Choline is an
essential nutrient for humans and many other animals.
Choline occurs as a
cation that forms various
salts
In chemistry, a salt is a chemical compound consisting of an ionic assembly of positively charged cations and negatively charged anions, which results in a compound with no net electric charge. A common example is table salt, with positively c ...
(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
phospholipids, such as
phosphatidylcholine
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 soybea ...
.
[ Choline is not formally classified as a ]vitamin
A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism. Essential nutrie ...
despite being an essential nutrient with an amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
–like structure and metabolism.[ In most animals, choline phospholipids are necessary components in ]cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
s, in the membranes of cell organelles, and in very low-density lipoprotein
Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins ( chylomicrons, VLDL, intermediate-density lipoprotein, low-density l ...
s.[ Choline is required to produce acetylcholine – a neurotransmitter – and ''S''-adenosylmethionine (SAM), a universal methyl donor. Upon methylation SAM is transformed into ]homocysteine
Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In th ...
.
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
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...
, sweating, diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
and fish-like body odor due to trimethylamine
Trimethylamine (TMA) is an organic compound with the formula N(CH3)3. It is a colorless, hygroscopic, and flammable tertiary amine. It is a gas at room temperature but is usually sold as a 40% solution in water. (It is also sold in pressurized ...
, 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
Among animals which produce eggs, the yolk (; also known as the vitellus) is the nutrient-bearing portion of the egg whose primary function is to supply food for the development of the embryo. Some types of egg contain no yolk, for example be ...
, dairy products
Dairy products or milk products, also known as lacticinia, are food products made from (or containing) milk. The most common dairy animals are cow, water buffalo, nanny goat, and ewe. Dairy products include common grocery store food items in ...
, peanuts, certain beans, nuts, seeds and vegetables
Vegetables are parts of plants that are consumed by humans or other animals as food. The original meaning is still commonly used and is applied to plants collectively to refer to all edible plant matter, including the flowers, fruits, stems ...
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
Hydroxide is a diatomic anion with chemical formula OH−. It consists of an oxygen and hydrogen atom held together by a single covalent bond, and carries a negative electric charge. It is an important but usually minor constituent of water. I ...
is known as choline base. It is hygroscopic
Hygroscopy is the phenomenon of attracting and holding water molecules via either absorption or adsorption from the surrounding environment, which is usually at normal or room temperature. If water molecules become suspended among the substan ...
and thus often encountered as a colorless viscous
The viscosity of a fluid is a measure of its resistance to deformation at a given rate. For liquids, it corresponds to the informal concept of "thickness": for example, syrup has a higher viscosity than water.
Viscosity quantifies the inte ...
hydrated syrup that smells of trimethylamine
Trimethylamine (TMA) is an organic compound with the formula N(CH3)3. It is a colorless, hygroscopic, and flammable tertiary amine. It is a gas at room temperature but is usually sold as a 40% solution in water. (It is also sold in pressurized ...
(TMA). Aqueous solutions of choline are stable, but the compound slowly breaks down to ethylene glycol
Ethylene glycol (IUPAC name: ethane-1,2-diol) is an organic compound (a vicinal diol) with the formula . It is mainly used for two purposes, as a raw material in the manufacture of polyester fibers and for antifreeze formulations. It is an odo ...
, polyethylene glycol
Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular we ...
s, 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
Ethylene oxide is an organic compound with the formula . It is a cyclic ether and the simplest epoxide: a three-membered ring consisting of one oxygen atom and two carbon atoms. Ethylene oxide is a colorless and flammable gas with a faintly sw ...
. Choline has historically been produced from natural sources, such as via hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolys ...
of lecithin.[
]
Metabolism
Biosynthesis
In plants, the first step in ''de novo'' biosynthesis of choline is the decarboxylation of serine 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 w ...
, 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 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. The ...
(3PG) receives 2 acyl groups from acyl-CoA 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 reacts with serine to form phosphatidylserine
Phosphatidylserine (abbreviated Ptd-L-Ser or PS) is a phospholipid and is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via ap ...
which decarboxylates 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 w ...
