E1001
   HOME

TheInfoList



OR:

Choline is an
essential nutrient 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 excret ...
for humans and many other animals. Choline occurs as a
cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
that forms various salts (X in the depicted formula is an undefined
counteranion image:Polystyrolsulfonat.svg, 160px, Polystyrene sulfonate, a cation-exchange resin, is typically supplied with as the counterion. In chemistry, a counterion (sometimes written as "counter ion", pronounced as such) is the ion that accompanies an ...
). 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 per se or in the form of choline
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s, such as phosphatidylcholine. Choline is not formally classified as a vitamin despite being an essential nutrient with an amino acid–like
structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...
and metabolism. In most animals, choline phospholipids are necessary components in cell membranes, in the membranes of cell
organelle In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...
s, and in very low-density lipoproteins. Choline is required to produce
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
– a
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...
– and ''S''-adenosylmethionine (SAM), a universal
methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
donor. Upon methylation SAM is transformed into homocysteine. Symptomatic choline deficiency causes
non-alcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic ...
and muscle damage. Excessive consumption of choline (greater than 7.5 g/day) can cause low blood pressure,
sweating Perspiration, also known as sweating, is the production of fluids secreted by the sweat glands in the skin of mammals. Two types of sweat glands can be found in humans: eccrine glands and apocrine glands. The eccrine sweat glands are distr ...
, diarrhea and fish-like body odor due to trimethylamine, which forms in its metabolism. Rich dietary sources of choline and choline phospholipids include
organ meats Offal (), also called variety meats, pluck or organ meats, is the organs of a butchered animal. The word does not refer to a particular list of edible organs, which varies by culture and region, but usually excludes muscle. Offal may also refer ...
and egg yolks, dairy products, peanuts, certain beans, nuts, seeds and vegetables with pasta and rice also contributing to choline intake in the American diet.


Chemistry

The cholines are a family of water-soluble
quaternary ammonium compound In chemistry, quaternary ammonium cations, also known as quats, are positively charged polyatomic ions of the structure , R being an alkyl group or an aryl group. Unlike the ammonium ion () and the primary, secondary, or tertiary ammonium catio ...
s. Choline is the parent compound of the cholines class, consisting of ethanolamine having three methyl substituents attached to the amino function. 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 made by treating TMA with
2-chloroethanol 2-Chloroethanol (also called ethylene chlorohydrin or glycol chlorohydrin) is an organic chemical compound with the chemical formula HOCH2CH2Cl and the ''simplest'' beta-halohydrin (chlorohydrin). This colorless liquid has a pleasant ether-like od ...
: :(CH3)3N + ClCH2CH2OH → (CH3)3N+CH2CH2OH · Cl The 2-chloroethanol can be generated from ethylene oxide. Choline has historically been produced from natural sources, such as via hydrolysis of
lecithin Lecithin (, from the Greek ''lekithos'' "yolk") 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 so ar ...
.


