Choline

Choline /ˈkoʊliːn/[3] is an essential nutrient for humans and

Choline
many other animals.[4] Choline occurs as a cation that forms
various salts (X− in the depicted formula is an undefined
counteranion).[5] To maintain health, it must be obtained from
the diet as choline or as choline phospholipids, like
phosphatidylcholine.[4] Humans, as well as most other animal
species, do make choline de novo; however, production is
generally insufficient. Choline is often not classified as a
vitamin, but as a nutrient with an amino acid–like
metabolism.[2] In most animals, choline phospholipids are
necessary components in cell membranes, in the membranes of
cell organelles, and in very low-density lipoproteins.[4] Choline
is required to produce acetylcholine – a neurotransmitter – and
S-adenosylmethionine (SAM), a universal methyl donor. Upon
methylation SAM is transformed into homocysteine. Names
Preferred IUPAC name
Symptomatic choline deficiency – rare in humans – causes 2-Hydroxy-N,N,N-trimethylethan-1-
nonalcoholic fatty liver disease and muscle damage.[4] aminium
Excessive consumption of choline (greater than 7.5 g/day) can
Other names
cause low blood pressure, sweating, diarrhea and fish-like body
2-Hydroxy-N,N,N-
odor due to trimethylamine, which forms in its metabolism.[4][6]
trimethylethanaminium

Rich dietary sources of choline and choline phospholipids

include organ meats and egg yolks, dairy products, peanuts, Bilineurine

certain beans, nuts, seeds and vegetables with pasta and rice (2-
also contributing to choline intake in the American diet.[4][7] Hydroxyethyl)trimethylammonium
Identifiers
CAS Number 62-49-7 (https://com
Contents monchemistry.cas.or
g/detail?cas_rn=62-4
Chemistry
9-7) choline
Metabolism hydroxide 
Biosynthesis
Absorption 3D model Interactive image (htt
(JSmol) ps://chemapps.stolaf.
Transport
Storage edu/jmol/jmol.php?m
Excretion odel=C%5BN%2B%5
D%28C%29%28C%2
Function 9CCO)
Phospholipid precursor
Acetylcholine synthesis Beilstein 1736748
Reference
Source of trimethylglycine
ChEBI CHEBI:15354 (http
Content in foods
s://www.ebi.ac.uk/che
Daily values
Dietary recommendations bi/searchId.do?chebiI
Intake in populations d=15354) 

Deficiency ChEMBL ChEMBL920 (https://

Signs and symptoms www.ebi.ac.uk/chemb
Causes and mechanisms ldb/index.php/compo
und/inspect/ChEMBL
Excess intake
920) 
Health effects
Neural tube closure ChemSpider 299 (https://www.che
Cardiovascular diseases and cancer mspider.com/Chemic
Cognition al-Structure.299.htm
l) 
Perinatal development
Functions in the fetus DrugBank DB00122 (https://ww
w.drugbank.ca/drugs/
Uses
DB00122) 
Antagonists and inhibitors
ECHA InfoCard 100.000.487 (https://
History
echa.europa.eu/subs
Discovery
tance-information/-/s
Discovery as a nutrient
ubstanceinfo/100.00
References 0.487)
EC Number 200-535-1
Chemistry Gmelin 324597
Reference
The cholines are a family of water-soluble quaternary IUPHAR/BPS 4551 (http://www.guid
ammonium compounds.[5][8] Choline is the parent compound of etopharmacology.or
the cholines class, consisting of ethanolamine having three g/GRAC/LigandDispl
methyl substituents attached to the amino function.[9] Choline ayForward?tab=sum
hydroxide is known as choline base. It is hygroscopic and thus
mary&ligandId=4551)
often encountered as a colorless viscous hydrated syrup that
smells of trimethylamine (TMA). Aqueous solutions of choline KEGG C00114 (https://www.
are stable, but the compound slowly breaks down to ethylene kegg.jp/entry/C0011
glycol, polyethylene glycols, and TMA.[1] 4) 

