Choline is a cation with the chemical formula . Choline forms various salts, such as choline chloride and choline bitartrate. An essential nutrient for animals, it is a structural component of phospholipids and cell membranes.
Choline is used to synthesize acetylcholine, a neurotransmitter involved in muscle control and numerous functions of the nervous system. Choline is involved in early development of the brain, gene expression, cell membrane signaling, and brain metabolism.
Although humans synthesize choline in the liver, the amount produced naturally is insufficient to meet cellular functions, requiring that some choline be obtained from foods or dietary supplements. Foods rich in choline include meats, poultry, eggs, fish, cruciferous vegetables, and beans. Choline is present in breast milk and is commonly added to infant formulas.
Chemistry Choline is a quaternary ammonium cation. The cholines are a family of water-soluble quaternary ammonium compounds. Choline is the parent compound of the choline class, consisting of an ethanolamine residue having three methyl groups attached to the same nitrogen atom. Choline hydroxide is known as choline base. It is hygroscopic and thus often encountered as a colorless viscous hydrated syrup that smells of trimethylamine (TMA). Aqueous solutions of choline are stable, but the compound slowly breaks down to ethylene glycol, polyethylene glycols, and TMA.
Choline chloride can be prepared by treating TMA with 2-chloroethanol:
Choline has historically been produced from natural sources, such as via the hydrolysis of lecithin.
Choline as a nutrient Choline is widespread in living beings. In most animals, choline phospholipids are necessary components in cell membranes, in the membranes of cell organelles, and in very low-density lipoproteins.
Choline is an essential nutrient for humans and many other animals. Humans are capable of some de novo synthesis of choline but require additional choline in the diet to maintain health. Dietary requirements can be met by choline by itself or in the form of choline phospholipids, such as phosphatidylcholine. Choline is not formally classified as a vitamin despite being an essential nutrient with an amino acid–like structure and metabolism.
Choline is required to produce acetylcholine – a neurotransmitter – and S-adenosylmethionine (SAM), a universal methyl donor. Upon methylation SAM is transformed into S-adenosyl homocysteine.
Symptomatic choline deficiency causes non-alcoholic fatty liver disease and muscle damage. Excessive consumption of choline (greater than 7.5 grams per day) can cause low blood pressure, sweating, diarrhea, and fish-like body smell due to trimethylamine, which forms in the metabolism of choline. Rich dietary sources of choline and choline phospholipids include liver, egg yolks, dairy products, peanuts, certain beans, nuts and seeds.
Metabolism Biosynthesis
In plants, the first step in de novo biosynthesis of choline is the decarboxylation of serine into ethanolamine, which is catalyzed by a 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 proceeds via the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, but biosynthesis is not enough to meet human requirements. In the hepatic PEMT route, 3-phosphoglycerate (3PG) receives 2 acyl groups from acyl-CoA forming a phosphatidic acid. It reacts with cytidine triphosphate to form cytidine diphosphate-diacylglycerol. Its hydroxyl group reacts with serine to form phosphatidylserine, which decarboxylates to ethanolamine and phosphatidylethanolamine (PE) forms. A PEMT enzyme moves three methyl groups from three S-adenosyl methionines (SAM) donors to the ethanolamine group of the phosphatidylethanolamine to form choline in the form of phosphatidylcholine. Three S-adenosylhomocysteines (SAHs) are formed as a byproduct.
Choline can also be released from more complex precursors. For example, phosphatidylcholines (PC) can be hydrolyzed to choline (Chol) in most cell types. The CDP-choline route can also produce choline: cytosolic choline kinases (CK) phosphorylate choline with ATP to phosphocholine (PChol). This happens in some cell types like liver and kidney. Choline-phosphate cytidylyltransferases (CPCT) convert PChol to CDP-choline (CDP-Chol) with cytidine triphosphate (CTP). CDP-choline and diglyceride are transformed to PC by diacylglycerol cholinephosphotransferase (CPT).
In humans, certain PEMT-enzyme mutations and estrogen deficiency (often due to menopause) increase the dietary need for choline. In rodents, 70% of phosphatidylcholines are formed via the PEMT route and only 30% via the CDP-choline route. In knockout mice, PEMT inactivation makes them completely dependent on dietary choline.
