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The most frequent genetic cause of hyperhomocysteinemia is a mutated methylenetetrahydrofolate reductase (MTHFR), predominantly when folate status is impaired. MTHFR synthesizes a major methyl donor for homocysteine remethylation to methionine. We administered the alternate choline\u2010derived methyl donor, betaine, to wild\u2010type mice and to littermates with mild or severe hyperhomocysteinemia due to hetero\u2010 or homozygosity for a disruption of the\n                    <jats:italic>Mthfr<\/jats:italic>\n                    gene. On control diets, plasma homocysteine and liver choline metabolite levels were strongly dependent on the\n                    <jats:italic>Mthfr<\/jats:italic>\n                    genotype. Betaine supplementation decreased homocysteine in all three genotypes, restored liver betaine and phosphocholine pools, and prevented severe steatosis in\n                    <jats:italic>Mthfr<\/jats:italic>\n                    \u2010deficient mice. Increasing betaine intake did not further decrease homocysteine. In humans with cardiovascular disease, we found a significant negative correlation between plasma betaine and homocysteine concentrations. Our results emphasize the strong interrelationship between homocysteine, folate, and choline metabolism. Hyperhomocysteinemic\n                    <jats:italic>Mthfr<\/jats:italic>\n                    \u2010compromised mice appear to be much more sensitive to changes of choline\/betaine intake than do wild\u2010type animals. Hyperhomocysteinemia, in the range of that associated with folate deficiency or with homozygosity for the 677T\n                    <jats:italic>MTHFR<\/jats:italic>\n                    variant, may be associated with disturbed choline metabolism.\n                  <\/jats:p>","DOI":"10.1096\/fj.02-0456fje","type":"journal-article","created":{"date-parts":[[2003,3,11]],"date-time":"2003-03-11T17:42:07Z","timestamp":1047404527000},"page":"1-25","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":143,"title":["Homocysteine\u2010betaine interactions in a murine model of 5,10\u2010methylenetetrahydrofolate reductase deficiency"],"prefix":"10.1096","volume":"17","author":[{"given":"Bernd C.","family":"Schwahn","sequence":"first","affiliation":[{"name":"Department of Pediatrics Human Genetics and Biology McGill University\u2010Montreal Children's Hospital Montreal Canada"},{"name":"Metabolic Unit University Children's Hospital D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhoutao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Human Genetics and Biology McGill University\u2010Montreal Children's Hospital Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice D.","family":"Laryea","sequence":"additional","affiliation":[{"name":"Metabolic Unit University Children's Hospital D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Udo","family":"Wendel","sequence":"additional","affiliation":[{"name":"Metabolic Unit University Children's Hospital D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Lussier\u2010Cacan","sequence":"additional","affiliation":[{"name":"Clinical Research Institute of Montreal Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Jacques","family":"Genest","sequence":"additional","affiliation":[{"name":"Department of Medicine McGill University Health Center Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei\u2010Heng","family":"Mar","sequence":"additional","affiliation":[{"name":"Department of Nutrition Schools of Public Health and Medicine University of North Carolina Chapel Hill USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven H.","family":"Zeisel","sequence":"additional","affiliation":[{"name":"Department of Nutrition Schools of Public Health and Medicine University of North Carolina Chapel Hill USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Castro","sequence":"additional","affiliation":[{"name":"Department of Food Science and Human Nutrition University of Illinois Urbana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Garrow","sequence":"additional","affiliation":[{"name":"Department of Food Science and Human Nutrition University of Illinois Urbana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rima","family":"Rozen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Human Genetics and Biology McGill University\u2010Montreal Children's Hospital Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2003,1,22]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-131-5-199909070-00008"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V104891"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)90165-5"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1053\/plac.1999.0417"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01271539"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.69.2.228"},{"key":"e_1_2_6_8_1","first-page":"1279","volume-title":"In The Metabolic and Molecular Bases of Inherited Disease","author":"Mudd S. 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