Effects of Dietary Folate Supplementation and Deficiency on Bhmt Knockout Mice (2012)

Undergraduate: Ignacio Cerdena

Faculty Advisor: Steven Zeisel
Department: Nutrition

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Elevated homocysteine (Hcy) is strongly associated with increased risks of coronary heart disease, neural tube defects, and Alzheimer’s. Hcy can be removed by remethylation forming methionine, and impairment of this process may result in elevated plasma Hcy. BHMT and MS are two enzymes that remethylate Hcy using betaine and 5-methyl THF as the methyl donors respectively. Mice deficient in BHMT (Bhmt KO) have seven-fold increased plasma Hcy. Our goal was to determine whether dietary folate could affect elevated plasma Hcy concentrations in Bhmt KO mice. We hypothesized that dietary folate supplementation would lower, while dietary folate deficiency increase the elevated Hcy levels in Bhmt KO mice. Seven week old Bhmt WT and KO mice were fed diets containing 0, 2, or 20 mg folate/kg diet and 1% succinyl sulfathiazole for 4 weeks. Plasma folate was measured through a microbiological assay. Plasma Hcy and cysteine were measured through a HPLC assay. Compared to a folate control diet, folate deficiency exacerbated the plasma Hcy concentrations in both Bhmt WT (deficient mice 6.2±0.57 µM vs control mice 4.8±0.52 µM) and Bhmt KO mice (deficient mice 73±13 µM vs control mice 44±9 µM). Folate supplementation was shown to have no significant decreasing effect on Hcy levels. These results suggest that the Bhmt pathway and its co-activators, like its parallel pathway and folate, are critical to adequate Hcy remethylation in mice and that one pathway cannot fully ]compensate for another.