Noncoding RNAs as additional mediators of epigenetic regulation in nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common cause of chronic liver disorder worldwide. It represents a spectrum that includes a continuum of different clinical entities ranging from simple steatosis to nonalcoholic steatohepatitis, which can evolve to cirrhosis and in some cases to hepatocellular carcinoma, ultimately leading to liver failure. The pathogenesis of NAFLD and the mechanisms underlying its progression to more pathological stages are not completely understood. Besides genetic factors, evidence indicates that epigenetic mechanisms occurring in response to environmental stimuli also contribute to the disease risk. Noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs, and circular RNAs, are one of the epigenetic factors that play key regulatory roles in the development of NAFLD. As the field of ncRNAs is rapidly evolving, the present review aims to explore the current state of knowledge on the roles of these RNA species in the pathogenesis of NAFLD, highlight relevant mechanisms by which some ncRNAs can modulate regulatory networks implicated in NAFLD, and discuss key challenges and future directions facing current research in the hopes of developing ncRNAs as next-generation non-invasive diagnostics and therapies in NAFLD and subsequent progression to hepatocellular carcinoma.

Recent insights into the pathogenesis and therapeutic targets of chronic liver diseases

“…Among them, miR-34a, miR-122 and miR-192 are the best candidates as biomarkers for NALFD diagnosis and staging, and may serve as therapeutic targets for NAFLD. [68][69][70][71][72] In a meta-analysis study, miR-34a showed the best diagnostic accuracy for discriminating NASH from NAFL. 72 In mice with miR-34a deficiency or overexpression in hepatocytes, or treated with miR-34a inhibitor, miR-34a has been demonstrated to promote NASH induced by a diet high in fat, cholesterol and fructose (HFCF).…”

Peroxisome Proliferator-Activated Receptor-γ as a Target and Regulator of Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease

“…As previously highlighted, peroxisome proliferator-activated receptors (PPARs) regulate lipid homeostasis and have been proposed as important regulators in the development of NAFLD and its various stages. Furthermore, their cross-regulation with ncRNAs has emerged as an additional layer of complexity in the regulatory mechanisms of several diseases, including NAFLD [ 85 , 86 , 87 ]. Thus, expanding our knowledge of the ncRNAs/PPARγ regulatory axis may help us better understand how epigenetic mechanisms contribute to the physiopathology of NAFLD and advance the process of developing potential ncRNAs/PPARγ-based therapeutics for this condition.…”