Metabolism


Biosynthesis

In plants, the first step in ''de novo'' biosynthesis of choline is the
decarboxylation Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is t ...
of
serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
into
ethanolamine Ethanolamine (2-aminoethanol, monoethanolamine, ETA, or MEA) is an organic chemical compound with the formula or . The molecule is bifunctional, containing both a primary amine and a primary alcohol. Ethanolamine is a colorless, viscous liquid wit ...
, which is catalyzed by a serine decarboxylase. The synthesis of choline from ethanolamine may take place in three parallel pathways, where three consecutive ''N''-methylation steps catalyzed by a
methyl transferase Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Ross ...
are carried out on either the free-base, phospho-bases, or phosphatidyl-bases. The source of the methyl group is ''S''-adenosyl--methionine and ''S''-adenosyl--homocysteine is generated as a side product. In humans and most other animals, de novo synthesis of choline is via the
phosphatidylethanolamine N-methyltransferase Phosphatidylethanolamine N-methyltransferase (abbreviated PEMT) 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– ...
(PEMT) pathway, but biosynthesis is not enough to meet human requirements. In the hepatic PEMT route,
3-phosphoglycerate 3-Phosphoglyceric acid (3PG, 3-PGA, or PGA) is the conjugate acid of 3-phosphoglycerate or glycerate 3-phosphate (GP or G3P). This glycerate is a biochemically significant metabolic intermediate in both glycolysis and the Calvin-Benson cycle. Th ...
(3PG) receives 2
acyl group In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen atom and an alkyl group (). In organic chemistry, the acyl group (IUPAC ...
s from
acyl-CoA Acyl-CoA is a group of coenzymes that metabolize fatty acids. Acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way ...
forming a
phosphatidic acid Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty ac ...
. It reacts with
cytidine triphosphate Cytidine triphosphate (CTP) is a pyrimidine nucleoside triphosphate. CTP, much like ATP, consists of a ribose sugar, and three phosphate groups. The major difference between the two molecules is the base used, which in CTP is cytosine. CTP is ...
to form cytidine diphosphate-diacylglycerol. Its
hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy g ...
reacts with
serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
to form phosphatidylserine which
decarboxylate Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is t ...
s to
ethanolamine Ethanolamine (2-aminoethanol, monoethanolamine, ETA, or MEA) is an organic chemical compound with the formula or . The molecule is bifunctional, containing both a primary amine and a primary alcohol. Ethanolamine is a colorless, viscous liquid wit ...
and
phosphatidylethanolamine Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. ''S''-Adenosyl methionine can s ...
(PE) forms. A PEMT enzyme moves three
methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
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. Choline can also be released from more complex choline containing molecules. 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 The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...
choline kinase Choline kinase (also known as CK, ChoK and choline phosphokinase) is an enzyme which catalyzes the first reaction in the choline pathway for phosphatidylcholine (PC) biosynthesis. This reaction involves the transfer of a phosphate group from adenos ...
s (CK) phosphorylate choline with
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...
to
phosphocholine Phosphocholine is an intermediate in the synthesis of phosphatidylcholine in tissues. Phosphocholine is made in a reaction, catalyzed by choline kinase, that converts ATP and choline into phosphocholine and ADP. Phosphocholine is a molecule ...
(PChol). This happens in some cell types like liver and kidney.
Choline-phosphate cytidylyltransferase Choline-phosphate cytidylyltransferase () is an enzyme that catalysis, catalyzes the chemical reaction :CTP + choline phosphate \rightleftharpoons diphosphate + CDP-choline where the two substrate (biochemistry), substrates of this enzyme are cyt ...
s (CPCT) transform PChol to
CDP-choline Citicoline (International Nonproprietary Name, 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 ...
(CDP-Chol) with cytidine triphosphate (CTP). CDP-choline and diglyceride are transformed to PC by
diacylglycerol cholinephosphotransferase In enzymology, a diacylglycerol cholinephosphotransferase () is an enzyme that catalyzes the chemical reaction CDP-choline + 1,2-diacylglycerol \rightleftharpoons CMP + a phosphatidylcholine Thus, the two substrates of this enzyme are CDP-chol ...
(CPT). In humans, certain PEMT-enzyme mutations and
estrogen deficiency Hypoestrogenism, or estrogen deficiency, refers to a lower than normal level of estrogen. It is an umbrella term used to describe estrogen deficiency in various conditions. Estrogen deficiency is also associated with an increased risk of cardiov ...
(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 A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
, PEMT inactivation makes them completely dependent on dietary choline.


Absorption

In humans, choline is absorbed from the
intestine The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans ...
s via the
SLC44A1 Choline transporter-like protein 1 is a protein that in humans is encoded by the ''SLC44A1'' gene. See also * Cluster of differentiation The cluster of differentiation (also known as cluster of designation or classification determinant and of ...
(CTL1) membrane protein via
facilitated diffusion Facilitated diffusion (also known as facilitated transport or passive-mediated transport) is the process of spontaneous passive transport (as opposed to active transport) of molecules or ions across a biological membrane via specific transmembra ...
governed by the choline concentration gradient and the electrical potential across the
enterocyte Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its ...
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 The portal vein or hepatic portal vein (HPV) is a blood vessel that carries blood from the gastrointestinal tract, gallbladder, pancreas and spleen to the liver. This blood contains nutrients and toxins extracted from digested contents. Approxima ...
, passes the liver and enters
systemic circulation The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
.
Gut microbe Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut mic ...
s degrade the unabsorbed choline to trimethylamine, which is oxidized in the liver to trimethylamine ''N''-oxide.
Phosphocholine Phosphocholine is an intermediate in the synthesis of phosphatidylcholine in tissues. Phosphocholine is made in a reaction, catalyzed by choline kinase, that converts ATP and choline into phosphocholine and ADP. Phosphocholine is a molecule ...
and
glycerophosphocholine L-Alpha glycerylphosphorylcholine (alpha-GPC, choline alfoscerate) 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 Alz ...
s 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.


