Choline

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Contents

Choline
Choline cation.png
Choline-cation-3D-balls.png
Names
IUPAC name
2-Hydroxyethyl(trimethyl)azanium [1]
Preferred IUPAC name
2-Hydroxy-N,N,N-trimethylethan-1-aminium
Other names
  • Bilineurine
  • (2-Hydroxyethyl)trimethylammonium
  • 2-Hydroxy-N,N,N-trimethylethanaminium
Identifiers
3D model (JSmol)
1736748
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.487 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 200-535-1
324597
KEGG
PubChem CID
UNII
  • InChI=1S/C5H14NO/c1-6(2,3)4-5-7/h7H,4-5H2,1-3H3/q+1 Yes check.svgY
    Key: OEYIOHPDSNJKLS-UHFFFAOYSA-N Yes check.svgY
  • C[N+](C)(C)CCO
Properties
[(CH3)3NCH2CH2OH]+
Molar mass 104.173 g·mol−1
Structure
Tetrahedral at the nitrogen atom
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Corrosive
GHS labelling:
GHS-pictogram-acid.svg
Danger
H314
P260, P264, P280, P301+P330+P331, P303+P361+P353, P304+P340, P305+P351+P338, P310, P321, P363, P405, P501
NFPA 704 (fire diamond)
NFPA 704.svgHealth 3: Short exposure could cause serious temporary or residual injury. E.g. chlorine gasFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazard COR: Corrosive; strong acid or base. E.g. sulfuric acid, potassium hydroxide
3
1
0
COR
Lethal dose or concentration (LD, LC):
3–6 g/kg (rat, oral) [2]
Safety data sheet (SDS)4
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Choline is a cation with the chemical formula [(CH3)3NCH2CH2OH]+. [1] [2] [3] Choline forms various salts, such as choline chloride and choline bitartrate. An essential nutrient for animals, it is a structural component of phospholipids and cell membranes. [2] [3]

Choline is used to synthesize acetylcholine, a neurotransmitter involved in muscle control and numerous functions of the nervous system. [2] [3] Choline is involved in early development of the brain, gene expression, cell membrane signaling, and brain metabolism. [3]

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. [3] Foods rich in choline include meats, poultry, eggs, and other animal-based products, cruciferous vegetables, beans, nuts, and whole grains. [3] Choline is present in breast milk and is commonly added as an ingredient to baby foods. [3]

Chemistry

Choline is a quaternary ammonium cation. The cholines are a family of water-soluble quaternary ammonium compounds. [2] Choline is the parent compound of the cholines class, consisting of ethanolamine residue having three methyl groups attached to the same nitrogen atom. [1] [2] 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. [2]

Choline chloride can be prepared by treating TMA with 2-chloroethanol: [2]

(CH3)3N + ClCH2CH2OH → [(CH3)3NCH2CH2OH]+Cl−

Choline has historically been produced from natural sources, such as via hydrolysis of lecithin. [2]

Choline as a nutrient

Choline is widespread in living beings. In most animals, choline phospholipids are necessary components in cell membranes, in the membranes of cell organelles, and in very low-density lipoproteins. [2]

Choline is an essential nutrient for humans and many other animals. [2] Humans are capable of some de novo synthesis of choline but require additional choline in the diet to maintain health. Dietary requirements can be met by choline by itself or in the form of choline phospholipids, such as phosphatidylcholine. [2] Choline is not formally classified as a vitamin despite being an essential nutrient with an amino acid–like structure and metabolism. [4]

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. [2]

Symptomatic choline deficiency causes non-alcoholic fatty liver disease and muscle damage. [2] Excessive consumption of choline (greater than 7.5 grams per day) can cause low blood pressure, sweating, diarrhea, and fish-like body smell due to trimethylamine, which forms in the metabolism of choline. [2] [5] Rich dietary sources of choline and choline phospholipids include organ meats, egg yolks, dairy products, peanuts, certain beans, nuts and seeds. Vegetables with pasta and rice also contribute to choline intake in the American diet. [2] [3]

Metabolism

Biosynthesis

Biosynthesis of choline in plants Choline biosynthesis.svg
Biosynthesis of choline in plants

