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A common variant in methylenetetrahydrofolate reductase (<jats:italic>MTHFR<\/jats:italic> 677C\u2192T) causes mild MTHFR deficiency with lower 5\u2010methyltetrahydrofolate for methylation reactions. The goal is to determine whether mild murine MTHFR deficiency contributes to NAFLD\u2010related effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>Wild\u2010type and <jats:italic>Mthfr<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice, a model for the human variant, are fed control (CD) or high\u2010fat (HFAT) diets for 8 weeks. On both diets, MTHFR deficiency results in decreased <jats:italic>S<\/jats:italic>\u2010adenosylmethionine, increased <jats:italic>S<\/jats:italic>\u2010adenosylhomocysteine, and decreased betaine with reduced methylation capacity, and changes in expression of several inflammatory or anti\u2010inflammatory mediators (<jats:italic>Saa1<\/jats:italic>, <jats:italic>Apoa1<\/jats:italic>, and <jats:italic>Pon1<\/jats:italic>). On CD, MTHFR deficiency leads to microvesicular steatosis with expression changes in lipid regulators <jats:italic>Xbp1s<\/jats:italic> and <jats:italic>Cyp7a1<\/jats:italic>. The combination of MTHFR deficiency and HFAT exacerbates changes in inflammatory mediators and introduces additional effects on inflammation (<jats:italic>Saa2<\/jats:italic>) and lipid metabolism (<jats:italic>Nr1h4<\/jats:italic>, <jats:italic>Srebf1c, Ppara<\/jats:italic>, and <jats:italic>Crot<\/jats:italic>). These effects are consistent with increased expression of pro\u2010inflammatory HDL precursors and greater lipid accumulation. MTHFR deficiency may enhance liver injury through alterations in methylation capacity, inflammatory response, and lipid metabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Individuals with the MTHFR variant may be at increased risk for liver disease and related complications, particularly when consuming high\u2010fat diets.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mnfr.201801001","type":"journal-article","created":{"date-parts":[[2018,11,8]],"date-time":"2018-11-08T19:43:50Z","timestamp":1541706230000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Mild Methylenetetrahydrofolate Reductase Deficiency Alters Inflammatory and Lipid Pathways in Liver"],"prefix":"10.1002","volume":"63","author":[{"given":"Daniel","family":"Leclerc","sequence":"first","affiliation":[{"name":"Departments of Human Genetics and Pediatrics McGill University McGill University Health Center (MUHC)  Montreal 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