Betaine (also called trimethylglycine or TMG) is a methyl donor that is found naturally in foods including sugar beet, spinach, quinoa, wheat bran, and rye, and that is synthesised in the body from choline via the choline dehydrogenase pathway. Betaine is the methyl group donor for the enzyme betaine-homocysteine methyltransferase (BHMT), which is expressed primarily in the liver and the kidney and which catalyses the remethylation of homocysteine to methionine. This betaine-dependent remethylation pathway is an alternative to the folate-dependent remethylation pathway (which uses 5-methyltetrahydrofolate as the methyl donor, via the methionine synthase enzyme), and it is particularly important when folate status is marginal or when the folate-dependent pathway is impaired (as in the MTHFR C677T polymorphism, which affects approximately 10-15% of the general population and which reduces the activity of the MTHFR enzyme that generates 5-methyltetrahydrofolate). The betaine-homocysteine methyltransferase pathway is therefore a critical backup system for the maintenance of normal homocysteine levels, and its impairment (as occurs in betaine deficiency or in BHMT polymorphisms) is associated with elevated homocysteine and with the increased cardiovascular risk that is associated with hyperhomocysteinemia.
The Betaine-Homocysteine Methyltransferase Pathway
The betaine-homocysteine methyltransferase (BHMT) pathway is one of the two primary pathways for the remethylation of homocysteine to methionine, and it is particularly important in the liver and the kidney, where the BHMT enzyme is highly expressed. The BHMT reaction is architecturally coupled to the methionine adenosyltransferase (MAT) reaction, which converts the methionine that is generated by BHMT to SAM — this architectural coupling ensures that the methionine that is generated by BHMT is efficiently converted to SAM and does not accumulate to levels that would inhibit the BHMT enzyme through product feedback inhibition. The BHMT pathway is distinct from the folate pathway in several important respects — it is not affected by the MTHFR C677T polymorphism (which makes it particularly useful for people with this polymorphism who have impaired folate-dependent remethylation); it is not dependent on vitamin B12 as a cofactor (which makes it useful for people with vitamin B12 deficiency, who have impaired folate-independent remethylation); and it is restricted to the liver and the kidney (whereas the folate pathway operates in all tissues).
The clinical importance of the BHMT pathway is underscored by the genetic deficiency of BHMT, which is a rare autosomal recessive disorder that is characterised by elevated homocysteine, elevated methionine, and a clinical syndrome that includes developmental delay, intellectual disability, and in some cases, seizures. The BHMT knockout mouse (which lacks the Bhmt gene) has markedly elevated homocysteine levels and a fatty liver phenotype, demonstrating the importance of the BHMT pathway for both homocysteine metabolism and liver function. The treatment of BHMT deficiency involves dietary methionine restriction (to reduce the homocysteine burden) and betaine supplementation (to bypass the defective BHMT enzyme and to provide an alternative pathway for homocysteine remethylation). The dramatic response to betaine supplementation in BHMT deficiency is one of the most powerful demonstrations of the essential role of betaine in human metabolism.
Betaine and Homocysteine Lowering
The homocysteine-lowering effect of betaine is one of the most important and most consistent effects of this nutrient. Multiple RCTs have demonstrated that betaine supplementation at 1.5-6g daily significantly reduces fasting homocysteine levels in people with hyperhomocysteinemia — a meta-analysis of 8 RCTs found that betaine supplementation reduced fasting homocysteine by approximately 1.5-3 micromol/L, with the greatest reductions seen in people with the highest baseline homocysteine levels. The mechanism of this homocysteine-lowering effect is the betaine-induced activation of the BHMT pathway, which diverts homocysteine away from the transsulfuration pathway and back to the remethylation pathway, converting it to methionine. The betaine-induced increase in methionine synthesis also increases the SAM/SAH ratio, which improves the activity of the methylation cycle and the downstream methylation reactions that are essential for DNA, RNA, protein, and neurotransmitter synthesis.
The clinical importance of the betaine-homocysteine connection for cardiovascular health is underscored by the association between elevated homocysteine and cardiovascular disease. Each 5 micromol/L increase in fasting homocysteine is associated with approximately 20% increased risk of coronary heart disease and stroke. The mechanisms by which homocysteine damages blood vessels include endothelial dysfunction (by reducing nitric oxide production and by increasing oxidative stress through the generation of superoxide from eNOS uncoupling), the promotion of LDL cholesterol oxidation (by increasing the oxidative stress in the vascular wall), the activation of the coagulation cascade (by increasing the expression of tissue factor and by inhibiting the anticoagulant pathways that normally protect the vascular endothelium), and the stimulation of vascular smooth muscle cell proliferation (through effects on the cell cycle regulators that control smooth muscle proliferation). Betaine supplementation, by lowering homocysteine, may reduce the cardiovascular risk that is associated with hyperhomocysteinemia, though the evidence from large cardiovascular outcome trials is not yet available.
Betaine and Liver Function
Betaine also has important effects on liver function, which are independent of its homocysteine-lowering effect. Betaine has been shown to reduce hepatic fat accumulation (hepatic steatosis) in animal models of fatty liver disease and in humans with non-alcoholic fatty liver disease (NAFLD). The mechanism of this hepatoprotective effect is thought to involve the betaine-induced increase in SAM levels (which increases phosphatidylcholine synthesis and VLDL assembly, promoting the export of fat from the liver), the betaine-induced reduction in the activity of the genes that promote lipogenesis (fat synthesis) in the liver (including the SREBP-1c and ChREBP transcription factors), and the betaine-induced improvement in insulin sensitivity in the liver. A double-blind RCT in 80 adults with NAFLD found that betaine supplementation at 2g twice daily (4g daily) for 12 months significantly reduced hepatic fat content (measured by MRI) and improved the markers of liver function (ALT, AST) compared to placebo. These findings suggest that betaine is a useful adjunct to lifestyle modification (diet and exercise) in the management of NAFLD, which is one of the most common liver disorders in the world and which is associated with obesity, the metabolic syndrome, and type 2 diabetes.
Practical Application
For general betaine supplementation (as a homocysteine-lowering and hepatoprotective strategy), the evidence-based dose is 1.5-6g of betaine daily (or 3-6g of betaine daily for the treatment of NAFLD), divided into 2 doses and taken with meals. Betaine is generally well-tolerated with no significant adverse effects at therapeutic doses, though very high doses can produce mild GI upset and a fishy body odour (due to the production of trimethylamine by the gut microbiota, which is then oxidised to trimethylamine N-oxide and excreted). For comprehensive homocysteine management, betaine pairs well with the folate pathway nutrients (5-MTHF at 400-800mcg daily for people with MTHFR polymorphisms, B12 as methylcobalamin at 500-1,000mcg daily, and B6 as PLP at 10-25mg daily), with NAC (which supports glutathione synthesis and provides additional sulfur amino acids for the transsulfuration pathway), with trimethylglycine (TMG, which is the same molecule as betaine and which is redundant if betaine is already being supplemented), and with the Mediterranean dietary pattern (which is associated with lower homocysteine levels and with better cardiovascular outcomes through its effects on the methyl donor status and on the inflammatory status of the vasculature).
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