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 ...
(PE) forms. A PEMT enzyme moves three methyl groups from three ''S''-adenosyl methionines (SAM) donors to the ethanolamine group of the phosphatidylethanolamine to form choline in the form of a phosphatidylcholine. Three ''S''-adenosylhomocysteines (SAHs) are formed as a byproduct.[
Choline can also be released from more complex choline containing molecules. For example, ]phosphatidylcholine
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 soybea ...
s (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 mitochondri ...
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 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
A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as su ...
are transformed to PC by diacylglycerol cholinephosphotransferase (CPT).[
In humans, certain PEMT-enzyme ]mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
s 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
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often ...
) increase the dietary need for choline. In rodents, 70% of phosphatidylcholines are formed via the PEMT route and only 30% via the CDP-choline route.[ In knockout mice, PEMT inactivation makes them completely dependent on dietary choline.][
]
Absorption
In humans, choline is absorbed from the intestines 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
Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...
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 membranes. SLC44A1 has limited ability to transport choline: at high concentrations part of it is left unabsorbed. Absorbed choline leaves the enterocytes via the portal vein, passes the liver and enters systemic circulation. Gut microbes degrade the unabsorbed choline to trimethylamine
Trimethylamine (TMA) is an organic compound with the formula N(CH3)3. It is a colorless, hygroscopic, and flammable tertiary amine. It is a gas at room temperature but is usually sold as a 40% solution in water. (It is also sold in pressurized ...
, 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 glycerophosphocholines are hydrolyzed via phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. Acids trigger the release of bound calcium from cellular stores and the consequent increase in free cytosolic Ca2+, an essential step in ...
s 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 (phosphatidylcholine
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 soybea ...
s and sphingomyelin
Sphingomyelin (SPH, ˌsfɪŋɡoˈmaɪəlɪn) is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphocholine and ceramide, or a phosp ...
s) are either hydrolyzed by phospholipases or enter the lymph
Lymph (from Latin, , meaning "water") is the fluid that flows through the lymphatic system, a system composed of lymph vessels (channels) and intervening lymph nodes whose function, like the venous system, is to return fluid from the tissues ...
incorporated into chylomicron
Chylomicrons (from the Greek χυλός, chylos, meaning ''juice'' (of plants or animals), and micron, meaning ''small particle''), also known as ultra low-density lipoproteins (ULDL), are lipoprotein particles that consist of triglycerides (85 ...
s.[
]
Transport
In humans, choline is transported as a free molecule in blood. Choline–containing phospholipids and other substances, like glycerophosphocholines, are transported in blood lipoprotein
A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, su ...
s. Blood plasma
Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intr ...
choline levels in healthy fasting
Fasting is the abstention from eating and sometimes drinking. From a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (see " Breakfast"), or to the metabolic state achieved after ...
adults is 7–20 micromoles
The mole, symbol mol, is the unit of amount of substance in the International System of Units (SI). The quantity amount of substance is a measure of how many elementary entities of a given substance are in an object or sample. The mole is define ...
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
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 conve ...
and thus requires transporters to pass through fat-soluble cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
s. 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 neur ...
* 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
Choline transporter-like protein 2 is a protein that in humans is encoded by the ''SLC44A2'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''gen ...
) 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 ''gen ...
)
* 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 d ...
)
SLC5A7s are sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...
- (Na+) and ATP-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 m ...
for choline, transport it primarily to neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s and are indirectly associated with the acetylcholine production.[ Their deficient function causes hereditary weakness in the pulmonary and other muscles in humans via acetylcholine deficiency. In knockout mice, their dysfunction results easily in death with cyanosis and paralysis.
