Choline is a cation with the chemical formula .[
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Choline is used to synthesize acetylcholine, a neurotransmitter involved in muscle control and numerous functions of the nervous system.[ Choline is involved in early development of the brain, gene expression, cell membrane signaling, and brain metabolism.][
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Although humans synthesize choline in the liver, the amount produced naturally is insufficient to meet cellular functions, requiring that some choline be obtained from foods or dietary supplements.[ Foods rich in choline include meats, poultry, eggs, and other animal-based products, cruciferous vegetables, beans, nuts, and .][ Choline is present in breast milk and is commonly added as an food additive to .][
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Chemistry
Choline is a quaternary ammonium cation. The cholines are a family of water-soluble quaternary ammonium compounds.[ Choline is the parent compound of the choline class, consisting of ethanolamine residue having three methyl groups attached to the same nitrogen atom.][ Choline hydroxide is known as choline base. It is hygroscopic and thus often encountered as a colorless viscous hydrated syrup that smells of trimethylamine (TMA). Aqueous solutions of choline are stable, but the compound slowly breaks down to ethylene glycol, polyethylene glycols, and TMA.]
Choline chloride can be prepared by treating TMA with 2-chloroethanol:
Choline has historically been produced from natural sources, such as via hydrolysis of lecithin.
Choline as a nutrient
Choline is widespread in living beings. In most animals, choline phospholipids are necessary components in , in the membranes of cell , and in very low-density lipoproteins.
Choline is an essential nutrient for humans and many other animals.[ Choline is not formally classified as a vitamin despite being an essential nutrient with an amino acid–like structure and metabolism.][
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Choline is required to produce acetylcholine – a neurotransmitter – and S-adenosylmethionine (SAM), a universal methyl donor. Upon methylation SAM is transformed into S-adenosyl homocysteine.
Symptomatic choline deficiency causes non-alcoholic fatty liver disease and muscle damage.[ Rich dietary sources of choline and choline phospholipids include organ meats, egg yolks, dairy products, , certain beans, nuts and seeds. Vegetables with pasta and rice also contribute to choline intake in the American diet.][
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Metabolism
Biosynthesis
In plants, the first step in de novo biosynthesis of choline is the decarboxylation of serine into ethanolamine, which is catalyzed by a decarboxylase.
In humans and most other animals, de novo synthesis of choline proceeds via the phosphatidylethanolamine N-methyltransferase (PEMT) pathway,[ but biosynthesis is not enough to meet human requirements.][ In the hepatic PEMT route, 3-phosphoglycerate (3PG) receives 2 from acyl-CoA forming a phosphatidic acid. It reacts with cytidine triphosphate to form cytidine diphosphate-diacylglycerol. Its hydroxyl group reacts with serine to form phosphatidylserine, which to ethanolamine and phosphatidylethanolamine (PE) forms. A PEMT enzyme moves three methyl groups from three S-adenosyl methionines (SAM) donors to the ethanolamine group of the phosphatidylethanolamine to form choline in the form of a phosphatidylcholine. Three S-adenosylhomocysteines (SAHs) are formed as a byproduct.][
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Choline can also be released from more complex precursors. For example, phosphatidylcholines (PC) can be hydrolyzed to choline (Chol) in most cell types. Choline can also be produced by the CDP-choline route, cytosolic (CK) phosphorylate choline with ATP to phosphocholine (PChol).[ This happens in some cell types like liver and kidney. Choline-phosphate cytidylyltransferases (CPCT) transform PChol to CDP-choline (CDP-Chol) with cytidine triphosphate (CTP). CDP-choline and diglyceride are transformed to PC by diacylglycerol cholinephosphotransferase (CPT).][
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In humans, certain PEMT-enzyme and estrogen deficiency (often due to menopause) increase the dietary need for choline. In rodents, 70% of phosphatidylcholines are formed via the PEMT route and only 30% via the CDP-choline route.[ In knockout mice, PEMT inactivation makes them completely dependent on dietary choline.][
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Absorption
In humans, choline is absorbed from the via the SLC44A1 (CTL1) membrane protein via facilitated diffusion governed by the choline concentration gradient and the electrical potential across the enterocyte membranes. SLC44A1 has limited ability to transport choline: at high concentrations part of it is left unabsorbed. Absorbed choline leaves the enterocytes via the portal vein, passes the liver and enters systemic circulation. degrade the unabsorbed choline to trimethylamine, which is oxidized in the liver to trimethylamine N-oxide.[
