Homocysteinemia in Mice with Genetic Betaine HomocysteineS -Methyltransferase Deficiency Is Independent of Dietary Folate Intake

Abstract

Elevated homocysteine (Hcy) concentrations are associated with increased risk of several chronic diseases. Hcy can be removed by methylating it to form methionine via either the betaine homocysteine S-methyltransferase (BHMT) or the methionine synthase (MS) pathway. BHMT uses betaine as the methyl donor, whereas MS uses 5-methyltetrahydrofolate. We previously found that mice with the gene encoding Bhmt deleted (Bhmt(-/-)) had altered Hcy metabolites in tissues. This study aimed to determine whether folate supplementation of Bhmt(-/-) mice reverses, and folate deficiency exacerbates, these metabolic changes. Bhmt(-/-) mice and their littermates (Bhmt(+/+) mice) were fed a folate-deficient (FD; 0 mg/kg diet), a folate control (FC; 2 mg/kg diet), or a folate-supplemented (FS; 20 mg/kg diet) diet for 4 wk. Bhmt(-/-) mice had higher plasma Hcy and hepatic S-adenosylhomocysteine (AdoHcy) concentrations and had lower hepatic S-adenosylmethionine (AdoMet) concentrations compared with Bhmt(+/+) mice for all diets. Although the FD diet increased plasma Hcy (P < 0.05) and hepatic AdoHcy (P < 0.001) concentrations in Bhmt(+/+) mice compared with FC and FS mice, the FD diet had no effect on the metabolites measured in Bhmt(-/-) mice. The FS diet did not ameliorate elevated plasma Hcy and elevated hepatic AdoHcy concentrations but did increase hepatic AdoMet concentrations in Bhmt(-/-) mice (P < 0.001) compared with FD and FC mice. We conclude that the BHMT pathway is a major route for the elimination of Hcy in mice and that the MS pathway has little excess capacity to methylate the Hcy that accumulates when the BHMT pathway is blocked.

Betaine‐homocysteine S ‐methyltransferase deficiency causes increased susceptibility to noise‐induced hearing loss associated with plasma hyperhomocysteinemia

“…Young (2–3‐mo‐old) C57BL/6J Bhmt −/− mice showed increased concentrations of plasma homocysteine compared with their wild‐type littermates, confirming previous reports (49) ( Fig. ).…”

“…Bhmt showed the highest cochlear expression of the methionine metabolism genes studied; furthermore, its expression in connexin 30–knockout mice has been related to stria vascularis permeability and hearing loss (8). In our hands and as reported, Bhmt −/− mice showed hyperhomocysteinemia and reduced hepatic methylation index (30, 49). However, no evident signs of hearing loss were observed at the ages studied compared with wild‐type mice.…”

Epigenetically mediated inhibition of S‐adenosylhomocysteine hydrolase and the associated dysregulation of 1‐carbon metabolism in nonalcoholic steatohepatitis and hepatocellular carcinoma

“…Indeed, several studies have demonstrated a positive effect of methyl-group donor supplementation on correcting 1-carbon metabolism perturbations (48,49); however, when these disturbances were caused by an impairment of the remethylation homocysteine to methionine and conversion of homocysteine to glutathione in the transsulfuration pathway, methyl donor supplementation was not effective. For example, it has been reported that the SAH-homocysteine disturbances caused by Bhmt-or Cbs-deficiency are independent of dietary methyl donor supplementation (50,51).…”

The Metabolic Burden of Methyl Donor Deficiency with Focus on the Betaine Homocysteine Methyltransferase Pathway

“…The results suggest that folate enhanced SAM production via the methionine synthase pathway, but was not able to remove tHcy in this mouse model. The BHMT pathway appears to substantially participate in tHcy metabolism in mice [50]. At least in this mouse model, folic acid supplementation did not counterbalance the metabolic burden caused by disrupting the BHMT enzyme.…”