Evaluation of Methionine Content in a High-Fat and Choline-Deficient Diet on Body Weight Gain and the Development of Non-Alcoholic Steatohepatitis in Mice

Abstract

AimNon-alcoholic steatohepatitis (NASH) is a globally recognized liver disease. A methionine- and choline-deficient diet is used to induce NASH in mice; however, this diet also causes severe body weight loss. To resolve this issue, we examined the effects of methionine content in a high-fat and choline-deficient (HFCD) diet on body weight and the development of NASH in mice.MethodsC57BL/6J mice (male, 10 weeks of age) were fed an L-amino acid rodent (control) diet, high-fat (HF) diet, or HFCD diet containing various amounts of methionine (0.1–0.6% (w/w)) for 12 weeks. Plasma lipid levels, hepatic lipid content and inflammatory marker gene expression were measured, and a pathological analysis was conducted to evaluate NASH.ResultsThe 0.1% methionine in HFCD diet suppressed body weight gain, which was lower than that with control diet. On the other hand, the 0.2% methionine in HFCD diet yielded similar body weight gains as the control diet, while more than 0.4% methionine showed the same body weight gains as the HF diet. Liver weights and hepatic lipid contents were the greatest with 0.1% methionine and decreased in a methionine dose-dependent manner. Pathological analysis, NAFLD activity scores and gene expression levels in the liver revealed that 0.1% and 0.2% methionine for 12 weeks induced NASH, whereas 0.4% and 0.6% methionine attenuated the induction of NASH by HFCD diet. However, the 0.2% methionine in HFCD diet did not induce insulin resistance, despite the body weight gain.ConclusionsThe 0.2% methionine in HFCD diet for 12 weeks was able to induce NASH without weight loss.

Choline Supplementation Prevents a Hallmark Disturbance of Kwashiorkor in Weanling Mice Fed a Maize Vegetable Diet: Hepatic Steatosis of Undernutrition

“…Although increased CDP-choline pathway activity is likely to have been metabolically relevant in MVD + C mice, accurate measurement of CDP activity requires stable isotope techniques that are beyond the scope of this initial study. Larger studies using isotopically labeled choline [ 47 ] are likely to provide more precise insight for understanding the predominant mechanism by which choline supplementation prevented hepatic steatosis in this novel mouse model of undernutrition.…”

Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

“…The addition of more than 0.4% methionine to the diet led to the same weight gain observed in the pure HF diet. Unfortunately, supplementation with methionine above 0.2% does not result in an inflammatory or a fibrotic NASH phenotype [152]. The MCD diet model is a rapid and reproducible model of a NASH liver phenotype, but it does not exhibit any of the metabolic features of human NAFLD, including obesity, insulin resistance or dyslipidemia.…”

Comparative study of liver injury induced by high-fat methionine- and choline-deficient diet in ICR mice originating from three different sources

“…High-fat diets cause obesity and insulin resistance, but 30 weeks are needed to establish NASH [14]. The MCD diet is often used to induce NASH by inducing hepatic steatosis and inflammation within 4 weeks, but it is characterized by severe weight loss [13]. Therefore, we attempted to induce NAFLD/NASH by using HFMCD diet.…”

“…The deficiency of the essential amino acid methionine decreases the biosynthesis of glutathione (GSH), the most potent antioxidant in the body, and leads to oxidative stress, which in turn contributes to liver damage [11]. However, MCD diet can cause serious weight loss, which is not usually observed in patients with NAFLD [12,13]. Another well-studied dietary model is high-fat diet-induced NAFLD accompanied by obesity, although the diverse composition of such diets makes it difficult to compare studies from different research groups.…”