Exploring the metabolic and molecular benefits of methyl donor supplementation in a model of metabolic and fatty liver disease

Introduction and Objectives: Metabolic fatty liver disease (MAFLD) is currently the most common cause of chronic liver damage worldwide. Differential methylation in genes and histones has been correlated with metabolic alterations present in the disease. Supplementation with methyl group donor molecules could work as a therapeutic strategy to reverse the progression of the disease. Materials and patients: Male C57BL/6J mice of 20-25g of initial weight were fed with a conventional diet (ND n=8); or a diet high in fat and sugar (HF n=8) for 18 weeks, or a diet high in fat and sugar for 10 weeks, plus 8 weeks of HF diet + methyl group donor supplementation (HFMS n=8). Insulin Tolerance test was performed before sacrifice. Liver, epididymal and visceral fat, and serum samples were collected. Biochemical and histological analyzes were performed. In the liver, global DNA methylation was quantified and the transcriptome was analyzed using dual-channel microarrays. Proteomic analysis was carried out by immunoblotting. Results: The supplemented animals (HFMS) showed a decrease in body weight epididymal and visceral fat (p<0.001). The HFMS group showed reduced serum levels of triglycerides and glucose and increased insulin sensitivity. Histological analysis of livers from ND and HFMS animals did not show characteristic MAFLD damage. Global DNA methylation was increased in the HFMS animals. Transcriptome analysis in the HFMS group showed a decrease in metabolic pathways associated with the development of MAFLD and an increase in lipid and cholesterol metabolic pathways. The proteomic analysis revealed an increase of the expression of H3K9 and DNMT1 and a decrease of H3K4, MJD2B and EZH1 proteins involved in the development of the disease. Conclusions: Supplementation with methyl group donors has beneficial effects on weight and body composition, improves hepatic metabolism of lipids, and increases the expression of molecules that regulate DNA methylation and histones, even when consumption of a high-fat diet is continued.