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Phosphocholine and glycerophosphocholines are hydrolyzed via to choline, which enters the portal vein. Due to their water solubility, some of them escape unchanged to the portal vein. Fat-soluble choline-containing compounds (phosphatidylcholines and ) are either hydrolyzed by phospholipases or enter the lymph incorporated into .[
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Transport
In humans, choline is transported as a free ion in blood. Choline–containing and other substances, like glycerophosphocholines, are transported in blood . Blood plasma choline levels in healthy fasting adults is 7–20 micromoles per liter (μmol/L) and 10 μmol/L on average. Levels are regulated, but choline intake and deficiency alter these levels. Levels are elevated for about 3 hours after choline consumption. Phosphatidylcholine levels in the plasma of fasting adults is 1.5–2.5 mmol/L. Its consumption elevates the free choline levels for about 8–12 hours, but does not affect phosphatidylcholine levels significantly.[
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Choline is a water-soluble ion and thus requires transporters to pass through fat-soluble . Three types of choline transporters are known:
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SLC5A7
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CTLs: CTL1 (SLC44A1), CTL2 (SLC44A2) and CTL4 (SLC44A4)
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OCTs: OCT1 (SLC22A1) and OCT2 (SLC22A2)
SLC5A7s are sodium- (Na+) and ATP-dependent transporters.[ They have high binding affinity for choline, transport it primarily to and are indirectly associated with the acetylcholine production.][ Their deficient function causes hereditary weakness in the pulmonary and other muscles in humans via acetylcholine deficiency. In knockout mice, their dysfunction results easily in death with cyanosis and paralysis.]
CTL1s have moderate affinity for choline and transport it in almost all tissues, including the intestines, liver, kidneys, placenta, and mitochondria. CTL1s supply choline for phosphatidylcholine and trimethylglycine production.[ CTL2s occur especially in the mitochondria in the tongue, kidneys, muscles, and heart. They are associated with the mitochondrial oxidation of choline to trimethylglycine. CTL1s and CTL2s are not associated with acetylcholine production, but transport choline together via the blood–brain barrier. Only CTL2s occur on the brain side of the barrier. They also remove excess choline from the neurons back to the blood. CTL1s occur only on the blood side of the barrier, but also on the membranes of and neurons.]
OCT1s and OCT2s are not associated with acetylcholine production.[ They transport choline with low affinity. OCT1s transport choline primarily in the liver and kidneys, while OCT2s transport choline in the kidneys and the brain.]
Storage
Choline is stored in the cell membranes and as phospholipids, and inside cells as phosphatidylcholines and glycerophosphocholines.[
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Excretion
Even at choline doses of 2–8 g, little choline is excreted into urine in humans. Excretion happens via transporters that occur within the kidneys (see transport). Trimethylglycine is demethylated in the liver and kidneys to dimethylglycine (tetrahydrofolate receives one of the methyl groups). Methylglycine forms are excreted into urine or are demethylated to glycine.[
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Function
Choline and its derivatives have many biological functions. Notably, choline serves as a precursor for other essential cell components and signaling molecules, such as phospholipids that form cell membranes, the neurotransmitter acetylcholine, and the osmoregulator trimethylglycine (betaine). Trimethylglycine in turn serves as a source of by participating in the biosynthesis of S-adenosylmethionine.
Phospholipid precursor
Choline is transformed into diverse phospholipids, like phosphatidylcholines and sphingomyelins.[ These are found in all cell membranes and the membranes of most cell organelles.][ Phosphatidylcholines are a structurally important part of the cell membranes. In humans, 40–50% of their phospholipids are phosphatidylcholines.][
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Choline phospholipids also form lipid rafts in the cell membranes along with cholesterol.[ The rafts are centers, for example for cholinergic receptors and receptor signal transduction enzymes.][
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Phosphatidylcholines are needed for the synthesis of : 70–95% of their phospholipids are phosphatidylcholines in humans.[
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Choline is also needed for the synthesis of pulmonary surfactant, which is a mixture consisting mostly of phosphatidylcholines. The surfactant is responsible for lung elasticity, that is, for the lung tissue's ability to contract and expand. For example, deficiency of phosphatidylcholines in the lung tissues has been linked to acute respiratory distress syndrome.