CTL1s have moderate affinity for choline and transport it in almost all tissues, including the intestines, liver, kidneys, ]placenta
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...
and mitochondria. CTL1s supply choline for phosphatidylcholine
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 soybea ...
and trimethylglycine
Trimethylglycine is an amino acid derivative that occurs in plants. Trimethylglycine was the first betaine discovered; originally it was simply called betaine because, in the 19th century, it was discovered in sugar beets. It has a sweet and umami ...
production.[ CTL2s occur especially in the mitochondria in the tongue, kidneys, muscles and heart. They are associated with the mitochondrial ]oxidation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...
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 astrocyte
Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...
s 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 membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
s and organelles as phospholipids, and inside cells as phosphatidylcholine
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 soybea ...
s and glycerophosphocholines.[
]
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
Transport (in British English), or transportation (in American English), is the intentional movement of humans, animals, and goods from one location to another. Modes of transport include air, land ( rail and road), water, cable, pipelin ...
). Trimethylglycine
Trimethylglycine is an amino acid derivative that occurs in plants. Trimethylglycine was the first betaine discovered; originally it was simply called betaine because, in the 19th century, it was discovered in sugar beets. It has a sweet and umami ...
is demethylated in the liver and kidneys to dimethylglycine
Dimethylglycine (DMG) is a derivative of the amino acid glycine with the structural formula (CH3)2NCH2COOH. It can be found in beans and liver, and has a sweet taste. It can be formed from trimethylglycine upon the loss of one of its methyl group ...
(tetrahydrofolate
Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative.
Metabolism
Human synthesis
Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate.
It is co ...
receives one of the methyl groups). Methylglycine forms, is excreted into urine, or is demethylated to glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid ( carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinog ...
.[
]
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
Osmoregulation is the active regulation of the osmotic pressure of an organism's body fluids, detected by osmoreceptors, to maintain the homeostasis of the organism's water content; that is, it maintains the fluid balance and the concentration of ...
trimethylglycine
Trimethylglycine is an amino acid derivative that occurs in plants. Trimethylglycine was the first betaine discovered; originally it was simply called betaine because, in the 19th century, it was discovered in sugar beets. It has a sweet and umami ...
(betaine
A betaine () in chemistry is any neutral chemical compound with a positively charged cationic functional group, such as a quaternary ammonium or phosphonium cation (generally: onium ions) that bears no hydrogen atom and with a negatively charge ...
). Trimethylglycine in turn serves as a source of methyl group
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 ma ...
s by participating in the biosynthesis of ''S''-adenosylmethionine.
Phospholipid precursor
Choline is transformed to different phospholipids, like phosphatidylcholine
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 soybea ...
s and sphingomyelin
Sphingomyelin (SPH, ˌsfɪŋɡoˈmaɪəlɪn) is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphocholine and ceramide, or a phosp ...
s. These are found in all cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
s and the membranes of most cell organelles.[ 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
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
. The rafts are centers, for example for receptors
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
and receptor signal transduction enzymes.[
Phosphatidylcholines are needed for the synthesis of ]VLDL
Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, intermediate-density lipoprotein, low-density lipo ...
s: 70–95% of their phospholipids are phosphatidylcholines in humans.[
Choline is also needed for the synthesis of ]pulmonary surfactant
Pulmonary surfactant is a surface-active complex of phospholipids and proteins formed by type II alveolar cells. The proteins and lipids that make up the surfactant have both hydrophilic and hydrophobic regions. By adsorbing to the air-water i ...
, 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.
Phosphatidylcholines are excreted into bile and work together with bile acid salts as surfactants in it, thus helping with the intestinal
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 and ...
absorption of lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...
s.[
]
Acetylcholine synthesis
Choline is needed to produce acetylcholine. This is a neurotransmitter which plays a necessary role in muscle contraction
Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as ...
, memory
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered ...
and neural development, for example.[ Nonetheless, there is little acetylcholine in the human body relative to other forms of choline.][ ]Neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s 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
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...
irreversibly in liver mitochondria to glycine betaine aldehyde by choline oxidases. 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 an amino acid derivative that occurs in plants. Trimethylglycine was the first betaine discovered; originally it was simply called betaine because, in the 19th century, it was discovered in sugar beets. It has a sweet and umami ...