Choline chloride can be made by treating TMA with 2- PubChem CID 305 (https://pubche
chloroethanol:[1] m.ncbi.nlm.nih.gov/c
ompound/305)
(CH3)3N + ClCH2CH2OH → (CH3)3N+ CH2CH2OH
UNII N91BDP6H0X (http
· Cl–
s://fdasis.nlm.nih.gov/
The 2-chloroethanol can be generated from ethylene oxide. srs/srsdirect.jsp?regn
Choline has historically been produced from natural sources, o=N91BDP6H0X) 
such as via hydrolysis of lecithin.[1] CompTox DTXSID8043789 (htt
Dashboard ps://comptox.epa.go
Metabolism (EPA)
v/dashboard/chemica
l/details/DTXSID8043
789)
Biosynthesis
InChI
In plants, the first step in de novo biosynthesis of choline is the InChI=1S/C5H14NO/c1-6(2,3)4-5-7/h7
decarboxylation of serine into ethanolamine, which is catalyzed H,4-5H2,1-3H3/q+1  
by a serine decarboxylase.[10] The synthesis of choline from Key: OEYIOHPDSNJKLS-UHFFFAOY
ethanolamine may take place in three parallel pathways, where SA-N 
three consecutive N-methylation steps catalyzed by a methyl SMILES
transferase are carried out on either the free-base,[11] phospho-
C[N+](C)(C)CCO
bases,[12] or phosphatidyl-bases.[13] The source of the methyl
group is S-adenosyl-l-methionine and S-adenosyl-l- Properties
homocysteine is generated as a side product.[14] Chemical C5H14NO+
formula
In humans and most other animals, de novo synthesis of choline
is via the phosphatidylethanolamine N-methyltransferase Molar mass 104.17 g/mol
(PEMT) pathway,[6] but biosynthesis is not enough to meet Appearance viscous deliquescent
human requirements.[15] In the hepatic PEMT route, 3- liquid (choline
phosphoglycerate (3PG) receives 2 acyl groups from acyl-CoA hydroxide)[1]
forming a phosphatidic acid. It reacts with cytidine triphosphate Solubility in very soluble (choline
to form cytidine diphosphate-diacylglycerol. Its hydroxyl group water hydroxide)[1]
reacts with serine to form phosphatidylserine which
decarboxylates to ethanolamine and phosphatidylethanolamine Solubility soluble in ethanol,[1]
(PE) forms. A PEMT enzyme moves three methyl groups from insoluble in
three S-adenosyl methionines (SAM) donors to the diethylether and
ethanolamine group of the phosphatidylethanolamine to form chloroform (choline
choline in the form of a phosphatidylcholine. Three S- hydroxide)[2]
adenosylhomocysteines (SAHs) are formed as a byproduct.[6]
Hazards
Choline can also be released from more complex choline GHS labelling:
containing molecules. For example, phosphatidylcholines (PC)
Pictograms
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 Signal word Danger
phosphocholine (PChol).[2] This happens in some cell types like
liver and kidney. Choline-phosphate cytidylyltransferases Hazard H314
statements
(CPCT) transform PChol to CDP-choline (CDP-Chol) with
cytidine triphosphate (CTP). CDP-choline and diglyceride are Precautionary P260, P264, P280,
transformed to PC by diacylglycerol cholinephosphotransferase statements P301+P330+P331,
(CPT).[6] P303+P361+P353,
P304+P340,
In humans, certain PEMT-enzyme mutations and estrogen P305+P351+P338,
deficiency (often due to menopause) increase the dietary need P310, P321, P363,
for choline. In rodents, 70% of phosphatidylcholines are formed
P405, P501
via the PEMT route and only 30% via the CDP-choline
route.[6] In knockout mice, PEMT inactivation makes them NFPA 704
completely dependent on dietary choline.[2] (fire diamond)
COR

Absorption
Lethal dose or concentration (LD,
In humans, choline is absorbed from the intestines via the LC):
SLC44A1 (CTL1) membrane protein via facilitated diffusion LD50 (median 3–6 g/kg bw, rats,
governed by the choline concentration gradient and the dose) oral[1]
electrical potential across the enterocyte membranes. SLC44A1
Safety data 4
has limited ability to transport choline: at high concentrations
part of it is left unabsorbed. Absorbed choline leaves the sheet (SDS)
enterocytes via the portal vein, passes the liver and enters Except where otherwise noted, data
systemic circulation. Gut microbes degrade the unabsorbed are given for materials in their
choline to trimethylamine, which is oxidized in the liver to standard state (at 25 °C [77 °F],
trimethylamine N-oxide.[6] 100 kPa).
 verify (what is   ?)
Phosphocholine and glycerophosphocholines are hydrolyzed
via phospholipases to choline, which enters the portal vein. Due Infobox references
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 Biosynthesis of choline in plants
or enter the lymph
incorporated into
chylomicrons.[6]

Transport

In humans, choline is transported as a free molecule 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.[6] Main pathways of choline (Chol) metabolism,
synthesis and excretion. Click for details. Some of
Choline is a water-soluble ion and thus requires the abbreviations are used in this section.
transporters to pass through fat-soluble cell
membranes. Three types of choline transporters are
known:[16]

SLC5A7
CTLs: CTL1 (SLC44A1), CTL2 (SLC44A2) and CTL4 (SLC44A4)
OCTs: OCT1 (SLC22A1) and OCT2 (SLC22A2)

