Advertisement

Histone Deacetylase HDAC8 and Insulin Resistance

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

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.

Keywords

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

List of 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

Notes

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.

References

  1. Alam N, Zimmerman L, Wolfson NA, Joseph CG, Fierke CA, Schueler-Furman O (2016) Structure-based identification of HDAC8 non-histone substrates. Structure 24:458–468CrossRefGoogle Scholar
  2. American Diabetes Association. 2(2015) Classification and diagnosis of diabetes. Diabetes Care 38(Suppl):S8–S16CrossRefGoogle Scholar
  3. Barzilay JI, Abraham L, Heckbert SR, Cushman M, Kuller LH, Resnick HE et al (2001) The relation of markers of inflammation to the development of glucose disorders in the elderly: the cardiovascular health study. Diabetes 50:2384–2389CrossRefGoogle Scholar
  4. Bonora E, Moghetti P, Zancanaro C, Cigolini M, Querena M, Cacciatori V et al (1989) Estimates of in vivo insulin action in man: comparison of insulin tolerance tests with euglycemic and hyperglycemic glucose clamp studies. J Clin Endocrinol Metab 68:374–378CrossRefGoogle Scholar
  5. Bradley EW, Carpio LR, Olson EN, Westendorf JJ (2015) Histone deacetylase 7 (Hdac7) suppresses chondrocyte proliferation and beta-catenin activity during endochondral ossification. J Biol Chem 290:118–126CrossRefGoogle Scholar
  6. Bricambert J, Favre D, Brajkovic S, Bonnefond A, Boutry R, Salvi R et al (2016) Impaired histone deacetylases 5 and 6 expression mimics the effects of obesity and hypoxia on adipocyte function. Mol Metab 5:1200–1207CrossRefGoogle Scholar
  7. Chakrabarti A, Oehme I, Witt O, Oliveira G, Sippl W, Romier C et al (2015) HDAC8: a multifaceted target for therapeutic interventions. Trends Pharmacol Sci 36:481–492CrossRefGoogle Scholar
  8. Chatterjee TK, Basford JE, Knoll E, Tong WS, Blanco V, Blomkalns AL et al (2014) HDAC9 knockout mice are protected from adipose tissue dysfunction and systemic metabolic disease during high-fat feeding. Diabetes 63:176–187CrossRefGoogle Scholar
  9. Chen WB, Gao L, Wang J, Wang YG, Dong Z, Zhao J et al (2016) Conditional ablation of HDAC3 in islet beta cells results in glucose intolerance and enhanced susceptibility to STZ-induced diabetes. Oncotarget 7:57485–57497PubMedPubMedCentralGoogle Scholar
  10. Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ et al (2011) National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 378:31–40CrossRefGoogle Scholar
  11. Daneshpajooh M, Bacos K, Bysani M, Bagge A, Ottosson Laakso E, Vikman P et al (2017) HDAC7 is overexpressed in human diabetic islets and impairs insulin secretion in rat islets and clonal beta cells. Diabetologia 60:116–125CrossRefGoogle Scholar
  12. DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA et al (2011) Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med 364:1104–1115CrossRefGoogle Scholar
  13. Etchegaray JP, Mostoslavsky R (2016) Interplay between metabolism and epigenetics: a nuclear adaptation to environmental changes. Mol Cell 62:695–711CrossRefGoogle Scholar
  14. Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL (2016) Trends in obesity among adults in the United States, 2005 to 2014. JAMA 315:2284–2291CrossRefGoogle Scholar
  15. Ford ES, Giles WH, Dietz WH (2002) Prevalence of the metabolic syndrome among US adults: findings from the third National Health and nutrition examination survey. JAMA 287:356–359CrossRefGoogle Scholar
  16. Fuchsberger C, Flannick J, Teslovich TM, Mahajan A, Agarwala V, Gaulton KJ et al (2016) The genetic architecture of type 2 diabetes. Nature 536:41–47CrossRefGoogle Scholar
  17. Gehart H, Kumpf S, Ittner A, Ricci R (2010) MAPK signalling in cellular metabolism: stress or wellness? EMBO Rep 11:834–840CrossRefGoogle Scholar
  18. Gut P, Verdin E (2013) The nexus of chromatin regulation and intermediary metabolism. Nature 502:489–498CrossRefGoogle Scholar
  19. Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10:32–42CrossRefGoogle Scholar
  20. Hallal PC, Andersen LB, Bull FC, Guthold R, Haskell W, Ekelund U et al (2012) Global physical activity levels: surveillance progress, pitfalls, and prospects. Lancet 380:247–257CrossRefGoogle Scholar
  21. Hong S, Zhou W, Fang B, Lu W, Loro E, Damle M et al (2016) Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion. Nat MedGoogle Scholar
  22. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM (1995) Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 95:2409–2415CrossRefGoogle Scholar
  23. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271:665–668CrossRefGoogle Scholar
  24. Ingham OJ, Paranal RM, Smith WB, Escobar RA, Yueh H, Snyder T et al (2016) Development of a potent and selective HDAC8 inhibitor. ACS Med Chem Lett 7:929–932CrossRefGoogle Scholar
  25. Jiang X, Ye X, Guo W, Lu H, Gao Z (2014) Inhibition of HDAC3 promotes ligand-independent PPARgamma activation by protein acetylation. J Mol Endocrinol 53:191–200CrossRefGoogle Scholar
