High homocysteine induces betaine depletion

Betaine is the substrate of the liver- and kidney- specific betaine-homocysteine methyltransferase (BHMT), an alternate pathway for homocysteine remethylation. We hypothesized that BHMT is a major pathway for homocysteine removal in cases of hyperhomocysteinemia (HHcy). Therefore, we measured betaine in plasma and tissues from patients and animal models of HHcy of genetic and acquired cause. Plasma was collected from patients presenting HHcy without any homocysteine interfering treatment. Plasma and tissues were collected from rat models of HHcy induced by diet and from a mouse model of CBS deficiency. S-adenosyl-methionine, S-adenosyl-homocysteine, methionine, betaine, and dimethylglycine were quantified by ESI-LC-MS/MS. mRNA expression was quantified using quantitative real-time PCR. For all patients with diverse causes of HHcy, plasma betaine concentrations were below the normal values of our laboratory. In the diet-induced HHcy rat model, betaine was decreased in all tissues analysed (liver, brain, heart). In the mouse CBS deficiency model, betaine was decreased in plasma, liver, heart and brain, but was conserved in kidney. Surprisingly, BHMT expression and activity was decreased in liver. However, in kidney, BHMT and SLC6A12 expression was increased in CBS-deficient mice. Chronic HHcy, irrespective of its cause, induces betaine depletion in plasma and tissues (liver, brain and heart), indicating a global decrease of the body betaine pool. In kidney, betaine concentrations were not affected, possibly due to overexpression of the betaine transporter SLC6A12 where betaine may be conserved because of its crucial role as an osmolyte.

Imbard, A., et al., High homocysteine induces betaine depletion. Biosci Rep, 2015.