.[ Trimethylglycine is a necessary ]osmoregulator
Osmoregulation is the active regulation of the osmotic pressure of an organism's body fluids, detected by osmoreceptors, to maintain the homeostasis of the organism's water content; that is, it maintains the fluid balance and the concentration of ...
. It also works as a substrate for the BHMT-enzyme, which methylates homocysteine
Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In th ...
to methionine. This is a ''S''-adenosylmethionine (SAM) precursor. SAM is a common reagent in biological methylation reactions. For example, it methylates guanidine
Guanidine is the compound with the formula HNC(NH2)2. It is a colourless solid that dissolves in polar solvents. It is a strong base that is used in the production of plastics and explosives. It is found in urine predominantly in patients experie ...
s of DNA and certain lysines of histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...
s. Thus it is part of gene expression and epigenetic regulation. 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 phospholipids, especially as phosphatidylcholine
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 soybea ...
s. 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
Among animals which produce eggs, the yolk (; also known as the vitellus) is the nutrient-bearing portion of the egg whose primary function is to supply food for the development of the embryo. Some types of egg contain no yolk, for example be ...
though it is found to a lesser degree in non-organ meats, grains, vegetable
Vegetables are parts of plants that are consumed by humans or other animals as food. The original meaning is still commonly used and is applied to plants collectively to refer to all edible plant matter, including the flowers, fruits, stems, ...
s, fruit
In botany, a fruit is the seed-bearing structure in flowering plants that is formed from the ovary after flowering.
Fruits are the means by which flowering plants (also known as angiosperms) disseminate their seeds. Edible fruits in particu ...
and dairy products
Dairy products or milk products, also known as lacticinia, are food products made from (or containing) milk. The most common dairy animals are cow, water buffalo, nanny goat, and ewe. Dairy products include common grocery store food items in ...
. Cooking oils and other food fats have about 5 mg/100 g of total choline. In the United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...
, 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 stand ...
express the amount of choline in a serving as a percentage of daily value
The Reference Daily Intake (RDI) used in nutrition labeling on food and dietary supplement products in the U.S. and Canada is the daily intake level of a nutrient that is considered to be sufficient to meet the requirements of 97–98% of healthy ...
(%DV) based on the adequate intake
The Dietary Reference Intake (DRI) is a system of nutrition recommendations from the National Academy of Medicine (NAM) of the National Academies (United States). It was introduced in 1997 in order to broaden the existing guidelines known as Reco ...
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 is rich in choline. Exclusive ]breastfeeding
Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...
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 formula
Infant formula, baby formula, or simply formula (American English); or baby milk, infant milk or first milk (British English), is a manufactured food designed and marketed for feeding to babies and infants under 12 months of age, usually prepar ...
s 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.[
]Trimethylglycine
Trimethylglycine is an amino acid derivative that occurs in plants. Trimethylglycine was the first betaine discovered; originally it was simply called betaine because, in the 19th century, it was discovered in sugar beets. It has a sweet and umami ...
is a functional metabolite 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 grain. It consists of the combined aleurone and pericarp. Corn (maize) bran also includes the pedicel (tip cap). Along with germ, it is an integral part of whole grains ...
(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 (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 milligram
The kilogram (also kilogramme) is the unit of mass in the International System of Units (SI), having the unit symbol kg. It is a widely used measure in science, engineering and commerce worldwide, and is often simply called a kilo colloquially. ...
s per day (mg/day). The European Food Safety Authority
The European Food Safety Authority (EFSA) is the agency of the European Union (EU) that provides independent scientific advice and communicates on existing and emerging risks associated with the food chain. EFSA was established in February 2002, ...
(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
The National Academy of Medicine (NAM), formerly called the Institute of Medicine (IoM) until 2015, is an American nonprofit, non-governmental organization. The National Academy of Medicine is a part of the National Academies of Sciences, Eng ...
