{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T14:58:40Z","timestamp":1772895520217,"version":"3.50.1"},"reference-count":53,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T00:00:00Z","timestamp":1707264000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["# PJT\u2010173521"],"award-info":[{"award-number":["# PJT\u2010173521"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Nutrition Food Res"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:sec><jats:title>Scope<\/jats:title><jats:p>Disturbances in one\u2010carbon 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 <jats:italic>Mthfr<jats:sup>677C &gt;T<\/jats:sup><\/jats:italic> variant on NAFLD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>This study uses the new <jats:italic>Mthfr<jats:sup>677C &gt;T<\/jats:sup><\/jats:italic> mouse model for the human <jats:italic>MTHFR<jats:sup>677C &gt;T<\/jats:sup><\/jats:italic> variant. <jats:italic>Mthfr<jats:sup>677CC<\/jats:sup><\/jats:italic> and <jats:italic>Mthfr<jats:sup>677TT<\/jats:sup><\/jats:italic> mice were\u00a0fed control diet (CD) or folate\u2010deficient (FD) diets for 4 months. FD and <jats:italic>Mthfr<jats:sup>677TT<\/jats:sup><\/jats:italic> alter choline\/methyl metabolites in liver and\/or plasma (decreased S\u2010adenosylmethionine (SAM):S\u2010adenosylhomocysteine (SAH) ratio, methyltetrahydrofolate, and betaine; increased homocysteine [Hcy]). FD, with contribution from <jats:italic>Mthfr<jats:sup>677TT<\/jats:sup><\/jats:italic>, 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 <jats:italic>Mthfr<jats:sup>677TT<\/jats:sup><\/jats:italic> in males. These changes are absent or reverse in females, consistent with the sex disparity of fibrosis. Sex\u2010based differences in methylation potential, betaine, sphingomyelin, and trimethylamine\u2010<jats:italic>N<\/jats:italic>\u2010oxide (TMAO) levels may prevent fibrogenesis in females. In contrast, <jats:italic>Mthfr<jats:sup>677TT<\/jats:sup><\/jats:italic> alters choline metabolism, dysregulates expression of lipid metabolism genes, and promotes steatosis in females.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study suggests that folate deficiency predisposes males to fibrosis, which is exacerbated by <jats:italic>Mthfr<jats:sup>677TT<\/jats:sup><\/jats:italic>, whereas <jats:italic>Mthfr<jats:sup>677TT<\/jats:sup><\/jats:italic> predisposes females to steatosis, and reveal novel contributory mechanisms for these NAFLD\u2010related disorders.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mnfr.202300355","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T07:34:17Z","timestamp":1707377657000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Folate Deficiency and\/or the Genetic Variant <i>Mthfr<sup>677C &gt;T<\/sup><\/i> Can Drive Hepatic Fibrosis or Steatosis in Mice, in a Sex\u2010Specific Manner"],"prefix":"10.1002","volume":"68","author":[{"given":"Daniel","family":"Leclerc","sequence":"first","affiliation":[{"name":"Departments of Human Genetics and Pediatrics McGill University Research Institute of the McGill University Health Center  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen E.","family":"Christensen","sequence":"additional","affiliation":[{"name":"Departments of Human Genetics and Pediatrics McGill University Research Institute of the McGill University Health Center  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alaina M.","family":"Reagan","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor ME USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vafa","family":"Keser","sequence":"additional","affiliation":[{"name":"Departments of Human Genetics and Pediatrics McGill University Research Institute of the McGill University Health Center  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Luan","sequence":"additional","affiliation":[{"name":"Departments of Human Genetics and Pediatrics McGill University Research Institute of the McGill University Health Center  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga V.","family":"Malysheva","sequence":"additional","affiliation":[{"name":"Division of Nutritional Sciences and Genomics Cornell University  Ithaca NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandi","family":"Wasek","sequence":"additional","affiliation":[{"name":"Center of Metabolomics Institute of Metabolic Disease Baylor Scott &amp; 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