Choline

Choline is metabolized within a cells mitochondria (via mitochondrial choline oxidase) and then again in the mitochondria by betaine aldehyde dehydrogenase, with this irreversible two-stage process resulting in production of trimethylglycine.^[1][2]

Choline is known to be oxidized into the metabolite trimethylglycine (TMG) within a cells mitochondria,^[1][2] and TMG plays a role in supporting methyl donation processes either directly (methylating homocysteine) or indirectly through supporting bodily production of S-adenosyl methionine (SAMe). Supplemental choline can, vicariously through these two metabolites, confer beneficial properties to whole body methylation.

It has been noted that in subjects with a mutation in the 5-methyltetrahydrofolate reductase (MTHFR) enzyme, the enzyme responsible for producing SAMe from folic acid, that the body seems to place more burden on choline and the betaine homocysteine methyltransferase enzyme. This has been demonstrated in men with the MTHFR C677T genotype (reduced activity) where 300mg, 500mg, or 1,100mg choline was given fro 12 weeks and appeared to improve methylation to a relatively larger degree in those with impaired MTHFR function.^[3]

Supplementation of 1,000mg choline (via 2,400mg choline bitartrate) appears to increase steady state plasma choline from 7.33µM to 11.1-11.7µM (51-60%) in otherwise healthy postmenopausal women.^[4]

Although there appear to be no differences between youth and elderly in fasting choline concentrations in serum or the response of serum choline to supplementation (50mg/kg choline in the form of choline bitartrate), it appears that the increase in choline containing compounds in the brain in the elderly (19% higher than baseline) was significantly less than that seen in youth (60%).^[5]

Choline is converted into acetylcholine (ACh) via the enzyme choline acetyltransferase (ChAT).

It is known that trimethylamine compounds (choline and trimethylglycine) can be metabolized by intestinal bacteria to form the gas trimethylamine (TMA) which is reminiscient of rotting fish^[6] but is absorbed through the colon wall and is metabolized by flavin monooxygenase (FMO3 in particular) to form odourless trimethylamine N-oxide (TMAO).^[7][8] When fed to mice when their normal chow diet (0.08-0.09% choline) was enhanced to either 0.5% or 1% choline by weight the higher doses were able to accelerate formation of atherosclerotic lesions; these lesions were highly correlated with serum TMAO and with hepatic FMO3 expression which was higher in female rats (1,000-fold).^[9] This study also confirmed that suppression of gastrointestinal flora (with antibiotics) reduced serum TMAO increases from dietary choline and prevented the increase in atherogenesis from choline (which appears to be mediated via TMAO) and that isotopically labelled oral choline products were found to be labelled TMAO; strongly suggesting a direct metabolic conversion.^[9] This paper has a few responses which are catered to prescribing possible solutions to the 'problematic' metabolism,^[10] commenting on intestinal metabolism,^[11] or commenting on the metabolonomic approach.^[12]

Preliminary (fairly convincing) that the metabolite of choline known as TMAO can be pro-atherogenic while choline itself does not appear to be pro-atherogenic, although ingestion of choline begets metabolism into TMAO

Production of trimethylamine from supplemental choline (27mM) has been noted in humans up to 18mM with Choline Chloride and 10mM with Choline stearate, but none with Lecithin.^[13] Similar lack of effects have been noted with lecithin and betaine elsewhere.^[8] A later study, however, did see an increase in TMAO upon phosphatidylcholine challenge conisting of eating two hardboiled eggs along with deuterium-labelled phosphatidylcholine; this increase was ablated when broad-spectrum antibiotics were administered to reduce intestinal microflora, suggesting that TMAO can be produced by intestinal microflora from choline sources.^[14] A prospective observational study also linked TMAO blood levels to adverse cardiovascular events, with those in the highest quartile of TMAO levels having a hazard ratio of 2.54 (95% CI 1.96 to 3.28) compared to the highest quartile.^[14]

Dietary choline sources, including lecithin (phosphatidylcholine), may increase serum TMAO in humans, although the evidence is mixed. Higher TMAO levels may lead to increased risk of cardiovascular disease.

One study measuring choline intake in mothers and the effects on the offspring noted that consumption of 930mg choline per day (during the 12 weeks of the third trimester) was able to reduce genetic expression of cortisol production in their offspring.^[15]

A deficiency in dietary choline is known to increase hepatic fatty acid (triglyceride) accumulation^[16] and impair triglyceride release from the liver into plasma^[17] due to reduced phosphatidylcholine (PC) synthesis; PC synthesis promotes vLDL (a lipoprotein) synthesis which effluxes triglycerides from the liver into plasma^[18][19] since PC itself is a necessary component of vLDL. This reduced production of PC is mostly due to reduced levels of the choline metabolite Trimethylglycine (TMG), since TMG directly initiates the first state of PC production (methylation via the BHMT enzyme^[20]) and by supporting S-adenosyl methionine (SAMe) production it also supports the final synthetic stage (phosphatidylethanolamine N-methyltransferase, which requires SAMe to creatine PC^[21]).

A choline deficiency, secondary to creating a deficiency of TMG, is able to reduce or prevent the transport of triglycerides into the blood and to peripheral tissues from the liver (such as adipose or skeletal muscle) resulting in both a state of low blood triglyceride and fatty liver

Trimethylglycine (TMG for short, and also known to incorrectly be referred to as betaine) is a metabolite of choline that occurs in the diet and mediates the methylation properties of choline supplementation.

It appears that supplementation of TMG at the dose of 1,000mg daily has been able to increase steady state concentrations of TMG from 31.4+/-13.6µM to 52.5+/-26.5µM (a 67% increase from baseline levels)^[22] whereas supplementation of the same dose of choline (1,000mg of choline via 2,400mg choline bitartrate) was able to increase steady state TMG from a median value of 30.7µM to 54.6-65µM (a 77-111% increase) alongside serum increases in choline itself (from 7.33µM to 11.1-11.7µM).^[4] This suggests that, at least at supplemental doses up to 1,000mg, that choline and trimethylglycine are equipotent at increasing serum TMG and methylation.

At least up to the dose of 1,000mg, it seems that TMG and choline are of the same potency in increasing bodily levels of TMG and overall methylation

Trimethylamine (TMA) is a metabolite of many small weight amino acid molecules (such as choline) that is known to have a fishy odour, and urinary levels are usually low enough to be without scent unless the person has abnormally high levels in their urine and body secretions (Trimethylaminuria) which is a condition known as "Fish Odour Syndrome";^[23] it is caused by either a mutation in the liver enzyme flavin containing mono-oxygenase type 3 (FMO3^[24]) which metabolizes TMA known as 'Primary trimethylaminuria' or from excess production of TMA in the intestinal tract from bacteria known as 'Secondary trimethylaminuria'.^[25][26] It is medically benign (ie. not a medical concern), but adherence to supplementation goes down since many subjects would rather not smell like fish and its mild trimethylaminuria could affect anywhere between 1 in 20 or 1 in 100 of persons.^[27]

Traditionally speaking, trimethylaminuria has been associated with dietary choline intake^[25][28][29] although it may also arise from trimethylglycine supplementation in high levels;^[30] in these instances, it appears that 100mg of Riboflavin (Vitamin B2) twice daily has limited evidence (case study) in reducing the scent of fish in those consuming supplementation.^[30]

It is possible that riboflavin can reduce the smell of fish that arises from when somebody with a mutation in the FMO3 gene (genetic susceptability to the fishy smell from some of these dietary factors) supplements choline