(NAM) recommendations apply in the United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...
,[ ] Australia and New Zealand
New Zealand ( mi, Aotearoa ) is an island country in the southwestern Pacific Ocean. It consists of two main landmasses—the North Island () and the South Island ()—and over 700 smaller islands. It is the sixth-largest island count ...
.
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 milligram
The kilogram (also kilogramme) is the unit of mass in the International System of Units (SI), having the unit symbol kg. It is a widely used measure in science, engineering and commerce worldwide, and is often simply called a kilo colloquially. ...
s 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
The National Health and Nutrition Examination Survey (NHANES) is a survey research program conducted by the National Center for Health Statistics (NCHS) to assess the health and nutritional status of adults and children in the United States, and t ...
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
The Dietary Reference Intake (DRI) is a system of nutrition recommendations from the National Academy of Medicine (NAM) of the National Academies (United States). It was introduced in 1997 in order to broaden the existing guidelines known as Reco ...
(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
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...
.
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
Trimethylglycine is an amino acid derivative that occurs in plants. Trimethylglycine was the first betaine discovered; originally it was simply called betaine because, in the 19th century, it was discovered in sugar beets. It has a sweet and umami ...
, which functions as an osmoregulator
Osmoregulation is the active regulation of the osmotic pressure of an organism's body fluids, detected by osmoreceptors, to maintain the homeostasis of the organism's water content; that is, it maintains the fluid balance and the concentration of ...
.[
]
Causes and mechanisms
Estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
production is a relevant factor which predisposes individuals to deficiency along with low dietary choline intake. Estrogens activate phosphatidylcholine
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 soybea ...
producing PEMT enzymes. Women before menopause
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often ...
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 polymorphism
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently lar ...
s (genetic factors) affecting choline and folate
Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing an ...
metabolism are also relevant. Certain gut microbes 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 VLDL
Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, intermediate-density lipoprotein, low-density lipo ...
s. Thus VLDL-mediated fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
transport out of the liver decreases leading to fat accumulation in the liver.[ Other simultaneously occurring mechanisms explaining the observed liver damage have also been suggested. For example, choline phospholipids are also needed in mitochondrial membranes. Their inavailability leads to the inability of mitochondrial membranes to maintain proper ]electrochemical gradient
An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts, the chemical gradient, or difference in solute concentration across a membrane, and ...
, which, among other things, is needed for degrading fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
s 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 cycl ...
. 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
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...
, nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
, diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
and fish-like body odor. The odor is due to trimethylamine
Trimethylamine (TMA) is an organic compound with the formula N(CH3)3. It is a colorless, hygroscopic, and flammable tertiary amine. It is a gas at room temperature but is usually sold as a 40% solution in water. (It is also sold in pressurized ...
(TMA) formed by the gut microbes from the unabsorbed choline (see trimethylaminuria
Trimethylaminuria (TMAU), also known as fish odor syndrome or fish malodor syndrome, is a rare metabolic disorder that causes a defect in the normal production of an enzyme named flavin-containing monooxygenase 3 (''FMO3''). When ''FMO3'' is not w ...
).[
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
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...
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. 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.
Health effects
Neural tube closure
Low maternal intake of choline is associated with an increased risk of neural tube defect
Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo b ...
s. Higher maternal intake of choline is likely associated with better neurocognition/neurodevelopment in children.[ ]Folate
Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing an ...
deficiency also causes NTDs. Choline and folate, interacting with vitamin B12, act as methyl donors to homocysteine
Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In th ...
to form methionine, 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 ]mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
s 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
Fatty liver disease (FLD), also known as hepatic steatosis, is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. Complicat ...
, which increases cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
and cardiovascular disease risk. Choline deficiency also decreases SAM production, which partakes in DNA methylation – this decrease may also contribute to carcinogenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
. Thus, deficiency and its association with such diseases has been studied.[ However, ]observational studies
In fields such as epidemiology, social sciences, psychology and statistics, an observational study draws inferences from a sample to a population where the independent variable is not under the control of the researcher because of ethical concern ...
of free populations have not convincingly shown an association between low choline intake and cardiovascular diseases or most cancers.[ Studies on prostate cancer have been contradictory.
