An Update in Epigenetics in Metabolic-Associated Fatty Liver Disease

Abstract

Metabolic-associated fatty liver disease (MAFLD) is characterized by hepatic steatosis accompanied by one of three features: overweight or obesity, T2DM, or lean or normal weight with evidence of metabolic dysregulation. It is distinguished by excessive fat accumulation in hepatocytes, and a decrease in the liver's ability to oxidize fats, the accumulation of ectopic fat, and the activation of proinflammatory pathways. Chronic damage will keep this pathophysiologic cycle active causing progression from hepatic steatosis to cirrhosis and eventually, hepatocarcinoma. Epigenetics affecting gene expression without altering DNA sequence allows us to study MAFLD pathophysiology from a different perspective, in which DNA methylation processes, histone modifications, and miRNAs expression have been closely associated with MAFLD progression. However, these considerations also faced us with the circumstance that modifying those epigenetics patterns might lead to MAFLD regression. Currently, epigenetics is an area of great interest because it could provide new insights in therapeutic targets and non-invasive biomarkers. This review comprises an update on the role of epigenetic patterns, as well as innovative therapeutic targets and biomarkers in MAFLD.

Effect of cofactors on NAFLD/NASH and MAFLD. A paradigm illustrating the pathomechanics of organ dysfunction

“…Epigenetic mechanisms, comprising histone methylation, abnormal DNA methylation, and circulating miRNA profiles, all interact with inherited risk factors to determine individual susceptibility to NAFLD and, compared to genetic mechanisms, are affected by the patient’s lifestyle changes [ 64 , 77 , 78 ] . The finding that adaptions to maternal obesity in early life increase the susceptibility to developing NAFLD and its complications in offspring [ 79 ] is an excellent example of the role of epigenetic factors in NAFLD pathobiology.…”

“…Together, genetic and epigenetic cofactors participate in NAFLD development and progression and carry translational implications, which can be exploited to implement personalized medicine approaches [ 64 , 83 ] . These include programs for targeted screening and surveillance of complications, prediction of the individual response to pharmacological therapies, and opportunities for using miRNAs for treating liver disease and utilizing the gene variant as the therapeutic target [ 78 , 84 ] . Lifestyle habits predisposing to the development and progression of NAFLD represent a holistic scenario including sedentary behavior and unhealthy dietary patterns, which are discussed below under Points 2 and 3.…”

Deciphering the role of aberrant DNA methylation in NAFLD and NASH

“…Epigenetic modifiers are being investigated as potential drug targets for NAFLD. Over the past two decades epigenetic alterations leading to NAFLD have been investigated and are being recognized as major determinants in its pathogenesis [ 15 , 64 ]. Recently Lonardo et al., have deliberated on the approaches targeting the genetic background, epigenetic modifiers and clinical features to achieve the goal of precision medicine in NAFLD patients [ 65 ].…”

Multi-Omics Nutritional Approaches Targeting Metabolic-Associated Fatty Liver Disease

“…In this context, a number of DNA sequence structural variants across the human genome have been associated with the susceptibility and severity of MAFLD trough interactions with nutritional factors [ 6 ]. In addition, dietary regulation of gene expression affecting MAFLD pathogenesis may involve epigenetic mechanisms including DNA methylation, histone modifications, and long non-coding RNA features [ 7 ]. Of note, gut microbiota dysbiosis is a common feature in MAFLD patients, mainly combined with nutritionally unbalanced poor diets [ 8 ].…”