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

Abstract

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.

Keywords: NAFLD; cirrhosis; fibrogenesis; methylenetetrahydrofolate reductase; mouse model.