Phosphatidylcholines are excreted into bile and work together with bile acid salts as in it, thus helping with the intestinal absorption of .[
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Acetylcholine synthesis
Choline is a precursor to acetylcholine, a neurotransmitter that plays a necessary role in muscle contraction, memory, and neural development.[ Neurons also store choline in the form of phospholipids in their cell membranes for the production of acetylcholine.][
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Source of trimethylglycine
In humans, choline is oxidized irreversibly in liver mitochondria to glycine betaine aldehyde by . This is oxidized by mitochondrial or cytosolic betaine-aldehyde dehydrogenases to trimethylglycine.[ Trimethylglycine is a necessary osmoregulator. It also works as a substrate for the BHMT-enzyme, which methylates homocysteine to methionine. This is a S-adenosylmethionine (SAM) precursor. SAM is a common reagent in biological methylation reactions. For example, it methylates of DNA and certain of . Thus, it is part of gene expression and epigenetic regulation. Choline deficiency thus leads to elevated homocysteine levels and decreased SAM levels in blood.][
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Content in foods
Choline occurs in foods as a free cation and in the form of phospholipids, especially as phosphatidylcholines. Choline is highest in organ meats and egg yolks, though it is found to a lesser degree in non-organ meats, grains, vegetables, fruit, and dairy products.[ and other food fats have about 5 mg/100 g of total choline.]
Human breast milk is rich in choline.[ Exclusive breastfeeding corresponds to about 120 mg of choline per day for the baby. An increase in a mother's choline intake raises the choline content of breast milk, and a low intake decreases it.]
Trimethylglycine is a functional metabolite of choline. It substitutes for choline nutritionally, but only partially.[ High amounts of trimethylglycine occur in wheat bran (1,339 mg/100 g), toasted wheat germ (1,240 mg/100 g) and spinach (600–645 mg/100 g), for example.]+Choline content of foods (mg/100 g) | Meats
! colspan="2" | Vegetables |
| Bacon, cooked | 124.89 | Green bean | 13.46 |
| Beef, trim-cut, cooked | 78.15 | Beetroot | 6.01 |
| Beef liver, pan fried | 418.22 | Broccoli | 40.06 |
| Chicken, roasted, with skin | 65.83 | Brussels sprout | 40.61 |
| Chicken, roasted, no skin | 78.74 | Cabbage | 15.45 |
| Chicken liver | 290.03 | Carrot | 8.79 |
| Atlantic cod | 83.63 | Cauliflower | 39.10 |
| Ground beef, 75–85% lean, broiled | 79.32–82.35 | Maize, yellow | 21.95 |
| Pork loin cooked | 102.76 | Cucumber | 5.95 |
| Shrimp, canned | 70.60 | Lettuce, iceberg | 6.70 |
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| Butter, salted | 18.77 | Pea | 27.51 |
| Cheese | 16.50–27.21 | Sauerkraut | 10.39 |
| Cottage cheese | 18.42 | Spinach | 22.08 |
| Milk, whole/skimmed | 14.29–16.40 | Sweet potato | 13.11 |
| Sour cream | 20.33 | Tomato | 6.74 |
| Yogurt, plain | 15.20 | Zucchini | 9.36 |
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| Oat bran, raw | 58.57 | Apple | 3.44 |
| Oatmeal, plain | 7.42 | Avocado | 14.18 |
| White rice | 2.08 | Banana | 9.76 |
| Brown rice | 9.22 | Blueberry | 6.04 |
| Wheat bran | 74.39 | Cantaloupe | 7.58 |
| Wheat germ, toasted | 152.08 | Grape | 7.53 |
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| Navy bean | 26.93 | Orange | 8.38 |
| Chicken egg | 251.00 | Peach | 6.10 |
| Olive oil | 0.29 | Pear | 5.11 |
| Peanut | 52.47 | Prune | 9.66 |
| Soybean, raw | 115.87 | Strawberry | 5.65 |
| Tofu, soft | 27.37 | Watermelon | 4.07 |
Daily values
The following table contains updated sources of choline to reflect the new Daily Value and the new Nutrition Facts and Supplement Facts Labels.[ It reflects data from the U.S. Department of Agriculture, Agricultural Research Service. FoodData Central, 2019.][
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+Selected Food Sources of Choline | Food | Milligrams (mg) per serving | Percent DV* |
| Beef liver, pan fried, | 356 | 65 |
| Egg, hard-boiled, 1 large egg | 147 | 27 |
| Beef top round, separable lean only, braised, | 117 | 21 |
| , roasted, | 107 | 19 |
| Chicken breast, roasted, | 72 | 13 |
| Beef, ground, 93% lean meat, broiled, | 72 | 13 |
| Atlantic cod, cooked, dry heat, | 71 | 13 |
| Shiitake, cooked, pieces | 58 | 11 |
| Red potato, baked, flesh and skin, 1 large potato | 57 | 10 |
| Wheat germ, toasted, | 51 | 9 |
| Kidney bean, canned, | 45 | 8 |
| Quinoa, cooked, | 43 | 8 |
| Milk, 1% fat, | 43 | 8 |
| Yogurt, vanilla, nonfat, | 38 | 7 |
| , boiled, | 32 | 6 |
| Broccoli, chopped, boiled, drained, | 31 | 6 |
| Cottage cheese, nonfat, | 26 | 5 |
| Tuna, white, canned in water, drained in solids, | 25 | 5 |
| , dry roasted, | 24 | 4 |
| Cauliflower, pieces, boiled, drained, | 24 | 4 |
| Green peas, boiled, | 24 | 4 |
| Sunflower seeds, oil roasted, | 19 | 3 |
| Brown rice, long-grain, cooked, | 19 | 3 |
| Pita, whole wheat, 1 large ( diameter) | 17 | 3 |
| Cabbage, boiled, | 15 | 3 |
| Tangerine (mandarin orange), sections, | 10 | 2 |
| Snap bean, raw, | 8 | 1 |
| Kiwifruit, raw, sliced | 7 | 1 |
| Carrots, raw, chopped, | 6 | 1 |
| , raw, with skin, quartered or chopped, | 2 | 0 |
DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for choline is 550 mg for adults and children age 4 years and older.