SLC5A7s are sodium- (Na+) and ATP-dependent transporters.[16][6] They have high binding affinity for
choline, transport it primarily to neurons and are indirectly associated with the acetylcholine production.[6]
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.[17]
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.[6] 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.[16]

OCT1s and OCT2s are not associated with the acetylcholine production.[6] They transport choline with
low affinity. OCT1s transport choline primarily in the liver and kidneys; OCT2s in kidneys and the
brain.[16]

Storage

Choline is stored in the cell membranes and organelles as phospholipids, and inside cells as
phosphatidylcholines and glycerophosphocholines.[6]

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.[6]

Function
Choline and its derivatives have many functions in humans and in other organisms. The most notable
function is that choline serves as a synthetic precursor for other essential cell components and signalling
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.[18][19]

Phospholipid precursor

Choline is transformed to different phospholipids, like phosphatidylcholines and sphingomyelins. These are
found in all cell membranes and the membranes of most cell organelles.[2] Phosphatidylcholines are
structurally important part of the cell membranes. In humans 40–50% of their phospholipids are
phosphatidylcholines.[6]

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

Phosphatidylcholines are needed for the synthesis of VLDLs: 70–95% of their phospholipids are
phosphatidylcholines in humans.[6]

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.[20]

Phosphatidylcholines are excreted into bile and work together with bile acid salts as surfactants in it, thus
helping with the intestinal absorption of lipids.[2]

Acetylcholine synthesis

Choline is needed to produce acetylcholine. This is a neurotransmitter which plays a necessary role in
muscle contraction, memory and neural development, for example.[6] Nonetheless, there is little
acetylcholine in the human body relative to other forms of choline.[2] Neurons also store choline in the form
of phospholipids to their cell membranes for the production of acetylcholine.[6]

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.[6] 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.[6]

Content in foods
Choline occurs in foods as a free molecule 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. Cooking oils and other food fats have
about 5 mg/100 g of total choline.[6] 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.[21] "Total choline" is defined as the sum of
free choline and choline-containing phospholipids, without accounting for mass fraction.[22][23][6]

Human breast milk is rich in choline. 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.[6] 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.[6][24]

Trimethylglycine is a functional metabolite of choline. It substitutes for choline nutritionally, but only
partially.[2] 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.[22]
 Choline content of foods (mg/100 g)[a][22]
Meats Vegetables
Bacon, cooked 124.89 Bean, snap 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
Cod, atlantic 83.63 Cauliflower 39.10
Ground beef, 75–85% lean, broiled 79.32–82.35 Sweetcorn, yellow 21.95
Pork loin cooked 102.76 Cucumber 5.95
Shrimp, canned 70.60 Lettuce, iceberg 6.70
Dairy products (cow) Lettuce, romaine 9.92
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
Grains Fruits
Oat bran, raw 58.57 Apple 3.44
Oats, plain 7.42 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, toasted 152.08 Grape 7.53
Others Grapefruit 5.63
Bean, navy 26.93 Orange 8.38
Egg, hen 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

a. 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.[21] It reflects data from the U.S. Department of Agriculture,
Agricultural Research Service. FoodData Central, 2019.[21]

Selected Food Sources of Choline[21]

Food Milligrams (mg) per serving Percent DV*
Beef liver, pan fried, 3 oz (85 g) 356 65
Egg, hard boiled, 1 large egg 147 27
Beef top round, separable lean only, braised, 3 oz (85 g) 117 21
Soybeans, roasted, 1⁄2 cup 107 19
Chicken breast, roasted, 3 oz (85 g) 72 13
Beef, ground, 93% lean meat, broiled, 3 oz (85 g) 72 13
Cod, Atlantic, cooked, dry heat, 3 oz (85 g) 71 13
Mushrooms, shiitake, cooked, 1⁄2 cup pieces 58 11
Potatoes, red, baked, flesh and skin, 1 large potato 57 10
Wheat germ, toasted, 1 oz (28 g) 51 9
Beans, kidney, canned, 1⁄2 cup 45 8
Quinoa, cooked, 1 cup 43 8
Milk, 1% fat, 1 cup 43 8
Yogurt, vanilla, nonfat, 1 cup 38 7
Brussels sprouts, boiled, 1⁄2 cup 32 6
Broccoli, chopped, boiled, drained, 1⁄2 cup 31 6
Cottage cheese, nonfat, 1 cup 26 5
Tuna, white, canned in water, drained in solids, 3 oz (85 g) 25 5
Peanuts, dry roasted, 1⁄4 cup 24 4
Cauliflower, 1 in (2.5 cm) pieces, boiled, drained, 1⁄2 cup 24 4
Peas, green, boiled, 1⁄2 cup 24 4
Sunflower seeds, oil roasted, 1⁄4 cup 19 3
Rice, brown, long-grain, cooked, 1 cup 19 3
Bread, pita, whole wheat, 1 large (61⁄2 in or 17 cm diameter) 17 3
Cabbage, boiled, 1⁄2 cup 15 3
Tangerine (mandarin orange), sections, 1⁄2 cup 10 2
Beans, snap, raw, 1⁄2 cup 8 1
Kiwifruit, raw, 1⁄2 cup sliced 7 1
Carrots, raw, chopped, 1⁄2 cup 6 1
Apples, raw, with skin, quartered or chopped, 1⁄2 cup 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 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. [21]

