Histone Deacetylase HDAC8 and Insulin Resistance

  • Vincent Wai-Sun Wong
  • Myth Tsz-Shun Mok
  • Alfred Sze-Lok ChengEmail author
Reference work entry


Insulin resistance is a pathological condition contributed by both genetic and environmental factors. In normal individuals, insulin functions to signal the liver, muscles, and adipose tissues to maintain blood glucose within physiological levels. When insulin resistance occurs, glucose accumulates in blood and contributes to the development of type 2 diabetes. At molecular level, the changes of metabolites in blood and different organs can be detected by cells, wherein proteins like histone deacetylases (HDACs) can respond by epigenetically modifying the gene expression in related metabolic pathways. The functions of HDACs are diverse, which are facilitated by their mobility among cellular compartments for targeting both nuclear and cytoplasmic protein substrates. Overexpression of HDACs is mostly pathogenic, which can disrupt insulin turnover and glucose homeostasis through different mechanisms in multiple organs. In the case of HDAC8, systemic obesity causes the activation of sterol regulatory element-binding protein-1 (SREBP-1) that binds to and upregulates HDAC8. Such augmented HDAC8 drives the expression of WNT signaling components and cooperates with enhancer of zeste homolog 2 (EZH2) to transcriptionally silence WNT antagonist genes. These effects and other molecular signaling changes promote glucose accumulation, insulin resistance, and development of other fatty liver-associated diseases and hepatocellular carcinoma. Given the consistent pathogenic effects of HDACs in different diseases, a large collection of HDAC inhibitors have been developed as novel therapeutic drugs, and some of which have demonstrated promising clinical effects in certain diseases despite side effects and durability concerns. These issues are expected to be addressed with the continual improvements of HDAC inhibitors. In particular, optimization of HDAC8 inhibitors holds great therapeutic potential owing to the unique targetable structure in HDAC8 compared with other HDAC isoforms.


Diabetes mellitus Glucose homeostasis Glycogenolysis Gluconeogenesis HDAC8 Hepatocellular carcinoma Histone deacetylase Hyperglycemia Insulin resistance Nonalcoholic fatty liver disease Obesity Pathogenesis Therapeutics 

List of Abbreviations


Adult T-cell leukemia


AKT serine/threonine kinase 1


AT-rich interactive domain-containing protein 1A


Cyclin D1


Cornelia de Lange syndrome


Casein kinase-2


C-reactive protein


Dachshund family transcription factor 1

(EIF2AK3, or PERK)

Eukaryotic translation initiation factor 2 alpha kinase 3


Estrogen receptor-α


Enhancer of zeste homolog 2


Fatty acid synthase


Fibroblast growth factor 23


Glucose transporter type 4


Glucocorticoid receptor


Histone 3 lysine 27 trimethylation


Histone 4 deacetylation


Histone acetyltransferases


Glycated hemoglobin


Histone deacetylase


Human ever-shorter telomeres 1B


High-fat diet


Heat shock protein 90


Half maximal inhibitory concentration




Insulin receptor stimulator-1


Liver X receptor-α


Mitogen-activated protein kinase


Nonalcoholic fatty liver disease


Nipped-B-like protein


Nuclear receptor coactivator 3


Naked cuticle homolog 1


Poly(ADP-ribose) polymerases


Phosphoinositide 3-kinase


Protein kinase A


Protein kinase G


Protein phosphatase 2 regulatory subunit B beta


Prickle planar cell polarity protein 1


Retinoic acid induced 1


Suberoylanilide hydroxamic acid


Structural maintenance of chromosomes 1A


Structural maintenance of chromosome 3


Sterol regulatory element-binding protein-1

(T2R13, or TRB3)

Taste 2 receptor member 13


Thyroid hormone receptor-associated protein 3


Tumor necrosis factor-alpha


Zinc finger RANBP2-type containing 2



This study is supported by the Collaborative Research Fund (C4017-14G) and the General Research Fund (14102914, 14108916, 14120816) of the Research Grants Council of Hong Kong, National Natural Science Foundation of China (81272305, 81302167), and Focused Investments Scheme B (1907309) of the Chinese University of Hong Kong.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Vincent Wai-Sun Wong
    • 1
  • Myth Tsz-Shun Mok
    • 2
  • Alfred Sze-Lok Cheng
    • 2
    Email author
  1. 1.Department of Medicine and TherapeuticsThe Chinese University of Hong KongShatinHong Kong
  2. 2.School of Biomedical SciencesThe Chinese University of Hong KongShatinHong Kong

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