In plants, the first step in de novo biosynthesis of choline is the decarboxylation of serine into ethanolamine, which is catalyzed by a serine decarboxylase. [6] The synthesis of choline from ethanolamine may take place in three parallel pathways, where three consecutive N-methylation steps catalyzed by a methyl transferase are carried out on either the free-base, [7] phospho-bases, [8] or phosphatidyl-bases. [9] The source of the methyl group is S-adenosyl-L-methionine and S-adenosyl-L-homocysteine is generated as a side product. [10]

Main pathways of choline (Chol) metabolism, synthesis and excretion. Click for details. Some of the abbreviations are used in this section. Choline metabolism.svg
Main pathways of choline (Chol) metabolism, synthesis and excretion. Click for details. Some of the abbreviations are used in this section.

In humans and most other animals, de novo synthesis of choline proceeds via the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, [5] but biosynthesis is not enough to meet human requirements. [11] In the hepatic PEMT route, 3-phosphoglycerate (3PG) receives 2 acyl groups 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 decarboxylates 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. [5]

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 choline kinases (CK) phosphorylate choline with ATP to phosphocholine (PChol). [4] 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). [5]

In humans, certain PEMT-enzyme mutations 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. [5] In knockout mice, PEMT inactivation makes them completely dependent on dietary choline. [4]

Absorption

In humans, choline is absorbed from the intestines 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. Gut microbes degrade the unabsorbed choline to trimethylamine, which is oxidized in the liver to trimethylamine N-oxide. [5]

Phosphocholine and glycerophosphocholines are hydrolyzed via phospholipases 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 sphingomyelins) are either hydrolyzed by phospholipases or enter the lymph incorporated into chylomicrons. [5]

Transport

In humans, choline is transported as a free ion in blood. Choline–containing phospholipids and other substances, like glycerophosphocholines, are transported in blood lipoproteins. 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 alters 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. [5]

Choline is a water-soluble ion and thus requires transporters to pass through fat-soluble cell membranes. Three types of choline transporters are known: [12]

SLC5A7s are sodium- (Na+) and ATP-dependent transporters. [12] [5] They have high binding affinity for choline, transport it primarily to neurons and are indirectly associated with the acetylcholine production. [5] 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. [13]

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. [5] 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 the 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 blood. CTL1s occur only on the blood side of the barrier, but also on the membranes of astrocytes and neurons. [12]

OCT1s and OCT2s are not associated with the acetylcholine production. [5] They transport choline with low affinity. OCT1s transport choline primarily in the liver and kidneys; OCT2s in kidneys and the brain. [12]

Storage

Choline is stored in the cell membranes and organelles as phospholipids, and inside cells as phosphatidylcholines and glycerophosphocholines. [5]

Excretion

Even at choline doses of 2–8 g, little choline is excreted into urine in humans. Excretion happens via transporters that occur within kidneys (see transport). Trimethylglycine is demethylated in the liver and kidneys to dimethylglycine (tetrahydrofolate receives one of the methyl groups). Methylglycine forms, is excreted into urine, or is demethylated to glycine. [5]

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 methyl groups by participating in the biosynthesis of S-adenosylmethionine. [14] [15]

Phospholipid precursor

Choline is transformed to diverse phospholipids, like phosphatidylcholines and sphingomyelins. [2] [3] These are found in all cell membranes and the membranes of most cell organelles. [4] Phosphatidylcholines are structurally important part of the cell membranes. In humans, 40–50% of their phospholipids are phosphatidylcholines. [5]

Choline phospholipids also form lipid rafts in the cell membranes along with cholesterol. [2] The rafts are centers, for example for cholinergic receptors and receptor signal transduction enzymes. [2] [4]

Phosphatidylcholines are needed for the synthesis of VLDLs: 70–95% of their phospholipids are phosphatidylcholines in humans. [5]

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 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. [16]

Phosphatidylcholines are excreted into bile and work together with bile acid salts as surfactants in it, thus helping with the intestinal absorption of lipids. [4]

Acetylcholine synthesis

Choline is a precursor to acetylcholine, a neurotransmitter that plays a necessary role in muscle contraction, memory and neural development. [2] [3] [5] Nonetheless, there is little acetylcholine in the human body relative to other forms of choline. [4] Neurons also store choline in the form of phospholipids to their cell membranes for the production of acetylcholine. [5]

