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Histone Deacetylase HDAC8 and Insulin Resistance

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Book cover Handbook of Nutrition, Diet, and Epigenetics

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Abstract

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.

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Abbreviations

(ALT):

Adult T-cell leukemia

(AKT):

AKT serine/threonine kinase 1

(ARID1A):

AT-rich interactive domain-containing protein 1A

(CCND1):

Cyclin D1

(CdLS):

Cornelia de Lange syndrome

(CK2):

Casein kinase-2

(CRP):

C-reactive protein

(DACH1):

Dachshund family transcription factor 1

(EIF2AK3, or PERK):

Eukaryotic translation initiation factor 2 alpha kinase 3

(ERRα):

Estrogen receptor-α

(EZH2):

Enhancer of zeste homolog 2

(FAS):

Fatty acid synthase

(FGF23):

Fibroblast growth factor 23

(GLUT4):

Glucose transporter type 4

(GR):

Glucocorticoid receptor

(H3K27me3):

Histone 3 lysine 27 trimethylation

(H4ac):

Histone 4 deacetylation

(HATs):

Histone acetyltransferases

(HbA1c):

Glycated hemoglobin

(HDAC):

Histone deacetylase

(hEST1B):

Human ever-shorter telomeres 1B

(HFD):

High-fat diet

(Hsp90):

Heat shock protein 90

(IC50):

Half maximal inhibitory concentration

(IL-6):

Interleukin-6

(IRS-1):

Insulin receptor stimulator-1

(LXRα):

Liver X receptor-α

(MAPK):

Mitogen-activated protein kinase

(NAFLD):

Nonalcoholic fatty liver disease

(NIPBL):

Nipped-B-like protein

(NCOA3):

Nuclear receptor coactivator 3

(NKD1):

Naked cuticle homolog 1

(PARP):

Poly(ADP-ribose) polymerases

(PI3K):

Phosphoinositide 3-kinase

(PKA):

Protein kinase A

(PKG):

Protein kinase G

(PPP2R2B):

Protein phosphatase 2 regulatory subunit B beta

(PRICKLE1):

Prickle planar cell polarity protein 1

(RAI1):

Retinoic acid induced 1

(SAHA):

Suberoylanilide hydroxamic acid

(SMC1A):

Structural maintenance of chromosomes 1A

(SMC3):

Structural maintenance of chromosome 3

(SREBP-1):

Sterol regulatory element-binding protein-1

(T2R13, or TRB3):

Taste 2 receptor member 13

(THRAP3):

Thyroid hormone receptor-associated protein 3

(TNF-α):

Tumor necrosis factor-alpha

(ZRANB2):

Zinc finger RANBP2-type containing 2

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Acknowledgments

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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Authors and Affiliations

  1. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong

    Vincent Wai-Sun Wong

  2. School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong

    Myth Tsz-Shun Mok & Alfred Sze-Lok Cheng

Authors
  1. Vincent Wai-Sun Wong
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  2. Myth Tsz-Shun Mok
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  3. Alfred Sze-Lok Cheng
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Corresponding author

Correspondence to Alfred Sze-Lok Cheng .

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Editors and Affiliations

  1. School of Life Sciences, University of Westminster, London, UK

    Vinood B. Patel

  2. Diabetes and Nutritional Sciences Research Division, Faculty of Life Sciences and Medicine, King’s College London, London, UK

    Victor R. Preedy

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Wong, V.WS., Mok, M.TS., Cheng, A.SL. (2019). Histone Deacetylase HDAC8 and Insulin Resistance. In: Patel, V., Preedy, V. (eds) Handbook of Nutrition, Diet, and Epigenetics. Springer, Cham. https://doi.org/10.1007/978-3-319-55530-0_23

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  • DOI: https://doi.org/10.1007/978-3-319-55530-0_23

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