Homocysteine‐betaine interactions in a murine model of 5,10‐methylenetetrahydrofolate reductase deficiency

Abstract

Hyperhomocysteinemia, a proposed risk factor for cardiovascular disease, is also observed in other common disorders. 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-derived methyl donor, betaine, to wild-type mice and to littermates with mild or severe hyperhomocysteinemia due to hetero- or homozygosity for a disruption of the Mthfr gene. On control diets, plasma homocysteine and liver choline metabolite levels were strongly dependent on the Mthfr genotype. Betaine supplementation decreased homocysteine in all three genotypes, restored liver betaine and phosphocholine pools, and prevented severe steatosis in Mthfr-deficient 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 Mthfr-compromised mice appear to be much more sensitive to changes of choline/betaine intake than do wild-type animals. Hyperhomocysteinemia, in the range of that associated with folate deficiency or with homozygosity for the 677T MTHFR variant, may be associated with disturbed choline metabolism.

Biomarkers Related to One-Carbon Metabolism as Potential Risk Factors for Distal Colorectal Adenomas

“…Because smoking is known to be associated with compromised folate status, this suggests an increased importance of alternative methyl group donors under folate deficient conditions, which for example has been shown for betaine (42,43) and may also apply to methionine and choline. In addition, smoking has been associated with lower circulating concentrations of vitamin B2 and B6 (44).…”

Polymorphisms in methionine synthase reductase and betaine-homocysteine S-methyltransferase genes: Risk of placental abruption

“…While BHMT, unlike MTRR, is not directly involved in the folate-dependent pathway, experiments have shown that homocysteine flux through the BHMT pathway is enhanced when folate-dependent remethylation is disrupted [22]. Betaine can effectively lower plasma homocysteine levels and there is a significant negative correlation between plasma homocysteine and plasma betaine, as shown in men with coronary artery disease [22]. Thus, BHMT may play a critical role in the remethylation of homocysteine when the folate-dependent pathway is compromised by either genetic or dietary factors.…”

Génétique moléculaire deMTHFR

“…Les taux d'homocystéine plasmatique totale de ces souris hétérozygotes et homozygotes sont respectivement 1, 6 et 10 fois supé-rieurs à ceux des témoins [25]. Ces souris présentent une stéatose hépatique qui pourrait être reliée à la diminution des taux de métabolites de la choline dans le foie [26]. Ces souris ont servi à tester l'effet de la bétaïne dans les cas de déficience en MTHFR [26].…”

“…Ces souris présentent une stéatose hépatique qui pourrait être reliée à la diminution des taux de métabolites de la choline dans le foie [26]. Ces souris ont servi à tester l'effet de la bétaïne dans les cas de déficience en MTHFR [26]. [27].…”