Dietary supplementation with methyl donor groups could prevent nonalcoholic fatty liver (2011)

We read with great interest the work by Kohly et al. in HEPATOLOGY,1 which describes a model of obesity and nonalcoholic fatty liver disease (NAFLD) generated by a diet with high amounts of fat and carbohydrates. Another way to implement a model of hepatic damage is the dietary depletion of methyl donor groups, such as choline or betaine,2, 3 which leads to nonalcoholic steatohepatitis (NASH). Other studies have reported that supplementation with these kinds of molecules can induce epigenetic changes and regulate the gene expression profile.4 In this sense, we hypothesized that dietary methyl donor supplementation could be able to reverse the negative effects of a nutritional model of nonalcoholic fatty liver in rats. To confirm this concept, we performed a study with 48 male Wistar rats that were divided into four dietary groups with 12 rats each (Fig. 1): control diet (C), methyl donor–supplemented control (Csupl), a diet high in fat and sugar (HFS), and an HFS diet supplemented with methyl donor groups, including betaine, choline, vitamin B12, and folic acid (HFSsupl). Chow (2014; Harlan Teklad Global Diets) and obesogenic diets (D12451; Research Diets) were provided ad libitum, and food intake was not affected by dietary treatment. The initial and final total fat mass, as well as the final fat content in the liver, were measured by EchoMRi analyzer.5 After 8 weeks of dietary treatment, the animals were sacrificed and tissues and plasma were frozen for later analysis. Hepatic fat content measured by EchoMRi analyzer. Data are presented as means ± standard deviations. Differences were analyzed by two-way analysis of variance (ANOVA) (Diet × Supplementation). Different letters indicate significant differences between groups. C, control diet; Csupl, methyl donor–supplemented control diet; HFS, high-fat, high-sugar diet; HFSsupl, methyl donor–supplemented HFS diet; ns, nonstatistical significance; *P < 0.05, ***P < 0.001. The obesogenic model was successfully achieved, showing statistical differences (P < 0.01) between control-fed and HFS-fed rats in different phenotypical variables such as body and fat depot weights and total fat. The analyses of plasma parameters revealed an increase in the atherogenic index. Moreover, the obesogenic diet induced an increase in liver fat stores when compared to the C group and, and as hypothesized, this damage was partially reversed with methyl donor supplementation (Fig. 1). In conclusion, the HFS diet led to an obese and NAFLD phenotype characterized by an increase in liver lipid accumulation. Nutritional supplementation with a cocktail of methyl donors partially reversed this extra-adipose lipid accumulation. These data suggest that methyl donor supplementation might prevent the establishment of NAFLD, a precursor to NASH and cirrhosis, and that different epigenetic changes altering the expression of genes related to liver fat metabolism could be involved. Pául Cordero Ph.D.*, Javier Campion Ph.D.*, Fermín I. Milagro Ph.D.*, J. Alfredo Martínez Ph.D.*, * Department of Nutrition and Food Science, Physiology and Toxicology, University of Navarra, Pamplona, Spain.