Source of trimethylglycine

In humans, choline is oxidized irreversibly in liver mitochondria to glycine betaine aldehyde by choline oxidases. This is oxidized by mitochondrial or cytosolic betaine-aldehyde dehydrogenases to trimethylglycine. [5] 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 guanidines of DNA and certain lysines of histones. Thus it is part of gene expression and epigenetic regulation. Choline deficiency thus leads to elevated homocysteine levels and decreased SAM levels in blood. [5]

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. [3] Cooking oils and other food fats have about 5 mg/100 g of total choline. [5] In the United States, food labels express the amount of choline in a serving as a percentage of Daily Value (%DV) based on the Adequate Intake of 550 mg/day. 100% of the daily value means that a serving of food has 550 mg of choline. [3] "Total choline" is defined as the sum of free choline and choline-containing phospholipids, without accounting for mass fraction. [3] [17]

Human breast milk is rich in choline. [2] [3] Exclusive breastfeeding corresponds to about 120 mg of choline per day for the baby. Increase in a mother's choline intake raises the choline content of breast milk and low intake decreases it. [5] Infant formulas may or may not contain enough choline. In the EU and the US, it is mandatory to add at least 7 mg of choline per 100  kilocalories (kcal) to every infant formula. In the EU, levels above 50 mg/100 kcal are not allowed. [5] [18]

Trimethylglycine is a functional metabolite of choline. It substitutes for choline nutritionally, but only partially. [4] 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. [17]

Choline content of foods (mg/100 g) [a] [17]
MeatsVegetables
Bacon, cooked124.89 Bean, snap 13.46
Beef, trim-cut, cooked78.15 Beetroot 6.01
Beef liver, pan fried418.22 Broccoli 40.06
Chicken, roasted, with skin65.83 Brussels sprout 40.61
Chicken, roasted, no skin78.74 Cabbage 15.45
Chicken liver 290.03 Carrot 8.79
Cod, atlantic 83.63 Cauliflower 39.10
Ground beef, 75–85% lean, broiled79.32–82.35 Sweetcorn, yellow21.95
Pork loin cooked102.76 Cucumber 5.95
Shrimp, canned70.60 Lettuce, iceberg 6.70
Dairy products (cow) Lettuce, romaine 9.92
Butter, salted18.77 Pea 27.51
Cheese16.50–27.21 Sauerkraut 10.39
Cottage cheese 18.42 Spinach 22.08
Milk, whole/skimmed14.29–16.40 Sweet potato 13.11
Sour cream 20.33 Tomato 6.74
Yogurt, plain15.20 Zucchini 9.36
GrainsFruits
Oat bran, raw58.57 Apple 3.44
Oats, plain7.42 Avocado 14.18
Rice, white 2.08 Banana 9.76
Rice, brown 9.22 Blueberry 6.04
Wheat bran 74.39 Cantaloupe 7.58
Wheat germ, toasted152.08 Grape 7.53
Others Grapefruit 5.63
Bean, navy 26.93Orange8.38
Egg, chicken 251.00 Peach 6.10
Olive oil 0.29 Pear 5.11
Peanut 52.47 Prune 9.66
Soybean, raw115.87 Strawberry 5.65
Tofu, soft27.37 Watermelon 4.07
  1. ↑ Foods are raw unless noted otherwise. Contents are "total choline" as defined above.

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. [3] It reflects data from the U.S. Department of Agriculture, Agricultural Research Service. FoodData Central, 2019. [3]