The U.S. Department of Agriculture's (USDA's) FoodData Central lists the nutrient content of many foods and provides a comprehensive list of foods containing choline arranged by nutrient content.
Dietary recommendations
Insufficient data is available to establish an estimated average requirement (EAR) for choline, so the Food and Nutrition Board established adequate intakes (AIs).[ These values have been shown to prevent hepatic alteration in men. However, the study used to derive these values did not evaluate whether less choline would be effective, as researchers only compared a choline-free diet to a diet containing 550 mg of choline per day. From this, the AIs for children and adolescents were extrapolated.]
Recommendations are in milligrams per day (mg/day). The European Food Safety Authority (EFSA) recommendations are general recommendations for the EU countries. The EFSA has not set any upper limits for intake.[ Australia, and New Zealand.]
| +Choline recommendations (mg/day) |
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| Infants and children |
| 0–6 months | Not established | 125 | Not established |
| 7–12 months | 160 | 150 | Not established |
| 1–3 years | 140 | 200 | 1,000 |
| 4–6 years | 170 | 250 | 1,000 |
| 7–8 years | 250 | 250 | 1,000 |
| 9–10 years | 250 | 375 | 1,000 |
| 11–13 years | 340 | 375 | 2,000 |
| Males |
| 14 years | 340 | 550 | 3,000 |
| 15–18 years | 400 | 550 | 3,000 |
| 19+ years | 400 | 550 | 3,500 |
| Females |
| 14 years | 340 | 400 | 3,000 |
| 15–18 years | 400 | 400 | 3,000 |
| 19+ y | 400 | 425 | 3,500 |
| If pregnant | 480 | 450 | 3,500 (3,000 if ≤18 y) |
| If breastfeeding | 520 | 550 | 3,500 (3,000 if ≤18 y) |
Intake in populations
Twelve surveys undertaken in 9 EU countries between 2000 and 2011 estimated choline intake of adults in these countries to be 269–468 milligrams per day. Intake was 269–444 mg/day in adult women and 332–468 mg/day in adult men. Intake was 75–127 mg/day in infants, 151–210 mg/day in 1- to 3-year-olds, 177–304 mg/day in 3- to 10-year-olds, and 244–373 mg/day in 10- to 18-year-olds. The total choline intake mean estimate was 336 mg/day in pregnant adolescents and 356 mg/day in pregnant women.[
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A study based on the NHANES 2009–2012 survey estimated the choline intake to be too low in some US subpopulations. Intake was 315.2–318.8 mg/d in 2+ year olds between this period. Out of 2+ year olds, only % of males and % of females exceeded the adequate intake (AI). AI was exceeded by % of 2- to 3-year-olds, % of 4- to 8-year-olds, % of 9- to 13-year-olds, % of 14–18 and % of 19+ year olds. The upper intake level was not exceeded in any subpopulations.
A 2013–2014 NHANES study of the US population found the choline intake of 2- to 19-year-olds to be mg/day and mg/day in adults 20 and over. Intake was mg/d in men 20 and over and 278 mg/d in women 20 and over.
Deficiency
Signs and symptoms
Symptomatic choline deficiency is rare in humans. Most obtain sufficient amounts of it from the diet and can biosynthesize limited amounts of it via PEMT.
