Epigenetics of Hepatic Insulin Resistance

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.

SAMe, Choline, and Valproic Acid as Possible Epigenetic Drugs: Their Effects in Pregnancy with a Special Emphasis on Animal Studies

“…Epigenetic changes are related to a variety of congenital malformations and diseases [1,72,73]. The disruption of epigenetic machinery can lead to oxidative stress, metabolic syndrome, obesity, insulin resistance, diabetes, and vascular dysfunction in humans [74,75]. Gene expression is regulated by complex epigenetic machinery via three main mechanisms: DNA methylation, modifications of core histone proteins, and by non-coding RNAs [4,76,77].…”

Epigenetics and Beyond: Targeting Histone Methylation to Treat Type 2 Diabetes Mellitus

“…The remaining heritability could be possibly explained by rare variants, including gene-environment interactions and epigenetics. Aberrant histone modifications prelude the development of various diseases, such as IR ( Maude et al, 2021 ). Several studies have focused on the relation of histone modification and T2DM.…”

“…For example, the progression of T2DM is accompanied by an increased level of H3K4me1 and H3K9me2 and a reduced level of H3K9ac and H3K23ac ( Figure 2 ) ( Tu et al, 2015 ). Global proteomic analysis revealed 15 histone modifications differentially abundant in high-fat diet (HFD)-induced mice ( Maude et al, 2021 ). HDAC8 was associated with the promotion of IR in NAFLD-associated hepatocellular carcinoma (HCC).…”

“…Hepatic insulin sensitivity can also be modified by specific dietary components that are involved in epigenetic modifications ( Maude et al, 2021 ). In mammals, SAM can provide methyl groups for DNA, RNA, and histones ( Ouyang et al, 2020 ).…”

“…Apart from its therapeutic potential, epigenetic modification could also serve as disease biomarkers, which promotes early detection of disease progression and improves the estimates of future disease risk ( Hornschuh et al, 2021 ). A total of 63 genomic regions associated with insulin sensitivity are identified from neonatal blood spot samples ( Maude et al, 2021 ). Such genomic regions may facilitate appropriate lifestyle interventions as biomarkers to reduce IR-related diseases.…”