High dietary methionine intake may contribute to the risk of nonalcoholic fatty liver disease by inhibiting hepatic H2S production.

Methionine, an essential sulfur-containing amino acid, is associated with hepatic lipid accumulation; however, the underlying mechanism is unknown. This study aimed to investigate the effects of different dietary methionine levels on hepatic lipid accumulation in mice and clarify the possible mechanisms involved. The Institute of Cancer Research (ICR) mice were fed a normal diet (ND, 0.86% methionine), high-methionine diet (HMD, 2.58% methionine), or methionine-restricted diet (MRD, 0.17% methionine) for 11 consecutive weeks. Our results showed that HMD increased the liver weight and liver index, plasma and hepatic lipid profiles, and hepatic fatty infiltration area and perirenal fat volume. In addition, HMD promoted lipid synthesis, inhibited lipid catabolism and glycolysis metabolism, reduced the activities of mitochondrial respiratory chain enzyme complexes (Ⅰ and Ⅴ) and adenosine triphosphate (ATP) production, and elevated oxidative stress and inflammation in the liver. Moreover, HMD inhibited homocysteine metabolism and significantly decreased the expression and activity of cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST), thereby reducing endogenous H2S production in the liver. Interestingly, MRD reversed these adverse effects, and promoted endogenous H2S production. In conclusion, inhibition of hepatic H2S production may be the mechanism behind an increased risk of nonalcoholic fatty liver disease (NAFLD) associated with high dietary methionine intake. Therefore, it is necessary to reduce methionine intake in the daily diet to prevent NAFLD and maintain good physical health.