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Review
. 2021 May 11:12:681356.
doi: 10.3389/fendo.2021.681356. eCollection 2021.

Epigenetics of Hepatic Insulin Resistance

Hannah Maude  1 , Claudia Sanchez-Cabanillas  1 , Inês Cebola  1
Affiliations
Review

Epigenetics of Hepatic Insulin Resistance

Hannah Maude et al. Front Endocrinol (Lausanne). .

Abstract

Insulin resistance (IR) is largely recognized as a unifying feature that underlies metabolic dysfunction. Both lifestyle and genetic factors contribute to IR. Work from recent years has demonstrated that the epigenome may constitute an interface where different signals may converge to promote IR gene expression programs. Here, we review the current knowledge of the role of epigenetics in hepatic IR, focusing on the roles of DNA methylation and histone post-translational modifications. We discuss the broad epigenetic changes observed in the insulin resistant liver and its associated pathophysiological states and leverage on the wealth of 'omics' studies performed to discuss efforts in pinpointing specific loci that are disrupted by these changes. We envision that future studies, with increased genomic resolution and larger cohorts, will further the identification of biomarkers of early onset hepatic IR and assist the development of targeted interventions. Furthermore, there is growing evidence to suggest that persistent epigenetic marks may be acquired over prolonged exposure to disease or deleterious exposures, highlighting the need for preventative medicine and long-term lifestyle adjustments to avoid irreversible or long-term alterations in gene expression.

Keywords: NAFLD (non-alcoholic fatty liver disease); epigenetics (DNA methylation, histone modifications); insulin resistance; liver; type 2 diabetes.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
DNA methylation, histone methylation and acetylation and their epigenetic machinery: sources of gene regulation in the liver. Repressed gene expression is shown where epigenetic modifiers remove active histone marks (e.g. H3K27ac and methylation of H3K4), including histone deacetylases (HDACs) and histone demethylases (HDMs). Active gene expression is shown where active histone marks are deposited by histone acetyltransferases (HATs) and histone methyltransferases (HMTs). DNA methylation is here shown to repress gene expression, which typically occurs following the methylation of gene promoters and is deposited by DNA methyltransferases (DNMTs) and removed by methylcytosine dioxygenases (TET enzymes).
Figure 2
Figure 2
Differential methylation of insulin signalling pathway genes in insulin resistant states. The insulin signalling pathway, with key proteins encoded by genes showing differential levels of DNA methylation in insulin-resistant states highlighted in red. Red arrows indicate increased (up) or decreased (down) gene expression and activity of the indicated signalling pathways in hepatic insulin resistance.
Figure 3
Figure 3
Epigenetic dysregulation of the IRS2 locus in the livers of T2D patients. Comparison of obese T2D and non-T2D revealed that the IRS2 locus, which encodes a core mediator of insulin signalling in the liver, is differentially methylated in the livers of T2D patients (41). Observed changes include the hypermethylation of a CpG site near the promoter of IRS2 and hypomethylation of an intronic SREBF1 binding site. SREBF1 has been previously shown to interfere with the binding of transactivators to IRS2 (42). Ultimately, these changes lead to the decreased expression of IRS2 in hepatocytes, effectively reducing insulin signalling and enhancing lipogenesis.
Figure 4
Figure 4
SIRT1 is a master regulator of hepatic insulin sensitivity. Under normal conditions, the functions of the histone deacetylase SIRT1 include to increase fatty acid oxidation and glucose production, by deacetylating both histone and non-histone proteins, including several key transcription factors which regulate gluconeogenic and lipogenic gene expression. Non-histone targets of SIRT1 are labelled with “Deacetylation”.
Figure 5
Figure 5
The liver epigenome is influenced by many factors. The epigenome and therefore gene expression, including of metabolic gene programs, can be altered by external factors as well as the underlying genetic sequence.
See this image and copyright information in PMC

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References

    1. Alberti K, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. . Harmonizing the Metabolic Syndrome: A Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation (2009) 120(16):1640–5. 10.1161/CIRCULATIONAHA.109.192644 - DOI - PubMed
    1. Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. . Global and Regional Diabetes Prevalence Estimates for 2019 and Projections for 2030 and 2045: Results From the International Diabetes Federation Diabetes Atlas. Diabetes Res Clin Pract (2019) 157:107843. 10.1016/j.diabres.2019.107843 - DOI - PubMed
    1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global Epidemiology of Nonalcoholic Fatty Liver Disease—Meta-Analytic Assessment of Prevalence, Incidence, and Outcomes. Hepatology (2016) 64(1):73–84. 10.1002/hep.28431 - DOI - PubMed
    1. Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C, Zuñiga FA. Association Between Insulin Resistance and the Development of Cardiovascular Disease. Cardiovasc Diabetol (2018) 17(1):1–14. 10.1186/s12933-018-0762-4 - DOI - PMC - PubMed
    1. Morsi M, Maher A, Aboelmagd O, Johar D, Bernstein L. A Shared Comparison of Diabetes Mellitus and Neurodegenerative Disorders. J Cell Biochem (2018) 119(2):1249–56. 10.1002/jcb.26261 - DOI - PubMed

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