Transport

In humans, choline is transported as a free molecule in blood. Choline–containing
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s 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. Choline is a water-soluble ion and thus requires transporters to pass through fat-soluble cell membranes. Three types of choline transporters are known: *
SLC5A7 The high-affinity choline transporter (ChT) also known as solute carrier family 5 member 7 is a protein in humans that is encoded by the ''SLC5A7'' gene. It is a cell membrane transporter and carries choline into acetylcholine-synthesizing neuro ...
* CTLs: CTL1 (
SLC44A1 Choline transporter-like protein 1 is a protein that in humans is encoded by the ''SLC44A1'' gene. See also * Cluster of differentiation The cluster of differentiation (also known as cluster of designation or classification determinant and of ...
), CTL2 ( SLC44A2) and CTL4 (
SLC44A4 Choline transporter-like protein 4 is a protein that in humans is encoded by the ''SLC44A4'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''gene ...
) * OCTs: OCT1 (
SLC22A1 Solute carrier family 22 member 1 is a protein that in humans is encoded by the gene ''SLC22A1''. Function Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenou ...
) and OCT2 (
SLC22A2 Solute carrier family 22 member 2 (also termed ''OCT2'' or ''organic cation transporter-2'') is a protein that in humans is encoded by the ''SLC22A2'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to de ...
) SLC5A7s are sodium- (Na+) and
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...
-dependent transporters. They have high
binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mol ...
for choline, transport it primarily to neurons and are indirectly associated with the
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
production. Their deficient function causes
hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic inform ...
weakness in the pulmonary and other muscles in humans via acetylcholine deficiency. In
knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
, their dysfunction results easily in death with
cyanosis Cyanosis is the change of body tissue color to a bluish-purple hue as a result of having decreased amounts of oxygen bound to the hemoglobin in the red blood cells of the capillary bed. Body tissues that show cyanosis are usually in locations ...
and
paralysis Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 50 ...
. CTL1s have moderate affinity for choline and transport it in almost all tissues, including the intestines, liver, kidneys, placenta and
mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
. 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 the acetylcholine production, but transport choline together via the
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
. 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. OCT1s and OCT2s are not associated with the acetylcholine production. They transport choline with low affinity. OCT1s transport choline primarily in the liver and kidneys; OCT2s in kidneys and the brain.


Storage

Choline is stored in the cell membranes and
organelle In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...
s as
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s, and inside cells as phosphatidylcholines and
glycerophosphocholine L-Alpha glycerylphosphorylcholine (alpha-GPC, choline alfoscerate) 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 Alz ...
s.


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 Sarcosine, also known as ''N''-methylglycine, or monomethylglycine, is a monopeptide with the formula CH3N(H)CH2CO2H. It exists at neutral pH as the zwitterion CH3N+(H)2CH2CO2−, which can be obtained as a white, water-soluble powder. Like some ...
forms, is excreted into urine, or is demethylated to glycine.


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
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s that form cell membranes, the
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...
acetylcholine, and the osmoregulator trimethylglycine ( betaine). Trimethylglycine in turn serves as a source of methyl groups by participating in the biosynthesis of ''S''-adenosylmethionine.


Phospholipid precursor

Choline is transformed to different
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s, like phosphatidylcholines and sphingomyelins. These are found in all cell membranes and the membranes of most cell
organelle In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...
s. Phosphatidylcholines are structurally important part of the cell membranes. In humans 40–50% of their phospholipids are phosphatidylcholines. Choline phospholipids also form
lipid rafts The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular membranes remains somewhat controversial. ...
in the cell membranes along with cholesterol. The rafts are centers, for example for receptors and receptor
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
enzymes. Phosphatidylcholines are needed for the synthesis of VLDLs: 70–95% of their phospholipids are phosphatidylcholines in humans. 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 Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Symptoms include shortness of breath (dyspnea), rapid breathing (tachypnea), and bluish skin colo ...
. Phosphatidylcholines are excreted into
bile Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile ...
and work together with
bile acid Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts. Primary b ...
salts as
surfactant Surfactants are chemical compounds that decrease the surface tension between two liquids, between a gas and a liquid, or interfacial tension between a liquid and a solid. Surfactants may act as detergents, wetting agents, emulsifiers, foaming ...
s in it, thus helping with the intestinal absorption of lipids.