Selected Food Sources of Choline [3]
FoodMilligrams (mg) per servingPercent DV*
Beef liver, pan fried, 3 oz (85 g)35665
Egg, hard boiled, 1 large egg14727
Beef top round, separable lean only, braised, 3 oz (85 g)11721
Soybeans, roasted, 1⁄2 cup10719
Chicken breast, roasted, 3 oz (85 g)7213
Beef, ground, 93% lean meat, broiled, 3 oz (85 g)7213
Cod, Atlantic, cooked, dry heat, 3 oz (85 g)7113
Mushrooms, shiitake, cooked, 1⁄2 cup pieces5811
Potatoes, red, baked, flesh and skin, 1 large potato5710
Wheat germ, toasted, 1 oz (28 g)519
Beans, kidney, canned, 1⁄2 cup458
Quinoa, cooked, 1 cup438
Milk, 1% fat, 1 cup438
Yogurt, vanilla, nonfat, 1 cup387
Brussels sprouts, boiled, 1⁄2 cup326
Broccoli, chopped, boiled, drained, 1⁄2 cup316
Cottage cheese, nonfat, 1 cup265
Tuna, white, canned in water, drained in solids, 3 oz (85 g)255
Peanuts, dry roasted, 1⁄4 cup244
Cauliflower, 1 in (2.5 cm) pieces, boiled, drained, 1⁄2 cup244
Peas, green, boiled, 1⁄2 cup244
Sunflower seeds, oil roasted, 1⁄4 cup193
Rice, brown, long-grain, cooked, 1 cup193
Bread, pita, whole wheat, 1 large (6+1⁄2 in or 17 cm diameter)173
Cabbage, boiled, 1⁄2 cup153
Tangerine (mandarin orange), sections, 1⁄2 cup102
Beans, snap, raw, 1⁄2 cup81
Kiwifruit, raw, 1⁄2 cup sliced71
Carrots, raw, chopped, 1⁄2 cup61
Apples, raw, with skin, quartered or chopped, 1⁄2 cup20

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. [19] The FDA does not require food labels to list choline content unless choline has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet. [3]

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. [3]

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). [3] [20] For adults, the AI for choline was set at 550 mg/day for men and 425 mg/day for women. [3] 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. [21] [22]

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. [5] Individual EU countries may have more specific recommendations. The National Academy of Medicine (NAM) recommendations apply in the United States, [3] Australia and New Zealand. [23]

Choline recommendations (mg/day)
AgeEFSA adequate intake [5] US NAM adequate intake [3] US NAM tolerable upper intake levels [3]
Infants and children
0–6 monthsNot established125Not established
7–12 months160150Not established
1–3 years1402001,000
4–6 years1702501,000
7–8 years2502501,000
9–10 years2503751,000
11–13 years3403752,000
Males
14 years3405503,000
15–18 years4005503,000
19+ years4005503,500
Females
14 years3404003,000
15–18 years4004003,000
19+ y4004253,500
If pregnant4804503,500 (3,000 if ≤18 y)
If breastfeeding5205503,500 (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. [5]

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 time period. Out of 2+ year olds, only 15.6±0.8% of males and 6.1±0.6% of females exceeded the adequate intake (AI). AI was exceeded by 62.9±3.1% of 2- to 3-year-olds, 45.4±1.6% of 4- to 8-year-olds, 9.0±1.0% of 9- to 13-year-olds, 1.8±0.4% of 14–18 and 6.6±0.5% of 19+ year olds. Upper intake level was not exceeded in any subpopulations. [24]

A 2013–2014 NHANES study of the US population found the choline intake of 2- to 19-year-olds to be 256±3.8 mg/day and 339±3.9 mg/day in adults 20 and over. Intake was 402±6.1 mg/d in men 20 and over and 278 mg/d in women 20 and over. [25]

Deficiency

Signs and symptoms

Symptomatic choline deficiency is rare in humans. Most obtain sufficient amounts of it from the diet and are able to biosynthesize limited amounts of it via PEMT. [4] Symptomatic deficiency is often caused by certain diseases or by other indirect causes. Severe deficiency causes muscle damage and non-alcoholic fatty liver disease, which may develop into cirrhosis. [26]

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 deficiency of choline derived trimethylglycine, which functions as an osmoregulator. [4]

Causes and mechanisms

Estrogen production is a relevant factor which predisposes individuals to deficiency along with low dietary choline intake. Estrogens activate phosphatidylcholine producing PEMT enzymes. Women before menopause have 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. [26]

In deficiency, availability of phosphatidylcholines in the liver are decreased – these are needed for formation of VLDLs. Thus VLDL-mediated fatty acid transport out of the liver decreases leading to fat accumulation in the liver. [5] 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 liver therefore decreases. [26]

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). [5]

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 hypothetized 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. [27] It is plausible that elevated TMA and TMAO levels are just a symptom of other underlying illnesses or genetic factors that predispose individuals for increased mortality. Such factors may have not been properly accounted for in certain studies observing TMA and TMAO level related mortality. Causality may be reverse or confounding and large choline intake might not increase mortality in humans. For example, kidney dysfunction predisposes for cardiovascular diseases, but can also decrease TMA and TMAO excretion. [28]

