Epigenetics, microRNA and Metabolic Syndrome: A Comprehensive Review

Abstract

Epigenetics refers to the DNA chemistry changes that result in the modification of gene transcription and translation independently of the underlying DNA coding sequence. Epigenetic modifications are reported to involve various molecular mechanisms, including classical epigenetic changes affecting DNA methylation and histone modifications and small RNA-mediated processes, particularly that of microRNAs. Epigenetic changes are reversible and are closely interconnected. They are recognised to play a critical role as mediators of gene regulation, and any alteration in these mechanisms has been identified to mediate various pathophysiological conditions. Moreover, genetic predisposition and environmental factors, including dietary alterations, lifestyle or metabolic status, are identified to interact with the human epigenome, highlighting the importance of epigenetic factors as underlying processes in the aetiology of various diseases such as MetS. This review will reflect on how both the classical and microRNA-regulated epigenetic changes are associated with the pathophysiology of metabolic syndrome. We will then focus on the various aspects of epigenetic-based strategies used to modify MetS outcomes, including epigenetic diet, epigenetic drugs, epigenome editing tools and miRNA-based therapies.

The metabolic syndrome, thiazolidinediones, and implications for intersection of chronic and inflammatory disease

“…The downstream actions include reducing the degree of activation of mTORC1, an important regulator of autophagy, and a driver of the increase in de novo lipid synthesis in the presence of hyperinsulinemia. Ongoing studies are evaluating whether metabolic pathways also coordinate the epigenetic regulation of transcriptional networks, which can occur through reversable methylation of specific cytosines in DNA and through specific methylation and acetylation marks of key lysine within specific histone components of chromatin [ 53 ]. For example, it is known that certain histone marks can pause the differentiation of adipocytes [ 54 ] while modification through NAD + generated by metabolism of α-ketoglutarate can remove these marks and allow differentiation to proceed [ 55 ].…”

Legacy in Cardiovascular Risk Factors Control: From Theory to Future Therapeutic Strategies?

“…An epigenome-wide association study showed that elevated BMI was associated with changes in DNA methylation, mostly in genes involved in lipid and lipoprotein metabolism, substrate transport, and inflammatory pathways and that these alterations are related to adiposity [ 80 ]. Mice deficient in histone demethylase HDM2a, an enzyme responsible for H3K9 demethylation, developed an adult-onset obesity, hypertriglyceridemia, and hypercholesterolemia, as well as insulin resistance compared to wild type controls [ 81 ]. Sirtuins, a class of HDACs, were reported to act as metabolic regulators of glucose homeostasis, insulin resistance, and its associated inflammation.…”

“…Sirtuins, a class of HDACs, were reported to act as metabolic regulators of glucose homeostasis, insulin resistance, and its associated inflammation. As an example, lack of SIRT1-, SIRT2-, and SIRT6-dependent deacetylation and activation of specific adipose gene programs was shown to contribute to the development of metabolic disorders, such as type 2 diabetes and obesity [ 81 ]. miRNA-mediated epigenetic changes also induce obesity-associated adipose tissue inflammation, a significant factor responsible for developing insulin resistance and type 2 diabetes.…”

“…miRNA-mediated epigenetic changes also induce obesity-associated adipose tissue inflammation, a significant factor responsible for developing insulin resistance and type 2 diabetes. Accordingly, obese adipocyte-derived exosomes have an increased expression of miR-29a; when transferred into adipocytes, myocytes, and hepatocytes, these exosomes produced insulin resistance in both in vitro and in vivo models [ 81 ]. Of note, epigenetic changes are heritable and can be transmitted to the offspring.…”

Metabolic Syndrome: From Molecular Mechanisms to Novel Therapies

“…An early recognition using clinical parameters and inflammatory markers is imperative in order to reduce morbidity and possibly mortality too, attributable to the syndrome. In addition, a number of susceptibility genes and adipokines have been identified that are thought to play a role in the genetic etiology of MetS, thus paving the way to new molecular insights [ 3 , 4 , 5 ]. Knowledge of the etiopathogenic pathways could facilitate novel therapeutic approaches to managing and treating MetS.…”