Acetylcholine synthesis

Choline is needed to produce
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
. This is a
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...
which plays a necessary role in muscle contraction, memory and
neural development The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The fie ...
, for example. Nonetheless, there is little acetylcholine in the human body relative to other forms of choline. Neurons also store choline in the form of phospholipids to their cell membranes for the production of acetylcholine.


Source of trimethylglycine

In humans, choline is oxidized irreversibly in liver mitochondria to
glycine betaine aldehyde Glycine betaine aldehyde, often simply called betaine aldehyde, is an intermediate in the metabolism of glycine, serine and threonine. The human aldehyde dehydrogenase () stimulates the transformation of betaine aldehyde to glycine betaine. Bet ...
by
choline oxidase In enzymology, a choline oxidase () is an enzyme that catalysis, catalyzes the chemical reaction :choline + O2 \rightleftharpoons betaine aldehyde + H2O2 Thus, the two substrate (biochemistry), substrates of this enzyme are choline and oxygen, O2 ...
s. This is oxidized by mitochondrial or cytosolic
betaine-aldehyde dehydrogenase In enzymology, a betaine-aldehyde dehydrogenase () is an enzyme that catalyzes the chemical reaction :betaine aldehyde + NAD+ + H2O \rightleftharpoons betaine + NADH + 2 H+ The 3 substrates of this enzyme are betaine aldehyde, NAD+, and H2O, ...
s to trimethylglycine. Trimethylglycine is a necessary osmoregulator. It also works as a substrate for the BHMT-enzyme, which methylates homocysteine to
methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
. This is a ''S''-adenosylmethionine (SAM) precursor. SAM is a common reagent in biological
methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
reactions. For example, it methylates guanidines of DNA and certain
lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
s of histones. Thus it is part of
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
and
epigenetic regulation In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
. Choline deficiency thus leads to elevated homocysteine levels and decreased SAM levels in blood.


Content in foods

Choline occurs in foods as a free molecule and in the form of
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s, especially as phosphatidylcholines. Choline is highest in
organ meats Offal (), also called variety meats, pluck or organ meats, is the organs of a butchered animal. The word does not refer to a particular list of edible organs, which varies by culture and region, but usually excludes muscle. Offal may also refer ...
and egg yolks though it is found to a lesser degree in non-organ
meat Meat is animal flesh that is eaten as food. Humans have hunted, farmed, and scavenged animals for meat since prehistoric times. The establishment of settlements in the Neolithic Revolution allowed the domestication of animals such as chic ...
s,
grain A grain is a small, hard, dry fruit (caryopsis) – with or without an attached hull layer – harvested for human or animal consumption. A grain crop is a grain-producing plant. The two main types of commercial grain crops are cereals and legum ...
s, vegetables, fruit and dairy products.
Cooking oil Cooking oil is plant, animal, or synthetic liquid fat used in frying, baking, and other types of cooking. It is also used in food preparation and flavoring not involving heat, such as salad dressings and bread dips, and may be called edible oil. ...
s and other food fats have about 5 mg/100 g of total choline. In the United States,
food labels The packaging and labeling of food is subject to regulation in most regions/jurisdictions, both to prevent false advertising and to promote food safety. Regulations by type Multi-faceted * Codex Alimentarius (international voluntary standard) ...
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. "Total choline" is defined as the sum of free choline and choline-containing phospholipids, without accounting for mass fraction.
Human breast milk Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by mammary glands located in the breast of a human female. Breast milk is the primary source of nutrition for newborns, containing fat, protein, carbohydrates ( lacto ...
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. 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 The calorie is a unit of energy. For historical reasons, two main definitions of "calorie" are in wide use. The large calorie, food calorie, or kilogram calorie was originally defined as the amount of heat needed to raise the temperature of on ...
(kcal) to every infant formula. In the EU, levels above 50 mg/100 kcal are not allowed. Trimethylglycine is a functional
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
of choline. It substitutes for choline nutritionally, but only partially. High amounts of trimethylglycine occur in
wheat bran Bran, also known as miller's bran, is the hard outer layers of Cereal, cereal grain. It consists of the combined aleurone and pericarp. Corn (maize) bran also includes the pedicel (tip cap). Along with cereal germ, germ, it is an integral pa ...
(1,339 mg/100 g), toasted
wheat germ Cereal germ or Wheat germ: The germ of a cereal is the reproductive part that germinates to grow into a plant; it is the embryo of the seed. Along with bran, germ is often a by-product of the milling that produces refined grain products. ...
(1,240 mg/100 g) and
spinach Spinach (''Spinacia oleracea'') is a leafy green flowering plant native to central and western Asia. It is of the order Caryophyllales, family Amaranthaceae, subfamily Chenopodioideae. Its leaves are a common edible vegetable consumed either f ...
(600–645 mg/100 g), for example.