Besides humans, fatty liver is also a typical sign of choline deficiency in other animals. Bleeding in the kidneys can also occur in some species. This is suspected to be due to a deficiency of choline-derived trimethylglycine, which functions as an osmoregulator.[
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Causes and mechanisms
Estrogen production is a relevant factor that predisposes individuals to deficiency, along with low dietary choline intake. Estrogens activate phosphatidylcholine-producing PEMT enzymes. Women before menopause have a lower dietary need for choline than men due to women's higher estrogen production. Without estrogen therapy, the choline needs of post-menopausal women are similar to men's. Some single-nucleotide polymorphisms (genetic factors) affecting choline and folate metabolism are also relevant. Certain gut microbes also degrade choline more efficiently than others, so they are also relevant.
In deficiency, the availability of phosphatidylcholines in the liver is decreased – these are needed for the formation of VLDLs. Thus, VLDL-mediated fatty acid transport out of the liver decreases, leading to fat accumulation in the liver.[ Other simultaneously occurring mechanisms explaining the observed liver damage have also been suggested. For example, choline phospholipids are also needed in mitochondrial membranes. Their unavailability leads to the inability of mitochondrial membranes to maintain proper electrochemical gradient, which, among other things, is needed for degrading fatty acids via β-oxidation. Fat metabolism within the liver therefore, decreases.]
Excess intake
Excessive doses of choline can have adverse effects. Daily 8–20 g doses of choline, for example, have been found to cause low blood pressure, nausea, diarrhea, and fish-like body odor. The odor is due to trimethylamine (TMA) formed by the gut microbes from the unabsorbed choline (see trimethylaminuria).[
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The liver oxidizes TMA to trimethylamine N-oxide (TMAO). Elevated levels of TMA and TMAO in the body have been linked to increased risk of atherosclerosis and mortality. Thus, excessive choline intake has been hypothesized to increase these risks in addition to carnitine, which also is formed into TMA and TMAO by gut bacteria. However, choline intake has not been shown to increase the risk of dying from cardiovascular diseases.
Health effects
Neural tube closure
Low maternal intake of choline is associated with an increased risk of neural tube defects (NTDs).[ Choline and folate, interacting with vitamin B12, act as methyl donors to homocysteine to form methionine, which can then go on to form S-adenosylmethionine (SAM).][ SAM is the substrate for almost all methylation reactions in mammals. It has been suggested that disturbed methylation via SAM could be responsible for the relation between folate and NTDs.][
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Cardiovascular diseases and cancer
Choline deficiency can cause fatty liver, which increases cancer and cardiovascular disease risk. Choline deficiency also decreases SAM production, which is involved in DNA methylation – this decrease may also contribute to carcinogenesis. Thus, deficiency and its association with such diseases have been studied.[ However, observational studies of free populations have not convincingly shown an association between low choline intake and cardiovascular diseases or most cancers.][ Studies on prostate cancer have been contradictory.]
Cognition
Studies observing the effect of higher choline intake and cognition have been conducted in human adults, with contradictory results.[
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Perinatal development
Both pregnancy and lactation increase the demand for choline dramatically. This demand may be met by upregulation of PEMT via increasing estrogen levels to produce more choline de novo, but even with increased PEMT activity, the demand for choline is still so high that bodily stores are generally depleted. This is exemplified by the observation that Pemt −/− mice (mice lacking functional PEMT) will abort at 9–10 days unless fed supplemental choline.
While maternal stores of choline are depleted during pregnancy and lactation, the placenta accumulates choline by pumping choline against the concentration gradient into the tissue, where it is then stored in various forms, mostly as acetylcholine. Choline concentrations in amniotic fluid can be ten times higher than in maternal blood.
Functions in the fetus
Choline is in high demand during pregnancy as a substrate for building cellular membranes (rapid fetal and mother tissue expansion), increased need for one-carbon moieties (a substrate for methylation of DNA and other functions), raising choline stores in fetal and placental tissues, and for increased production of lipoproteins (proteins containing "fat" portions).
Choline uptake into the brain is controlled by a low-affinity transporter located at the blood–brain barrier.
Uses
Choline chloride and choline bitartrate are used in dietary supplements. Bitartrate is used more often due to its lower hygroscopicity.[ Certain choline salts are used to supplement chicken, turkey, and some other . Some salts are also used as industrial chemicals: for example, in photolithography to remove photoresist.]
The most common forms of dietary choline supplements are shown in the following table:
|
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| 40.5% |
| 41.13 |
| 35.28% |
| 21.33% |
14-29% |
1.67% – 2.20% |
History
Discovery
In 1849, Adolph Strecker was the first to isolate choline from pig bile.
In 1865, Oscar Liebreich isolated " neurine" from animal brains.
Discovery as a nutrient
In the early 1930s, Charles Best and colleagues noted that fatty liver in rats on a special diet and diabetic dogs could be prevented by feeding them lecithin,[ proving in 1932 that choline in lecithin was solely responsible for this preventive effect.]