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. [21]

Dietary recommendations
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.[6] Individual EU countries may have more specific recommendations. The National
Academy of Medicine (NAM) recommendations apply in the United States,[21] Australia and New
Zealand.[25]

Choline recommendations (mg/day)

EFSA adequate US NAM adequate US NAM tolerable upper intake
Age
intake[6] intake[21] levels[21]
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
520 550 3,500 (3,000 if ≤18 y)
breastfeeding

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.[6]
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.[26]

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.[27]

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.[2] 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.[28]

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.[2]

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.[28]

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.[6] Other simultaneously occurring mechanisms explaining the observed liver
damage have also been suggested. For example, choline phospholipids are also needed in mitochondrial
membranes. Their inavailability 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.[28]

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).[6]
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.[29] 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.[30]

Health effects

Neural tube closure

Some human studies showed low maternal intake of choline to significantly increase the risk of neural tube
defects (NTDs) in newborns.[4] Folate deficiency also causes NTDs. 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).[4] 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.[31] This may also apply to choline. 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.[4]

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.[6]
However, observational studies of free populations have not convincingly shown an association between
low choline intake and cardiovascular diseases or most cancers.[4][6] Studies on prostate cancer have been
contradictory.[32][33]

Cognition

Studies observing the effect between higher choline intake and cognition have been conducted in human
adults, with contradictory results.[4][34] Similar studies on human infants and children have been
contradictory and also limited.[4]

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.[35]
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.[35]

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).[36][37][38] 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.[39] 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.[40] 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.[41][42]

Choline uptake into the brain is controlled by a low-affinity transporter located at the blood–brain
barrier.[43] Transport occurs when arterial 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.[44]

Uses
Choline chloride and choline bitartrate are used in dietary supplements. Bitartrate is used more often due to
its lower hygroscopicity.[2] 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.[1] Choline theophyllinate and choline salicylate are used as medicines,[1][45] as well as
structural analogs, like methacholine and carbachol.[46] Radiolabeled cholines, like 11 C-choline, are used in
medical imaging.[47] Other commercially used salts include tricholine citrate and choline bicarbonate.[1]

Antagonists and inhibitors

Hundreds of choline antagonists and enzyme inhibitors have been developed for research purposes.
Aminomethylpropanol is among the first ones used as a research tool. It inhibits choline and
trimethylglycine synthesis. It is able to induce choline deficiency that in turn results in fatty liver in rodents.
Diethanolamine is another such compound, but also an environmental pollutant. N-cyclohexylcholine
inhibits choline uptake primarily in brains. Hemicholinium-3 is a more general inhibitor, but also
moderately inhibits choline kinases. More specific choline kinase inhibitors have also been developed.
Trimethylglycine synthesis inhibitors also exist: carboxybutylhomocysteine is an example of a specific
BHMT inhibitor.[2]
The cholinergic hypothesis of dementia has not only lead to medicinal acetylcholinesterase inhibitors, but
also to a variety of acetylcholine inhibitors. Examples of such inhibiting research chemicals include
triethylcholine, homocholine and many other N-ethyl derivates of choline, which are false neurotransmitter
analogs of acetylcholine. Choline acetyltransferase inhibitors have also been developed.[2]

History

Discovery

In 1849, Adolph Strecker was the first to isolate choline from pig bile.[48][49] In 1852, L. Babo and M.
Hirschbrunn extracted choline from white mustard seeds and named it sinkaline.[49] 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 C5 H13 NO.[50][15] 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.[51][52]

In 1865, Oscar Liebreich isolated "neurine" from animal brains.[53][15] The structural formulas of
acetylcholine and Liebreich's "neurine" were resolved by Adolf von Baeyer in 1867.[54][49] 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.[55][56][49] The compound now known as neurine is unrelated to
choline.[15]

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,[15] proving in 1932 that choline in lecithin was solely
responsible for this preventive effect.[57] In 1998, the US National Academy of Medicine reported their
first recommendations for choline in the human diet.[58]

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