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HCU can be treated by using betaine to lower tissue and plasma levels of homocysteine (Hcy). Here, we show that mice with severely elevated Hcy and potentially deficient in the folate species tetrahydrofolate (THF) exhibit a very limited response to betaine indicating that THF plays a critical role in treatment efficacy. Analysis of a mouse model of HCU revealed a 10\u2010fold increase in hepatic levels of 5\u2010methyl \u2010THF and a 30\u2010fold accumulation of formiminoglutamic acid, consistent with a paucity of THF. Neither of these metabolite accumulations were reversed or ameliorated by betaine treatment. Hepatic expression of the THF\u2010generating enzyme dihydrofolate reductase (DHFR) was significantly repressed in HCU mice and expression was not increased by betaine treatment but appears to be sensitive to cellular redox status. Expression of the DHFR reaction partner thymidylate synthase was also repressed and metabolomic analysis detected widespread alteration of hepatic histidine and glutamine metabolism. Many individuals with HCU exhibit endothelial dysfunction. DHFR plays a key role in nitric oxide (NO) generation due to its role in regenerating oxidized tetrahydrobiopterin, and we observed a significant decrease in plasma NOx (NO\n                    <jats:sub>2<\/jats:sub>\n                    \u2009+\u2009NO\n                    <jats:sub>3<\/jats:sub>\n                    ) levels in HCU mice. Additional impairment of NO generation may also come from the HCU\u2010mediated induction of the 20\u2010hydroxyeicosatetraenoic acid generating cytochrome CYP4A. Collectively, our data shows that HCU induces dysfunctional one\u2010carbon metabolism with the potential to both impair betaine treatment and contribute to multiple aspects of pathogenesis in this disease.\n                  <\/jats:p>","DOI":"10.1096\/fj.202302585r","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T09:39:03Z","timestamp":1720604343000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dysregulation of hepatic one\u2010carbon metabolism in classical homocystinuria: Implications of redox\u2010sensitive DHFR repression and tetrahydrofolate depletion for pathogenesis and treatment"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8044-3263","authenticated-orcid":false,"given":"Kenneth N.","family":"Maclean","sequence":"first","affiliation":[{"name":"Department of Pediatrics University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip D.","family":"Neill","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan R.","family":"Chanin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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