Daniel Leclerc

Scope Disturbances in one‐carbon metabolism contribute to nonalcoholic fatty liver disease (NAFLD) which encompasses steatosis, steatohepatitis, fibrosis, and cirrhosis. The goal is to examine impact of folate deficiency and the Mthfr 677C >T variant on NAFLD. Methods and results This study uses the new Mthfr 677C >T mouse model for the human MTHFR 677C >T variant. Mthfr 677CC and Mthfr 677TT mice were fed control diet (CD) or folate‐deficient (FD) diets for 4 months. FD and Mthfr 677TT alter choline/methyl metabolites in liver and/or plasma (decreased S‐adenosylmethionine (SAM):S‐adenosylhomocysteine (SAH) ratio, methyltetrahydrofolate, and betaine; increased homocysteine [Hcy]). FD, with contribution from Mthfr 677TT , provokes fibrosis in males. Studies of normal livers reveal alterations in plasma markers and gene expression that suggest an underlying predisposition to fibrosis induced by FD and/or Mthfr 677TT in males. These changes are absent or reverse in females, consistent with the sex disparity of fibrosis. Sex‐based differences in methylation potential, betaine, sphingomyelin, and trimethylamine‐ N ‐oxide (TMAO) levels may prevent fibrogenesis in females. In contrast, Mthfr 677TT alters choline metabolism, dysregulates expression of lipid metabolism genes, and promotes steatosis in females. Conclusion This study suggests that folate deficiency predisposes males to fibrosis, which is exacerbated by Mthfr 677TT , whereas Mthfr 677TT predisposes females to steatosis, and reveal novel contributory mechanisms for these NAFLD‐related disorders.