Betaine (also called trimethylglycine or TMG) is an amino acid derivative that is found in high concentrations in beets, spinach, quinoa, and whole grains, and it is one of the two methyl donors in the human body — the other being S-adenosylmethionine (SAM), which is the primary methyl donor for the methylation reactions that are essential for the DNA methylation, the histone methylation, the neurotransmitter synthesis, the phosphatidylcholine synthesis, and the regulation of the one-carbon metabolism. Unlike SAM, which is synthesised from methionine and ATP and which is used for the majority of the methyl transfer reactions in the body, betaine is used primarily as a methyl donor for the remethylation of homocysteine to methionine by the betaine-homocysteine methyltransferase (BHMT) enzyme in the liver and the kidneys. This betaine-dependent remethylation pathway is the alternative to the folate-dependent remethylation pathway (which uses 5-methyltetrahydrofolate as the methyl donor and the vitamin B12-dependent methionine synthase enzyme), and it is particularly important when the folate-dependent pathway is compromised (by the MTHFR polymorphisms, by the folate deficiency, or by the vitamin B12 deficiency). Without adequate betaine, the remethylation of homocysteine is impaired, homocysteine accumulates, and the elevated blood homocysteine (hyperhomocysteinaemia) is the diagnostic marker of the betaine deficiency and the primary risk factor for the cardiovascular disease, the thrombosis, and the cognitive decline that are the hallmark of the hyperhomocysteinaemia.
Betaine and the Homocysteine Metabolism
Homocysteine is a sulfur-containing amino acid that is generated as an intermediate in the metabolism of the essential amino acid methionine — it is formed when SAM donates its methyl group to a methyl acceptor (producing S-adenosylhomocysteine, SAH, which is then hydrolysed to homocysteine and adenosine) and it is either remethylated back to methionine (by the betaine-dependent BHMT or by the folate-dependent methionine synthase) or converted to cysteine (by the transsulfuration pathway, which requires vitamin B6 as a cofactor). The remethylation of homocysteine to methionine is the primary pathway for the disposal of the excess homocysteine, and it is dependent on the availability of the methyl donors (betaine and 5-methyltetrahydrofolate) and of the cofactors (vitamin B12). When either the betaine or the folate pathway is compromised, the homocysteine accumulates in the blood (hyperhomocysteinaemia), and this elevated homocysteine is one of the most important risk factors for the cardiovascular disease, the stroke, the thrombosis, and the cognitive decline.
The clinical importance of the betaine for the homocysteine metabolism is underscored by the observation that betaine supplementation lowers the blood homocysteine levels in people with the MTHFR polymorphisms, in people with the folate deficiency, and in people with the elevated baseline homocysteine. Multiple clinical trials have demonstrated that betaine supplementation at 3-6g daily reduces the fasting homocysteine by 10-20% and reduces the post-methionine load homocysteine by 30-50% in people with the MTHFR C677T polymorphism — this is the genetic condition that is most commonly associated with the impaired folate metabolism and the elevated homocysteine. The betaine supplementation is therefore one of the most effective interventions for the management of the hyperhomocysteinaemia that is associated with the MTHFR polymorphisms and with the folate deficiency.
Betaine and the Fatty Liver
Betaine is also involved in the phosphatidylcholine synthesis and in the VLDL formation — it provides the methyl groups for the conversion of the phosphatidylethanolamine to the phosphatidylcholine, and this phosphatidylcholine is essential for the packaging of the fat in the liver as VLDL particles for the export to the peripheral tissues. Without adequate betaine, the phosphatidylcholine synthesis is impaired, the fat cannot be packaged and exported from the liver, and it accumulates as the hepatic steatosis (fatty liver). The betaine supplementation has been shown to reduce the liver fat content in people with the NAFLD and in animal models of the fatty liver disease — this is one of the most important metabolic effects of the betaine and it explains why betaine is included in many liver support formulations.
Practical Application
For general betaine supplementation, the evidence-based approach is to supplement with 1.5-3g of betaine daily (as the betaine anhydrous or as the betaine hydrochloride form), which is the dose range that has been shown to lower the homocysteine levels in clinical trials. The betaine is generally well-tolerated with no significant adverse effects at doses up to 6g daily, though very high doses may produce the gastrointestinal symptoms (nausea, diarrhoea). For comprehensive methylation support, betaine pairs well with the folate (as 5-MTHF at 400-800mcg daily, which provides the methyl donor for the methionine synthase reaction), with the vitamin B12 (as methylcobalamin at 500-1000mcg daily, which is the cofactor for the methionine synthase reaction), with the vitamin B6 (which is required for the transsulfuration pathway that disposes of the excess homocysteine by converting it to cysteine), and with the magnesium (which is a cofactor for many of the enzymes of the one-carbon metabolism and of the methylation cycle).
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