Health effects

Neural tube closure

Low maternal intake of choline is associated with an increased risk of neural tube defects. Higher maternal intake of choline is likely associated with better neurocognition/neurodevelopment in children. [29] [2] Choline and folate, interacting with vitamin B12, act as methyl donors to homocysteine to form methionine, which can then go on to form SAM (S-adenosylmethionine). [2] 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. [30] This may also apply to choline.[ citation needed ] Certain mutations that disturb choline metabolism increase the prevalence of NTDs in newborns, but the role of dietary choline deficiency remains unclear, as of 2015. [2]

Cardiovascular diseases and cancer

Choline deficiency can cause fatty liver, which increases cancer and cardiovascular disease risk. Choline deficiency also decreases SAM production, which partakes in DNA methylation – this decrease may also contribute to carcinogenesis. Thus, deficiency and its association with such diseases has been studied. [5] However, observational studies of free populations have not convincingly shown an association between low choline intake and cardiovascular diseases or most cancers. [2] [5] Studies on prostate cancer have been contradictory. [31] [32]

Cognition

Studies observing the effect between higher choline intake and cognition have been conducted in human adults, with contradictory results. [2] [33] Similar studies on human infants and children have been contradictory and also limited. [2]

Perinatal development

Both pregnancy and lactation increase 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. [34]

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. [34]

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). [35] [36] [37] In particular, there is interest in the impact of choline consumption on the brain. This stems from choline's use as a material for making cellular membranes (particularly in making phosphatidylcholine). Human brain growth is most rapid during the third trimester of pregnancy and continues to be rapid to approximately five years of age. [38] During this time, the demand is high for sphingomyelin, which is made from phosphatidylcholine (and thus from choline), because this material is used to myelinate (insulate) nerve fibers. [39] Choline is also in demand for the production of the neurotransmitter acetylcholine, which can influence the structure and organization of brain regions, neurogenesis, myelination, and synapse formation. Acetylcholine is even present in the placenta and may help control cell proliferation and differentiation (increases in cell number and changes of multiuse cells into dedicated cellular functions) and parturition. [40] [41]

Choline uptake into the brain is controlled by a low-affinity transporter located at the blood–brain barrier. [42] Transport occurs when arterial blood plasma choline concentrations increase above 14 μmol/L, which can occur during a spike in choline concentration after consuming choline-rich foods. Neurons, conversely, acquire choline by both high- and low-affinity transporters. Choline is stored as membrane-bound phosphatidylcholine, which can then be used for acetylcholine neurotransmitter synthesis later. Acetylcholine is formed as needed, travels across the synapse, and transmits the signal to the following neuron. Afterwards, acetylcholinesterase degrades it, and the free choline is taken up by a high-affinity transporter into the neuron again. [43]

Uses

Choline chloride and choline bitartrate are used in dietary supplements. Bitartrate is used more often due to its lower hygroscopicity. [4] Certain choline salts are used to supplement chicken, turkey and some other animal feeds. Some salts are also used as industrial chemicals: for example, in photolithography to remove photoresist. [2] Choline theophyllinate and choline salicylate are used as medicines, [2] [44] as well as structural analogs, like methacholine and carbachol. [45] Radiolabeled cholines, like 11C-choline, are used in medical imaging. [46] Other commercially used salts include tricholine citrate and choline bicarbonate. [2]

History

Discovery

In 1849, Adolph Strecker was the first to isolate choline from pig bile. [47] [48] In 1852, L. Babo and M. Hirschbrunn extracted choline from white mustard seeds and named it sinkaline. [48] In 1862, Strecker repeated his experiment with pig and ox bile, calling the substance choline for the first time after the Greek word for bile, chole, and identifying it with the chemical formula C5H13NO. [49] [11] In 1850, Theodore Nicolas Gobley extracted from the brains and roe of carps a substance he named lecithin after the Greek word for egg yolk, lekithos, showing in 1874 that it was a mixture of phosphatidylcholines. [50] [51]

In 1865, Oscar Liebreich isolated "neurine" from animal brains. [52] [11] The structural formulas of acetylcholine and Liebreich's "neurine" were resolved by Adolf von Baeyer in 1867. [53] [48] Later that year "neurine" and sinkaline were shown to be the same substances as Strecker's choline. Thus, Bayer was the first to resolve the structure of choline. [54] [55] [48] The compound now known as neurine is unrelated to choline. [11]

