Dysregulation of hepatic one‐carbon metabolism in classical homocystinuria: Implications of redox‐sensitive DHFR repression and tetrahydrofolate depletion for pathogenesis and treatment
Rattachement africain : us. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Abstract Cystathionine beta‐synthase‐deficient homocystinuria (HCU) is a life‐threatening disorder of sulfur metabolism. 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‐fold increase in hepatic levels of 5‐methyl ‐THF and a 30‐fold 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‐generating 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 2 + NO 3 ) levels in HCU mice. Additional impairment of NO generation may also come from the HCU‐mediated induction of the 20‐hydroxyeicosatetraenoic acid generating cytochrome CYP4A. Collectively, our data shows that HCU induces dysfunctional one‐carbon metabolism with the potential to both impair betaine treatment and contribute to multiple aspects of pathogenesis in this disease.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Dysregulation of hepatic one‐carbon metabolism in classical homocystinuria: Implications of redox‐sensitive DHFR repression and tetrahydrofolate depletion for pathogenesis and treatment
- Date Crossref
- 10/07/2024
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
-
University of Colorado Denver pays non établi dans la noticeUniversité ou école supérieure
-
University of Montana pays non établi dans la noticeUniversité ou école supérieure
-
Department of Pediatrics University of Colorado School of Medicine Aurora Colorado USA pays non établi dans la noticeUniversité ou école supérieure
-
Department of Obstetrics and Gynecology University of Colorado School of Medicine Aurora Colorado USA pays non établi dans la noticeUniversité ou école supérieure
-
Department of Pathology University of Colorado School of Medicine Aurora Colorado USA pays non établi dans la noticeUniversité ou école supérieure
-
Center of Metabolomics Institute of Metabolic Disease pays non établi dans la noticeStructure de recherche
-
Department of Pharmaceutical Sciences Skaggs School of Pharmacy and Pharmaceutical Sciences pays non établi dans la noticeUniversité ou école supérieure
-
Department of Medicine University of Colorado School of Medicine Aurora Colorado USA pays non établi dans la noticeUniversité ou école supérieure
University of Colorado Denver, University of Montana et Department of Pediatrics University of Colorado School of Medicine Aurora Colorado USA, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.