  26. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K (2006) Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116:1784–1792CrossRefGoogle Scholar
  27. Kahn SE (2003) The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 46:3–19CrossRefGoogle Scholar
  28. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA et al (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403CrossRefGoogle Scholar
  29. Lenoir O, Flosseau K, Ma FX, Blondeau B, Mai A, Bassel-Duby R et al (2011) Specific control of pancreatic endocrine beta- and delta-cell mass by class IIa histone deacetylases HDAC4, HDAC5, and HDAC9. Diabetes 60:2861–2871CrossRefGoogle Scholar
  30. Lundh M, Galbo T, Poulsen SS, Mandrup-Poulsen T (2015) Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats. Diabetes Obes Metab 17:703–707CrossRefGoogle Scholar
  31. Ma RC, Hu C, Tam CH, Zhang R, Kwan P, Leung TF et al (2013) Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4. Diabetologia 56:1291–1305CrossRefGoogle Scholar
  32. Makinistoglu MP, Karsenty G (2015) The class II histone deacetylase HDAC4 regulates cognitive, metabolic and endocrine functions through its expression in osteoblasts. Mol Metab 4:64–69CrossRefGoogle Scholar
  33. McGee SL, van Denderen BJ, Howlett KF, Mollica J, Schertzer JD, Kemp BE et al (2008) AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5. Diabetes 57:860–867CrossRefGoogle Scholar
  34. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H (2001) Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia 44(Suppl 2):S14–S21CrossRefGoogle Scholar
  35. Muntner P, Gu D, Wildman RP, Chen J, Qan W, Whelton PK et al (2005) Prevalence of physical activity among Chinese adults: results from the international collaborative study of cardiovascular disease in Asia. Am J Public Health 95:1631–1636CrossRefGoogle Scholar
  36. Ozcan L, Ghorpade DS, Zheng Z, de Souza JC, Chen K, Bessler M et al (2016) Hepatocyte DACH1 is increased in obesity via nuclear exclusion of HDAC4 and promotes hepatic insulin resistance. Cell Rep 15:2214–2225CrossRefGoogle Scholar
  37. Popov VB, Jornayvaz FR, Akgul EO, Kanda S, Jurczak MJ, Zhang D et al (2016) Second-generation antisense oligonucleotides against beta-catenin protect mice against diet-induced hepatic steatosis and hepatic and peripheral insulin resistance. FASEB J 30:1207–1217CrossRefGoogle Scholar
  38. Qu X, Huang C, Qu H, Jia B, Cui Q, Sun C et al (2016) Histone deacetylase 6 promotes insulin resistance via deacetylating phosphatase and tensin homolog (PTEN) in ovarian OVCAR-3 cells. Int J Clin Exp Pathol 9:7105–7113Google Scholar
  39. Sassone-Corsi P (2013) Physiology. When metabolism and epigenetics converge. Science 339:148–150CrossRefGoogle Scholar
  40. Sathishkumar C, Prabu P, Balakumar M, Lenin R, Prabhu D, Anjana RM et al (2016) Augmentation of histone deacetylase 3 (HDAC3) epigenetic signature at the interface of proinflammation and insulin resistance in patients with type 2 diabetes. Clin Epigenetics 8:125CrossRefGoogle Scholar
  41. Sun Z, Miller RA, Patel RT, Chen J, Dhir R, Wang H et al (2012) Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat Med 18:934–942CrossRefGoogle Scholar
  42. Tian Y, Wong VW, Wong GL, Yang W, Sun H, Shen J et al (2015) Histone deacetylase HDAC8 promotes insulin resistance and beta-catenin activation in NAFLD-associated hepatocellular carcinoma. Cancer Res 75:4803–4816CrossRefGoogle Scholar
  43. Tian Y, Mok MT, Yang P, Cheng AS (2016) Epigenetic activation of Wnt/beta-catenin signaling in NAFLD-associated hepatocarcinogenesis. Cancers (Basel) 8:E76CrossRefGoogle Scholar
  44. Wild S, Roglic G, Green A, Sicree R, King H (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053CrossRefGoogle Scholar
  45. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M et al (2011) Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140:124–131CrossRefGoogle Scholar
  46. Winkler R, Benz V, Clemenz M, Bloch M, Foryst-Ludwig A, Wardat S et al (2012) Histone deacetylase 6 (HDAC6) is an essential modifier of glucocorticoid-induced hepatic gluconeogenesis. Diabetes 61:513–523CrossRefGoogle Scholar
  47. Wolfson NA, Pitcairn CA, Fierke CA (2013) HDAC8 substrates: histones and beyond. Biopolymers 99:112–126CrossRefGoogle Scholar
  48. Wong VW, Hui AY, Tsang SW, Chan JL, Tse AM, Chan KF et al (2006) Metabolic and adipokine profile of Chinese patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 4:1154–1161CrossRefGoogle Scholar
  49. Wong VW, Wong GL, Yeung DK, Lau TK, Chan CK, Chim AM et al (2015) Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy. J Hepatol 62:182–189CrossRefGoogle Scholar
  50. Yalow RS, Berson SA (1959) Assay of plasma insulin in human subjects by immunological methods. Nature 184(Suppl 21):1648–1649CrossRefGoogle Scholar
  51. Yalow RS, Berson SA (1960) Plasma insulin concentrations in nondiabetic and early diabetic subjects. Determinations by a new sensitive immuno-assay technic. Diabetes 9:254–260CrossRefGoogle Scholar

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

Personalised recommendations