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. 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. 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

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. Individual EU countries may have more specific recommendations. The National Academy of Medicine (NAM) recommendations apply in the United States,
Australia Australia, officially the Commonwealth of Australia, is a Sovereign state, sovereign country comprising the mainland of the Australia (continent), Australian continent, the island of Tasmania, and numerous List of islands of Australia, sma ...
and New Zealand.


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. 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 % 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. 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 are able to biosynthesize limited amounts of it. Symptomatic deficiency is often caused by certain diseases or by other indirect causes. Severe deficiency causes muscle damage and
non-alcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic ...
, which may develop into cirrhosis. 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.


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 Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal ...
, 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 microbe Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut mic ...
s also degrade choline more efficiently than others, so they are also relevant. 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. Other simultaneously occurring mechanisms explaining the observed liver damage have also been suggested. For example, choline phospholipids are also needed in
mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
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 In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycle, ...
. Fat metabolism within 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 microbe Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut mic ...
s from the unabsorbed choline (see trimethylaminuria). 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 Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids into mitochondria to be oxidized for energy production, an ...
, 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 disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
s. 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 Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
predisposes for
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
s, but can also decrease TMA and TMAO excretion.


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. Folate deficiency also causes NTDs. Choline and folate, interacting with vitamin B12, act as methyl donors to homocysteine to form
methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
, which can then go on to form SAM ( ''S''-adenosylmethionine). 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. 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,


Cardiovascular diseases and cancer

Choline deficiency can cause fatty liver, which increases cancer and
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
risk. Choline deficiency also decreases SAM production, which partakes in
DNA methylation DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts t ...
– this decrease may also contribute to carcinogenesis. Thus, deficiency and its association with such diseases has 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 Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
have been contradictory.


Cognition

Studies observing the effect between higher choline intake and
cognition Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
have been conducted in human adults, with contradictory results. Similar studies on human infants and children have been contradictory and also limited.


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. 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 Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
. Choline concentrations in
amniotic fluid The amniotic fluid is the protective liquid contained by the amniotic sac of a gravid amniote. This fluid serves as a cushion for the growing fetus, but also serves to facilitate the exchange of nutrients, water, and biochemical products betwee ...
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 In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
of DNA and other functions), raising choline stores in fetal and placental tissues, and for increased production of lipoproteins (proteins containing "fat" portions). 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. 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 fiber An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...
s. Choline is also in demand for the production of the
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
, which can influence the structure and organization of brain regions,
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
, myelination, and
synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...
formation. Acetylcholine is even present in the placenta and may help control
cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...
and differentiation (increases in cell number and changes of multiuse cells into dedicated cellular functions) and parturition. Choline uptake into the brain is controlled by a low-affinity transporter located at the
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
. Transport occurs when arterial
plasma Plasma or plasm may refer to: Science * Plasma (physics), one of the four fundamental states of matter * Plasma (mineral), a green translucent silica mineral * Quark–gluon plasma, a state of matter in quantum chromodynamics Biology * Blood pla ...
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 Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme Enzymes () are proteins that a ...
degrades it, and the free choline is taken up by a high-affinity transporter into the neuron again.


Uses

Choline chloride and choline bitartrate are used in
dietary supplement A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...
s. Bitartrate is used more often due to its lower hygroscopicity. Certain choline salts are used to supplement chicken, turkey and some other
animal feed Animal feed is food given to domestic animals, especially livestock, in the course of animal husbandry. There are two basic types: fodder and forage. Used alone, the word ''feed'' more often refers to fodder. Animal feed is an important input to ...
s. Some salts are also used as industrial chemicals: for example, in
photolithography In integrated circuit manufacturing, photolithography or optical lithography is a general term used for techniques that use light to produce minutely patterned thin films of suitable materials over a substrate, such as a silicon wafer, to protect ...
to remove photoresist.
Choline theophyllinate Choline theophyllinate (INN), also known as oxtriphylline, is a cough medicine derived from xanthine that acts as a bronchodilator to open up airways in the lung. Chemically, it is a salt of choline and theophylline. It classifies as an expecto ...
and choline
salicylate Salicylic acid is an organic compound with the formula HOC6H4CO2H. A colorless, bitter-tasting solid, it is a precursor to and a metabolite of aspirin (acetylsalicylic acid). It is a plant hormone, and has been listed by the EPA Toxic Substance ...
are used as medicines, as well as structural analogs, like methacholine and
carbachol Carbachol, also known as carbamylcholine and sold under the brand name Miostat among others, is a cholinomimetic drug that binds and activates acetylcholine receptors. Thus it is classified as a cholinergic agonist. It is primarily used for var ...
. Radiolabeled cholines, like 11C-choline, are used in
medical imaging Medical imaging is the technique and process of imaging the interior of a body for clinical analysis and medical intervention, as well as visual representation of the function of some organs or tissues (physiology). Medical imaging seeks to rev ...
. Other commercially used salts include tricholine citrate and choline bicarbonate.