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, [11] proving in 1932 that choline in lecithin was solely responsible for this preventive effect. [56] In 1998, the US National Academy of Medicine reported their first recommendations for choline in the human diet. [57]

Related Research Articles

<span class="mw-page-title-main">Pantothenic acid</span> Chemical compound

Pantothenic acid (vitamin B5) is a B vitamin and an essential nutrient. All animals need pantothenic acid in order to synthesize coenzyme A (CoA), which is essential for cellular energy production and for the synthesis and degradation of proteins, carbohydrates, and fats.

A nutrient is a substance used by an organism to survive, grow and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi and protists. Nutrients can be incorporated into cells for metabolic purposes or excreted by cells to create non-cellular structures such as hair, scales, feathers, or exoskeletons. Some nutrients can be metabolically converted into smaller molecules in the process of releasing energy such as for carbohydrates, lipids, proteins and fermentation products leading to end-products of water and carbon dioxide. All organisms require water. Essential nutrients for animals are the energy sources, some of the amino acids that are combined to create proteins, a subset of fatty acids, vitamins and certain minerals. Plants require more diverse minerals absorbed through roots, plus carbon dioxide and oxygen absorbed through leaves. Fungi live on dead or living organic matter and meet nutrient needs from their host.

<span class="mw-page-title-main">Lecithin</span> Generic term for amphiphilic substances of plant and animal origin

Lecithin is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues which are amphiphilic – they attract both water and fatty substances, and are used for smoothing food textures, emulsifying, homogenizing liquid mixtures, and repelling sticking materials.

<span class="mw-page-title-main">Phosphatidylcholine</span> Class of phospholipids

Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can easily be obtained from a variety of readily available sources, such as egg yolk or soybeans, from which they are mechanically or chemically extracted using hexane. They are also a member of the lecithin group of yellow-brownish fatty substances occurring in animal and plant tissues. Dipalmitoylphosphatidylcholine (lecithin) is a major component of the pulmonary surfactant, and is often used in the lecithin–sphingomyelin ratio to calculate fetal lung maturity. While phosphatidylcholines are found in all plant and animal cells, they are absent in the membranes of most bacteria, including Escherichia coli. Purified phosphatidylcholine is produced commercially.

<span class="mw-page-title-main">Trimethylamine</span> Chemical compound responsible for rotten fish odor

Trimethylamine (TMA) is an organic compound with the formula N(CH3)3. It is a trimethylated derivative of ammonia. TMA is widely used in industry. At higher concentrations it has an ammonia-like odor, and can cause necrosis of mucous membranes on contact. At lower concentrations, it has a "fishy" odor, the odor associated with rotting fish.

<span class="mw-page-title-main">Trimethylaminuria</span> Medical condition

Trimethylaminuria (TMAU), also known as fish odor syndrome or fish malodor syndrome, is a rare metabolic disorder that causes a defect in the normal production of an enzyme named flavin-containing monooxygenase 3 (FMO3). When FMO3 is not working correctly or if not enough enzyme is produced, the body loses the ability to properly convert the fishy-smelling chemical trimethylamine (TMA) from precursor compounds in food digestion into trimethylamine oxide (TMAO), through a process called N-oxidation.

<span class="mw-page-title-main">Trimethylglycine</span> Chemical compound

Trimethylglycine is an amino acid derivative with the formula (CH3)3N+CH2CO−2. A colorless, water-soluble solid, it occurs in plants.Trimethylgl ycine is is a zwitterion: the molecule contains both a quaternary ammonium group and a carboxylate group. Trimethylglycine was the first betaine discovered; originally it was simply called betaine because it was discovered in sugar beets. Several other betaines are now known.

A betaine in chemistry is any neutral chemical compound with a positively charged cationic functional group that bears no hydrogen atom, such as a quaternary ammonium or phosphonium cation, and with a negatively charged functional group, such as a carboxylate group that may not be adjacent to the cationic site. Historically, the term was reserved for trimethylglycine (TMG), which is involved in methylation reactions and detoxification of homocysteine. This is a modified amino acid consisting of glycine with three methyl groups serving as methyl donor for various metabolic pathways.

