Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent, chronic liver diseases, worldwide. It is a multifactorial disease caused by complex interactions between genetic, epigenetic and environmental factors. Recently, several microRNAs, some of which epigenetically regulated, have been found to be up- and/or down-regulated during NAFLD development. However, in NAFLD, the essential role of the Polycomb Group protein Enhancer of Zeste Homolog 2 (EZH2), which controls the epigenetic silencing of specific genes and/or microRNAs by trimethylating Lys27 on histone H3, still remains unknown. In this study, we demonstrate that the nuclear expression/activity of the EZH2 protein is down-regulated both in livers from NAFLD rats and in the free fatty acid-treated HepG2. The drop in EZH2 is inversely correlated with: (i) lipid accumulation; (ii) the expression of pro-inflammatory markers including TNF-α and TGF-β; and (iii) the expression of miR-200b and miR-155. Consistently, the pharmacological inhibition of EZH2 by 3-Deazaneplanocin A (DZNep) significantly reduces EZH2 expression/activity, while it increases lipid accumulation, inflammatory molecules and microRNAs. In conclusion, the results of this study suggest that the defective activity of EZH2 can enhance the NAFLD development by favouring steatosis and the de-repression of the inflammatory genes and that of specific microRNAs.
Highlights
Over the past two decades, the incidence of non-alcoholic fatty liver disease (NAFLD) has risen sharply in several Western Countries and across Asia, while the prevalence of this disease in children is of growing concern [1,2,3]
These findings suggest that epigenomic control may be crucial for the development and progression of Non-alcoholic fatty liver disease (NAFLD), there is a distinct lack of research demonstrating the potential role of Enhancer of Zeste Homolog 2 (EZH2) in NAFLD pathogenesis
The intra-hepatic expression of the pro-inflammatory and pro-fibrogenic molecules such as TNF-α and TGF-β are undetectable by mRNA and/or protein analysis as they are quickly processed in the liver before being released into the bloodstream
Summary
Over the past two decades, the incidence of non-alcoholic fatty liver disease (NAFLD) has risen sharply in several Western Countries and across Asia, while the prevalence of this disease in children is of growing concern [1,2,3]. The term NAFLD implies a variety of liver histopathological disorders resulting from the effect of the interactions between specific genetic backgrounds (i.e., the presence of specific gene polymorphisms) and environmental factors (hypercaloric diets and/or sedentary lifestyle) [4,5,6] Besides these pathogenetic factors, it is widely accepted that epigenetic mechanisms may contribute to the development and progression of NAFLD causing the more severe, non-alcoholic steatohepatitis (NASH) [7,8]. DNA is associated with the histological severity of NAFLD These findings suggest that epigenomic control may be crucial for the development and progression of NAFLD, there is a distinct lack of research demonstrating the potential role of EZH2 in NAFLD pathogenesis. In this study we have investigated the EZH2 expression and activity in in vivo and in vitro NAFLD and its potential correlation with disease features
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