Folate Deficiency and/or the Genetic Variant Mthfr677C >T Can Drive Hepatic Fibrosis or Steatosis in Mice, in a Sex‐Specific Manner

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 Mthfr677C >T variant on NAFLD. Methods and results This study uses the new Mthfr677C >T mouse model for the human MTHFR677C >T variant. Mthfr677CC and Mthfr677TT mice were fed control diet (CD) or folate‐deficient (FD) diets for 4 months. FD and Mthfr677TT 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 Mthfr677TT, 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 Mthfr677TT 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, Mthfr677TT 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 Mthfr677TT, whereas Mthfr677TT predisposes females to steatosis, and reveal novel contributory mechanisms for these NAFLD‐related disorders. Control diet (CD) and folate‐deficient (FD) diets are fed to Mthfr677CC and Mthfr677TT mice for 4 months. Males have lower levels of key methyl/choline metabolites in liver than females, which may favor fibrosis. Males have sex‐specific expression changes in fibrogenesis‐related genes, and increased susceptibility to fibrosis due to FD, exacerbated by Mthfr677TT. In females, Mthfr677TT alters triglyceride and cholesterol levels, as well as expression of genes in lipid metabolism, increasing steatosis. This work highlights sex‐specific contributory mechanisms to NAFLD.