Reduced MTHFD1 activity in male mice perturbs folate- and choline-dependent one-carbon metabolism as well as transsulfuration

Abstract

Impaired utilization of folate is caused by insufficient dietary intake and/or genetic variation and has been shown to prompt changes in related pathways, including choline and methionine metabolism. These pathways have been shown to be sensitive to variation within the Mthfd1 gene, which codes for a folate-metabolizing enzyme responsible for generating 1-carbon (1-C)-substituted folate derivatives. The Mthfd1gt/+ mouse serves as a potential model of human Mthfd1 loss-offunction genetic variants that impair MTHFD1 function. This study investigated the effects of the Mthfd1 gt/+ genotype and folate intake on markers of choline, folate, methionine, and transsulfuration metabolism. Male Mthfd1gt/+ and Mthfd1+/+ mice were randomly assigned at weaning (3 wk of age) to either a control (2 mg/kg folic acid) or folate-deficient (0 mg/k folic acid) diet for 5 wk. Mice were killed at 8 wk of age following 12 h of food deprivation; blood and liver samples were analyze for choline, methionine, and transsulfuration biomarkers. Independent of folate intake, mice with the Mthfd1gt/+ genotype ad higher hepatic concentrations of choline (P = 0.005), betaine (P = 0.013), and dimethylglycine (P = 0.004) andlower hepatic concentrations of glycerophosphocholine (P = 0.002) relative to Mthfd1+/+ mice. Mthfd1gt/+ mice also had higher plasma concentrations of homocysteine (P = 0.0016) and cysteine (P < 0.001) as well as lower plasma concentrations of methionine (P = 0.0003) and cystathionine (P = 0.011). The metabolic alterations observed in Mthfd1gt/+ mice indicate perturbed choline and folate-dependent 1-C metabolism andsupport the future use of Mthfd1gt/+ mice as a tool to investigate the impact of impaired 1-C metabolism on disease outcomes. © 2013 American Society for Nutrition.