]
Cognition
Studies observing the effect between higher choline intake and cognition 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
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
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
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...
accumulates choline by pumping choline against the concentration gradient into the tissue, where it is then stored in various forms, mostly as acetylcholine. Choline concentrations in amniotic fluid can be ten times higher than in maternal blood.
Functions in the fetus
Choline is in high demand during pregnancy as a substrate for building cellular membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (th ...
s (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). 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
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 soybea ...
). Human brain growth is most rapid during the third trimester
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but can ...
of pregnancy and continues to be rapid to approximately five years of age. During this time, the demand is high for sphingomyelin
Sphingomyelin (SPH, ˌsfɪŋɡoˈmaɪəlɪn) is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphocholine and ceramide, or a phosp ...
, which is made from phosphatidylcholine (and thus from choline), because this material is used to myelinate
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to Insulator (electricity), insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The ...
(insulate) nerve fibers. 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
Birth is the act or process of bearing or bringing forth offspring, also referred to in technical contexts as parturition. In mammals, the process is initiated by hormones which cause the muscular walls of the uterus to contract, expelling the f ...
.
Choline uptake into the brain is controlled by a low-affinity transporter located at the blood–brain barrier. 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. Neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s, 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.
Uses
Choline chloride
The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride sa ...
and choline bitartrate
, Section2 = {{Chembox Properties
, C=4 , H=5 , O=6
, Formula_Charge = −
, ConjugateAcid = Tartaric acid
, ConjugateBase = Tartrate
Bitartrate is an anion which is the conjugate base of tartaric acid. It may also refer to any salt or ...
are used in dietary supplements. Bitartrate is used more often due to its lower hygroscopic
Hygroscopy is the phenomenon of attracting and holding water molecules via either absorption or adsorption from the surrounding environment, which is usually at normal or room temperature. If water molecules become suspended among the substan ...
ity.[ Certain choline salts are used to supplement ]chicken
The chicken (''Gallus gallus domesticus'') is a domesticated junglefowl species, with attributes of wild species such as the grey and the Ceylon junglefowl that are originally from Southeastern Asia. Rooster or cock is a term for an adu ...
, turkey
Turkey ( tr, Türkiye ), officially the Republic of Türkiye ( tr, Türkiye Cumhuriyeti, links=no ), is a transcontinental country located mainly on the Anatolian Peninsula in Western Asia, with a small portion on the Balkan Peninsula in ...
and some other animal feeds. Some salts are also used as industrial chemicals: for example, in photolithography to remove photoresist
A photoresist (also known simply as a resist) is a light-sensitive material used in several processes, such as photolithography and photoengraving, to form a patterned coating on a surface. This process is crucial in the electronic industry.
...
. Choline theophyllinate 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 analog
A structural analog (analogue in modern traditional English; Commonwealth English), also known as a chemical analog or simply an analog, is a compound having a structure similar to that of another compound, but differing from it in respect to a c ...
s, like methacholine
Methacholine ( INN, USAN) (trade name Provocholine), also known as Acetyl-β-methylcholine, is a synthetic choline ester that acts as a non-selective muscarinic receptor agonist in the parasympathetic nervous system.
Medical uses
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 va ...
. Radiolabeled
A radioactive tracer, radiotracer, or radioactive label is a chemical compound in which one or more atoms have been replaced by a radionuclide so by virtue of its radioactive decay it can be used to explore the mechanism of chemical reactions by tr ...
cholines, like 11C-choline, are used in medical imaging. Other commercially used salts include tricholine citrate
Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in the ...
and choline bicarbonate
In inorganic chemistry, bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion with the chemical formula .
Bicarbonate serves a crucial biochem ...
