Dynamic changes in hepatic DNA methylation during the development of nonalcoholic fatty liver disease induced by a...

DNA methylation is an important epigenetic mechanism of gene expression control. The present study aimed to evaluate the temporal effect of isocaloric high-sugar diet (HSD) intake on the development of nonalcoholic fatty liver disease (NAFLD) and the role of DNA methylation in this event. Newly weaned Wistar rats were divided into eight groups and fed a standard chow diet or an HSD ad libitum for 4 weeks, 8 weeks, 15 weeks, and 18 weeks. After the experimental periods, the animals were euthanized and their livers were removed for histological analysis, gene expression of maintenance methylase (Dnmt1), de novo methylases (Dnmt3a and Dnmt3b), demethylases (Tet2 and Tet3) of DNA, and global DNA methylation. HSD intake led to the gradual development of NAFLD. HSD intake for 18 weeks was associated with downregulation of Dnmt1 expression and global DNA hypomethylation; these results were negatively correlated with more severe steatosis scores observed in these animals. The HSD consumption for 18 weeks was also associated with a decrease in Dnmt3a and Tet2 expression. Interestingly, the expression of de novo methyltransferase Dnmt3b was reduced by HSD during all experimental periods. Together, these results indicate that the downregulation of de novo DNA methylation, Dnmt3b, induced by HSD is the primary factor in the development of NAFLD. On the other hand, disease progression is associated with downregulation of maintenance DNA methylation and global DNA hypomethylation. These results suggest a link between the dynamic changes in hepatic DNA methylation and the development of NAFLD induced by an HSD intake.