Antagonists and inhibitors

Hundreds of choline
antagonists An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
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 Hemicholinium-3 (HC3), also known as hemicholine, is a drug which blocks the reuptake of choline by the high-affinity choline transporter (ChT; encoded in humans by the gene ''SLC5A7'') at the presynapse. The reuptake of choline is the rate-li ...
is a more general inhibitor, but also moderately inhibits
choline kinase Choline kinase (also known as CK, ChoK and choline phosphokinase) is an enzyme which catalyzes the first reaction in the choline pathway for phosphatidylcholine (PC) biosynthesis. This reaction involves the transfer of a phosphate group from adenos ...
s. More specific choline kinase inhibitors have also been developed. Trimethylglycine synthesis inhibitors also exist: carboxybutylhomocysteine is an example of a specific BHMT inhibitor. The cholinergic hypothesis of dementia has not only lead to medicinal acetylcholinesterase inhibitors, but also to a variety of
acetylcholine inhibitor Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Pa ...
s. Examples of such inhibiting research chemicals include
triethylcholine Triethylcholine is a drug which mimics choline, and causes failure of cholinergic transmission by interfering with synthesis of acetylcholine in nerve endings. Effects Triethylcholine produces a slowly developing neuromuscular weakness ...
, homocholine and many other ''N''-ethyl derivates of choline, which are
false neurotransmitter A false neurotransmitter is a chemical compound which closely imitates the action of a neurotransmitter in the nervous system. Examples include 5-MeO-αMT (mimicking serotonin) and α-methyldopa. These chemicals can be accumulated by a neuron or s ...
analogs of acetylcholine.
Choline acetyltransferase Choline acetyltransferase (commonly abbreviated as ChAT, but sometimes CAT) is a transferase enzyme responsible for the synthesis of the neurotransmitter acetylcholine. ChAT catalyzes the transfer of an acetyl group from the coenzyme acetyl-Co ...
inhibitors have also been developed.


History


Discovery

In 1849, Adolph Strecker was the first to isolate choline from pig
bile Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile ...
. In 1852, L. Babo and M. Hirschbrunn extracted choline from white mustard seeds and named it ''sinkaline''. 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. In 1850, Theodore Nicolas Gobley extracted from the brains and roe of
carp Carp are various species of oily freshwater fish from the family Cyprinidae, a very large group of fish native to Europe and Asia. While carp is consumed in many parts of the world, they are generally considered an invasive species in parts of ...
s a substance he named ''
lecithin Lecithin (, from the Greek ''lekithos'' "yolk") 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 so ar ...
'' after the Greek word for egg yolk, ''lekithos'', showing in 1874 that it was a mixture of
phosphatidylcholines Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soybean ...
. In 1865, Oscar Liebreich isolated "''neurine''" from animal brains. The
structural formula The structural formula of a chemical compound is a graphic representation of the molecular structure (determined by structural chemistry methods), showing how the atoms are possibly arranged in the real three-dimensional space. The chemical bondi ...
s of
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
and Liebreich's "neurine" were resolved by Adolf von Baeyer in 1867. 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. The compound now known as
neurine Neurine is an alkaloid found in egg yolk, brain, bile and in cadavers. It is formed during putrefaction of biological tissues by the dehydration of choline. It is a poisonous, syrupy liquid with a fishy odor. Neurine is a quaternary ammonium sa ...
is unrelated to choline.


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 Lecithin (, from the Greek ''lekithos'' "yolk") 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 so ar ...
, proving in 1932 that choline in lecithin was solely responsible for this preventive effect. In 1998, the US National Academy of Medicine reported their first recommendations for choline in the human diet.


References

{{Authority control Essential nutrients Primary alcohols Cholinergics Quaternary ammonium compounds Dietary supplements