Choline

Choline is a molecule mostly used for either its cognitive boosting properties (turning into acetylcholine, the learning neurotransmitter) or as a liver health agent, able to reduce fatty liver buildup. Found in high amounts in eggs, the yolks in particular.

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Also Known As

Trimethylethanolamine, Choline Bitartrate


Do Not Confuse With

DMAE, Lecithin


Things to Note

  • Choline has been reported (anecdotally) to possess stimulatory properties

Is a Form of


Goes Well With

  • Riboflavin (Vitamin B2) may reduce the fishy odor that some people experience with choline supplementation

Stacks Part Of


    Caution Notice

    Examine.com Medical Disclaimer

    Doses for choline vary significantly.

    Typically a dose of 250mg to 500mg is used for general health purposes once daily.

    For mechanisms through acetylcholine, the choline should be pulsed in high doses acutely as higher doses are partitioned to the brain to a greater extent. 1-2g is typically used.

    Doses should be titrated to suit the individual, as too high of a dose at any given time may give the user a headache. It is suggested that doses start out at 50-100mg daily and that users adjust upwards in accordance with their tolerance.


    Table of Contents:


    Edit1. Sources and Structure

    1.1. Biological Significance

    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]


    Edit2. Molecular Targets

    2.1. Methyl Donation

    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. Supplemental choline can, vicariously through these two metabolites, confer beneficial properties to whole body methylation.


    Edit3. Pharmacology

    3.1. Serum

    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.[3]


    Edit4. Neurology

    4.1. Neuropharmacology

    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%).[4]

    4.2. Cholinergic Neurotransmission

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


    Edit5. Cardiovascular Health

    5.1. Artherosclerosis

    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[5] but is absorbed through the colon wall and is metabolized by flavin monooxygenase (FMO3 in particular) to form odourless trimethylamine N-oxide (TMAO).[6][7] 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 artherosclerotic lesions; these lesions were highly corrected with serum TMAO and with hepatic FMO3 expression which was higher in female rats (1,000-fold).[8] 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.[8] This paper has a few responses which are catered to prescribing possible solutions to the 'problematic' metabolism,[9] commenting on intestinal metabolism,[10] or commenting on the metabolonomic approach.[11]

    Preliminary (fairly convincing) that the metabolite of choline known as TMAO can be pro-artherogenic while choline itself does not appear to be pro-artherogenic, 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.[12] Similar lack of effects have been noted with lecithin and betaine elsewhere.[7]

    Dietary choline sources, including lecithin (phosphatidylcholine), fail to significantly increase serum TMAO in humans


    Edit6. Sexuality and Pregnancy

    6.1. Pregnancy

    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.[13]


    Edit7. Peripheral Organ Systems

    7.1. Liver

    A deficiency in dietary choline is known to increase hepatic fatty acid (triglyceride) accumulation[14] and impair triglyceride release from the liver into plasma[15] due to reduced Phosphatidylcholine (PC) synthesis; PC synthesis promotes vLDL (a lipoprotein) synthesis which effluxes triglycerides from the liver into plasma[16][17] 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[18]) and by supporting S-Adenosyl Methionine (SAMe) production it also supports the final synthetic stage (phosphatidylethanolamine N-methyltransferase, which requires SAMe to creatine PC[19]).

    A choline deficiency, secondary to creating a deficiency of TMG, is able to reduce ot 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


    Edit8. Nutrient-Nutrient Interactions

    8.1. Trimethylglycine (TMG or Betaine)

    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)[20] 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).[3] 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

    8.2. Riboflavin

    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";[21] it is caused by either a mutation in the liver enzyme flavin containing mono-oxygenase type 3 (FMO3[22]) which metabolizes TMA known as 'Primary trimethylaminuria' or from excess production of TMA in the intestinal tract from bacteria known as 'Secondary trimethylaminuria'.[23][24] 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 it mild trimethylaminuria could affect anywhere between 1 in 20 or 1 in 100 of persons.[25]

    Traditionally speaking, trimethylaminuria has been associated with dietary choline intake[23][26][27] although it may also arise from Trimethylglycine supplementation in high levels;[28] 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.[28]

