlights the novel mechanism of HDAC3-regulated Ucp1 expression during β-AR stimulation.

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Section: Discussionmentioning

confidence: 99%

β-adrenergic Receptor Stimulation Revealed a Novel Regulatory Pathway via Suppressing Histone Deacetylase 3 to Induce Uncoupling Protein 1 Expression in Mice Beige Adipocyte

Yuliana

Jheng

Kawarasaki

et al. 2018

IJMS

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“…Of the 2 classes of HATs, Type‐A HATs, including the CBP/p300 family, modify multiple sites in histone tails and act as transcriptional co‐activators, whereas Type‐B HATs, including HAT1, are cytoplasmic and acetylate newly formed histone proteins, but not those already complexed to DNA . HDACs are divided into 4 classes; class I HDACs, including HDAC 1, 2, 3 and 8, are nucleic, whereas class II HDACs, including HDAC 4, 5, 6, 7, 9 and 10, move between the nucleus and cytoplasm . Class III HDACs, also known as sirtuins, include SIRTs 1 to 7, and are associated with longevity and a decrease in disorders of aging, including T2D .…”

Section: Epigenetic Modificationsmentioning

confidence: 99%

“…8 HDACs are divided into 4 classes; class I HDACs, including HDAC 1, 2, 3 and 8, are nucleic, whereas class II HDACs, including HDAC 4, 5, 6, 7, 9 and 10, move between the nucleus and cytoplasm. 9 Class III HDACs, also known as sirtuins, include SIRTs 1 to 7, and are associated with longevity and a decrease in disorders of aging, including T2D. 10 HDAC11 is the only class IV HDAC, of which little is known.…”

Section: Histone Modificationsmentioning

confidence: 99%

Epigenetic effects of metformin: From molecular mechanisms to clinical implications

Bridgeman

Ellison

Melton

et al. 2018

Diabetes Obesity Metabolism

152

100

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There is a growing body of evidence that links epigenetic modifications to type 2 diabetes. Researchers have more recently investigated effects of commonly used medications, including those prescribed for diabetes, on epigenetic processes. This work reviews the influence of the widely used antidiabetic drug metformin on epigenomics, microRNA levels and subsequent gene expression, and potential clinical implications. Metformin may influence the activity of numerous epigenetic modifying enzymes, mostly by modulating the activation of AMP-activated protein kinase (AMPK). Activated AMPK can phosphorylate numerous substrates, including epigenetic enzymes such as histone acetyltransferases (HATs), class II histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), usually resulting in their inhibition; however, HAT1 activity may be increased. Metformin has also been reported to decrease expression of multiple histone methyltransferases, to increase the activity of the class III HDAC SIRT1 and to decrease the influence of DNMT inhibitors. There is evidence that these alterations influence the epigenome and gene expression, and may contribute to the antidiabetic properties of metformin and, potentially, may protect against cancer, cardiovascular disease, cognitive decline and aging. The expression levels of numerous microRNAs are also reportedly influenced by metformin treatment and may confer antidiabetic and anticancer activities. However, as the reported effects of metformin on epigenetic enzymes act to both increase and decrease histone acetylation, histone and DNA methylation, and gene expression, a significant degree of uncertainty exists concerning the overall effect of metformin on the epigenome, on gene expression, and on the subsequent effect on the health of metformin users.

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“…In China, an additional HDACi known as chidamide (Epidaza®), was approved for treatment of PTCL by the Chinese FDA in 2015. Although most HDACi are approved for cancer type indications, studies have suggested potential roles in schizophrenia [79] and Type2 diabetes [80]. However, similar to the DNMTi drugs, current HDACi have broad effects across the genome and lack locus-specificity.…”

Section: Epigenetic Applications In Personalized Medicinementioning

confidence: 99%

The role of epigenomics in personalized medicine

Kronfol

Dozmorov

Huang

et al. 2017

Expert Review of Precision Medicine and Drug Development

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Introduction Epigenetics is the study of reversible modifications to chromatin and their extensive and profound effects on gene regulation. To date, the role of epigenetics in personalized medicine has been under-explored. Therefore, this review aims to highlight the vast potential that epigenetics holds. Areas covered We first review the cell-specific nature of epigenetic states and how these can vary with developmental stage and in response to environmental factors. We then summarize epigenetic biomarkers of disease, with a focus on diagnostic tests, followed by a detailed description of current and pipeline drugs with epigenetic modes of action. Finally, we discuss epigenetic biomarkers of drug response. Expert commentary Epigenetic variation can yield information on cellular states and developmental histories in ways that genotype information cannot. Furthermore, in contrast to fixed genome sequence, epigenetic patterns are plastic, so correcting aberrant, disease-causing epigenetic marks holds considerable therapeutic promise. While just six epigenetic drugs are currently approved for use in the United States, a larger number is being developed. However, a drawback to current therapeutics is their non-specific effects. Development of locus-specific epigenetic modifiers, used in conjunction with epigenetic biomarkers of response, will enable truly precision interventions.

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Histone deacetylase inhibitors: Future therapeutics for insulin resistance and type 2 diabetes

Cited by 87 publications

References 86 publications

β-adrenergic Receptor Stimulation Revealed a Novel Regulatory Pathway via Suppressing Histone Deacetylase 3 to Induce Uncoupling Protein 1 Expression in Mice Beige Adipocyte

β-adrenergic Receptor Stimulation Revealed a Novel Regulatory Pathway via Suppressing Histone Deacetylase 3 to Induce Uncoupling Protein 1 Expression in Mice Beige Adipocyte

Epigenetic effects of metformin: From molecular mechanisms to clinical implications

The role of epigenomics in personalized medicine

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