Folate Deficiency and/or the Genetic Variant Mthfr^{677C >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 Mthfr(677C >T) variant on NAFLD. Methods and results: This study uses the new Mthfr(677C >T) mouse model for the human MTHFR677C >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 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 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.