    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

    References

    1. Choline oxidation and choline dehydrogenase
    2. Ueland PM. Choline and betaine in health and disease. J Inherit Metab Dis. (2011)
    3. Wallace JM, et al. Choline supplementation and measures of choline and betaine status: a randomised, controlled trial in postmenopausal women. Br J Nutr. (2012)
    4. Cohen BM, et al. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. JAMA. (1995)
    5. al-Waiz M, et al. The exogenous origin of trimethylamine in the mouse. Metabolism. (1992)
    6. Lang DH, et al. Isoform specificity of trimethylamine N-oxygenation by human flavin-containing monooxygenase (FMO) and P450 enzymes: selective catalysis by FMO3. Biochem Pharmacol. (1998)
    7. Zhang AQ, Mitchell SC, Smith RL. Dietary precursors of trimethylamine in man: a pilot study. Food Chem Toxicol. (1999)
    8. Wang Z, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. (2011)
    9. Rak K, Rader DJ. Cardiovascular disease: the diet-microbe morbid union. Nature. (2011)
    10. Davidson S. Flagging flora: heart disease link. Nature. (2011)
    11. Mayr M. Recent highlights of metabolomics in cardiovascular research. Circ Cardiovasc Genet. (2011)
    12. Zeisel SH, Wishnok JS, Blusztajn JK. Formation of methylamines from ingested choline and lecithin. J Pharmacol Exp Ther. (1983)
    13. Maternal choline intake alters the epigenetic state of fetal cortisol-regulating genes in humans
    14. Bruni C, Hegsted DM. Effects of choline-deficient diets on the rat hepatocyte. Electron microscopic observations. Am J Pathol. (1970)
    15. Lombardi B, Pani P, Schlunk FF. Choline-deficiency fatty liver: impaired release of hepatic triglycerides. J Lipid Res. (1968)
    16. Sowden MP, et al. Apolipoprotein B mRNA and lipoprotein secretion are increased in McArdle RH-7777 cells by expression of betaine-homocysteine S-methyltransferase. Biochem J. (1999)
    17. Yao ZM, Vance DE. The active synthesis of phosphatidylcholine is required for very low density lipoprotein secretion from rat hepatocytes. J Biol Chem. (1988)
    18. Emmert JL, et al. Hepatic and renal betaine-homocysteine methyltransferase activity in pigs as affected by dietary intakes of sulfur amino acids, choline, and betaine. J Anim Sci. (1998)
    19. Ridgway ND, Vance DE. Kinetic mechanism of phosphatidylethanolamine N-methyltransferase. J Biol Chem. (1988)
    20. Alfthan G, et al. The effect of low doses of betaine on plasma homocysteine in healthy volunteers. Br J Nutr. (2004)
    21. Humbert JA, Hammond KB, Hathaway WE. Trimethylaminuria: the fish-odour syndrome. Lancet. (1970)
    22. Treacy EP, et al. Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum Mol Genet. (1998)
    23. Mitchell SC. The fish-odor syndrome. Perspect Biol Med. (1996)
    24. Fraser-Andrews EA, et al. Fish odour syndrome with features of both primary and secondary trimethylaminuria. Clin Exp Dermatol. (2003)
    25. Zschocke J, et al. Mild trimethylaminuria caused by common variants in FMO3 gene. Lancet. (1999)
    26. Pardini RS, Sapien RE. Trimethylaminuria (fish odor syndrome) related to the choline concentration of infant formula. Pediatr Emerg Care. (2003)
    27. Rehman HU. Fish odor syndrome. Postgrad Med J. (1999)
    28. Riboflavin-Responsive Trimethylaminuria in a Patient with Homocystinuria on Betaine Therapy
    29. Harris RC, Söderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond). (1992)
    30. Diet and Refsum's disease. The determination of phytanic acid and phytol in certain foods and the application of this knowledge to the choice of suitable convenience foods for patients with Refsum's disease
    31. Rawson ES, et al. Creatine supplementation does not improve cognitive function in young adults. Physiol Behav. (2008)
    32. Benton D, Donohoe R. The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores. Br J Nutr. (2011)
    33. Phytanic acid: measurement of plasma concentrations by gas–liquid chromatography–mass spectrometry analysis and associations with diet and other plasma fatty acids
    34. Deuster PA, et al. Choline ingestion does not modify physical or cognitive performance. Mil Med. (2002)
    35. Warber JP, et al. The effects of choline supplementation on physical performance. Int J Sport Nutr Exerc Metab. (2000)
    36. Spector SA, et al. Effect of choline supplementation on fatigue in trained cyclists. Med Sci Sports Exerc. (1995)

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