<span class="mw-page-title-main">Phosphatidylserine</span> Chemical compound

Phosphatidylserine is a phospholipid and is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via apoptotic mimicry. Its exposure on the outer surface of a membrane marks the cell for destruction via apoptosis.

Trimethylamine <i>N</i>-oxide Chemical compound

Trimethylamine N-oxide (TMAO) is an organic compound with the formula (CH3)3NO. It is in the class of amine oxides. Although the anhydrous compound is known, trimethylamine N-oxide is usually encountered as the dihydrate. Both the anhydrous and hydrated materials are white, water-soluble solids.

Steven H. Zeisel is an American academic. He is Professor Emeritus in Nutrition and Pediatrics at the University of North Carolina at Chapel Hill.

<span class="mw-page-title-main">Flavin-containing monooxygenase 3</span> Protein-coding gene in the species Homo sapiens

Flavin-containing monooxygenase 3 (FMO3), also known as dimethylaniline monooxygenase [N-oxide-forming] 3 and trimethylamine monooxygenase, is a flavoprotein enzyme (EC 1.14.13.148) that in humans is encoded by the FMO3 gene. This enzyme catalyzes the following chemical reaction, among others:

<span class="mw-page-title-main">Citicoline</span> Chemical compound

Citicoline (INN), also known as cytidine diphosphate-choline (CDP-choline) or cytidine 5'-diphosphocholine is an intermediate in the generation of phosphatidylcholine from choline, a common biochemical process in cell membranes. Citicoline is naturally occurring in the cells of human and animal tissue, in particular the organs.

<span class="mw-page-title-main">Phosphatidylethanolamine N-methyltransferase</span> Class of enzymes

Phosphatidylethanolamine N-methyltransferase is a transferase enzyme which converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver. In humans it is encoded by the PEMT gene within the Smith–Magenis syndrome region on chromosome 17.

<span class="mw-page-title-main">Glycerophosphorylcholine</span> Chemical compound

L-α-Glycerophosphorylcholine is a natural choline compound found in the brain. It is also a parasympathomimetic acetylcholine precursor which has been investigated for its potential for the treatment of Alzheimer's disease and other dementias.

<span class="mw-page-title-main">Nutritional neuroscience</span> Scientific discipline

Nutritional neuroscience is the scientific discipline that studies the effects various components of the diet such as minerals, vitamins, protein, carbohydrates, fats, dietary supplements, synthetic hormones, and food additives have on neurochemistry, neurobiology, behavior, and cognition.

A bioactive compound is a compound that has an effect on a living organism, tissue or cell, usually demonstrated by basic research in vitro or in vivo in the laboratory. While dietary nutrients are essential to life, bioactive compounds have not been proved to be essential – as the body can function without them – or because their actions are obscured by nutrients fulfilling the function.

Relatively speaking, the brain consumes an immense amount of energy in comparison to the rest of the body. The mechanisms involved in the transfer of energy from foods to neurons are likely to be fundamental to the control of brain function. Human bodily processes, including the brain, all require both macronutrients, as well as micronutrients.

In general, cognitive support diets are formulated to include nutrients that have a known role in brain development, function and/or maintenance, with the goal of improving and preserving mental processes such as attentiveness, short-term and long-term memory, learning, and problem solving. Currently, there is very little conclusive research available regarding cat cognition as standardized tests for evaluating cognitive ability are less established and less reliable than cognitive testing apparatus used in other mammalian species, like dogs. Much of what is known about feline cognition has been inferred from a combination of owner-reported behaviour, brain necropsies, and comparative cognitive neurology of related animal models. Cognition claims appear primarily on kitten diets which include elevated levels of nutrients associated with optimal brain development, although there are now diets available for senior cats that include nutrients to help slow the progression of age-related changes and prevent cognitive decline. Cognition diets for cats contain a greater portion of omega-3 fatty acids, especially docosahexaenoic acid (DHA) as well as eicosapentaenoic acid (EPA), and usually feature a variety of antioxidants and other supporting nutrients thought to have positive effects on cognition.

Nutritional epigenetics is a science that studies the effects of nutrition on gene expression and chromatin accessibility. It is a subcategory of nutritional genomics that focuses on the effects of bioactive food components on epigenetic events.

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