Document Type
Article
Publication Date
3-1-2024
Original Citation
Leclerc D,
Christensen K,
Reagan A,
Keser V,
Luan Y,
Malysheva O,
Wasek B,
Bottiglieri T,
Caudill M,
Howell G,
Rozen R.
Folate Deficiency and/or the Genetic Variant Mthfr(677C >T) Can Drive Hepatic Fibrosis or Steatosis in Mice, in a Sex-Specific Manner Mol Nutr Food Res. 2024;68(5):e2300355.
Keywords
JMG, Male, Humans, Female, Mice, Animals, Non-alcoholic Fatty Liver Disease, Betaine, Folic Acid Deficiency, Folic Acid, Methylenetetrahydrofolate Reductase (NADPH2), Genotype, Liver Cirrhosis, S-Adenosylmethionine, Choline, Homocysteine
JAX Source
Mol Nutr Food Res. 2024;68(5):e2300355.
ISSN
1613-4133
PMID
38327171
DOI
https://doi.org/10.1002/mnfr.202300355
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 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.
Comments
© 2024 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.