.[
]
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, ri ...
and enzyme inhibitor
An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a sp ...
s have been developed for research purposes. Aminomethylpropanol is among the first ones used as a research tool. It inhibits choline and trimethylglycine
Trimethylglycine is an amino acid derivative that occurs in plants. Trimethylglycine was the first betaine discovered; originally it was simply called betaine because, in the 19th century, it was discovered in sugar beets. It has a sweet and umami ...
synthesis. It is able to induce choline deficiency that in turn results in fatty liver
Fatty liver disease (FLD), also known as hepatic steatosis, is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. Complicat ...
in rodents. Diethanolamine
Diethanolamine, often abbreviated as DEA or DEOA, is an organic compound with the formula HN(CH2CH2OH)2. Pure diethanolamine is a white solid at room temperature, but its tendencies to absorb water and to supercool meaning that it is often encoun ...
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-l ...
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
Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cati ...
hypothesis of dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
has not only lead to medicinal acetylcholinesterase inhibitor
Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level and ...
s, but also to a variety of acetylcholine inhibitors. 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 inhibitors have also been developed.[
]
History
Discovery
In 1849, Adolph Strecker
Adolph Strecker (October 21, 1822 – November 7, 1871) was a German chemist who is remembered primarily for his work with amino acids.
Life and work
Strecker was born in Darmstadt, the son of Friedrich Ludwig Strecker, an archivist working for ...
was the first to isolate choline from pig bile. In 1852, L. Babo and M. Hirschbrunn extracted choline from white mustard
White mustard (''Sinapis alba'') is an annual plant of the family Brassicaceae. It is sometimes also referred to as ''Brassica alba'' or ''B. hirta''. Grown for its seeds, used to make the condiment mustard, as fodder crop, or as a green manure ...
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
In chemistry, a chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbol ...
C5H13NO. In 1850, Theodore Nicolas Gobley
TheodoreSome earlier Wikipedia versions, e.g. wiki.de, write Nicolas-Theodore; family sources (see wiki.fr article discussion) guarantee Theodore as ordinary given name, plus a publication in March 1848, "Recherches sur la présence de l'arsenic d ...
extracted from the brains and roe
Roe ( ) or hard roe is the fully ripe internal egg masses in the ovaries, or the released external egg masses, of fish and certain marine animals such as shrimp, scallop, sea urchins and squid. As a seafood, roe is used both as a cooked in ...
of carps a substance he named '' lecithin'' after the Greek word for egg yolk
Among animals which produce eggs, the yolk (; also known as the vitellus) is the nutrient-bearing portion of the egg whose primary function is to supply food for the development of the embryo. Some types of egg contain no yolk, for example ...
, ''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
Matthias Eugen Oscar Liebreich (14 February 1839 – 2 July 1908) was a German pharmacologist.
Biography
He was a native of Königsberg. He studied chemistry under Carl Remigius Fresenius (1818–1897) in Wiesbaden, and studied medicine in König ...
isolated "''neurine''" from animal brains. The structural formulas of acetylcholine and Liebreich's "neurine" were resolved by Adolf von Baeyer
Johann Friedrich Wilhelm Adolf von Baeyer (; 31 October 1835 – 20 August 1917) was a German chemist who synthesised indigo and developed a nomenclature for cyclic compounds (that was subsequently extended and adopted as part of the IUPAC org ...
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
Fatty liver disease (FLD), also known as hepatic steatosis, is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. Complicat ...
in rats on a special diet and diabetic
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
dogs could be prevented by feeding them lecithin,[ proving in 1932 that choline in lecithin was solely responsible for this preventive effect. In 1998, the US ]National Academy of Medicine
The National Academy of Medicine (NAM), formerly called the Institute of Medicine (IoM) until 2015, is an American nonprofit, non-governmental organization. The National Academy of Medicine is a part of the National Academies of Sciences, Eng ...
reported their first recommendations for choline in the human diet.
References
{{Authority control
Essential nutrients
Primary alcohols
Cholinergics
Quaternary ammonium compounds
Dietary supplements