Absorption In humans, choline is absorbed from the intestines via the SLC44A1 (CTL1) membrane protein by facilitated diffusion governed by the choline concentration gradient and the electrical potential across the enterocyte membranes. SLC44A1 has limited ability to transport choline: at high concentrations, some of it remains unabsorbed. Absorbed choline leaves the enterocytes via the portal vein, passes the liver, and enters systemic circulation. Gut microbes degrade the unabsorbed choline to trimethylamine, which is oxidized in the liver to trimethylamine N-oxide.
Phosphocholine and glycerophosphocholines are hydrolyzed via phospholipases to choline, which enters the portal vein. Due to their water solubility, some of them escape unchanged to the portal vein. Fat-soluble choline-containing compounds (phosphatidylcholines and sphingomyelins) are either hydrolyzed by phospholipases or enter the lymph incorporated into chylomicrons.
Transport In humans, choline is transported as a free ion in blood. Choline–containing phospholipids and other substances, like glycerophosphocholines, are transported in blood lipoproteins. Blood plasma choline levels in healthy fasting adults is 7–20 micromoles per liter (μmol/L) and 10 μmol/L on average. Levels are regulated, but choline intake and deficiency can alter them. Levels are elevated for about 3 hours after choline consumption. Phosphatidylcholine levels in the plasma of fasting adults are 1.5–2.5 mmol/L. Its consumption elevates free choline levels for about 8–12 hours but does not significantly affect phosphatidylcholine levels.
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 CTLs: CTL1 (SLC44A1), CTL2 (SLC44A2) and CTL4 (SLC44A4) OCTs: OCT1 (SLC22A1) and OCT2 (SLC22A2)
SLC5A7s are sodium- (Na+) and ATP-dependent transporters. They have high binding affinity for choline, transport it primarily to neurons and are indirectly associated with the acetylcholine production. Their deficient function causes hereditary weakness in the pulmonary and other muscles in humans due to acetylcholine deficiency. In knockout mice, their dysfunction results easily in death with cyanosis and paralysis.
CTL1s have moderate affinity for choline and transport it in almost all tissues, including the intestines, liver, kidneys, placenta, and mitochondria. CTL1s supply choline for phosphatidylcholine and trimethylglycine production. CTL2s occur, especially in the mitochondria in the tongue, kidneys, muscles, and heart. They are associated with the mitochondrial oxidation of choline to trimethylglycine. CTL1s and CTL2s are not associated with acetylcholine production, but transport choline together via the blood–brain barrier. Only CTL2s occur on the brain side of the barrier. They also remove excess choline from neurons and return it to the 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 acetylcholine production. They transport choline with low affinity. OCT1s transport choline primarily in the liver and kidneys, while OCT2s transport choline in the kidneys and the brain.
Storage Choline is stored in the cell membranes and organelles as phospholipids, and inside cells as phosphatidylcholines 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 the kidneys (see transport). Trimethylglycine is demethylated in the liver and kidneys to dimethylglycine (tetrahydrofolate receives one of the methyl groups). Methylglycine forms are excreted into urine or are demethylated to glycine.
Function Choline and its derivatives have many biological functions. Notably, choline serves as a precursor for other essential cell components and signaling molecules, such as phospholipids that form cell membranes, the neurotransmitter acetylcholine, and the osmoregulator trimethylglycine (betaine). Trimethylglycine in turn serves as a source of methyl groups by participating in the biosynthesis of S-adenosylmethionine.
Phospholipid precursor Choline is converted into diverse phospholipids, like phosphatidylcholines and sphingomyelins. These are found in all cell membranes and the membranes of most cell organelles. Phosphatidylcholines are a structurally important part of cell membranes. In humans, 40–50% of their phospholipids are phosphatidylcholines.
Choline phospholipids also form lipid rafts in the cell membranes along with cholesterol. The rafts are centers, for example for cholinergic receptors and receptor signal transduction enzymes.
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 the lung tissue's ability to contract and expand. For example, deficiency of phosphatidylcholines in the lung tissues has been linked to acute respiratory distress syndrome.
Phosphatidylcholines are excreted into bile and work together with bile acid salts as surfactants in it, thus helping with the intestinal absorption of lipids.
Acetylcholine synthesis Choline is a precursor to acetylcholine, a neurotransmitter that plays a necessary role in muscle contraction, memory, and neural development. Nonetheless, there is little acetylcholine in the human body relative to other forms of choline. Neurons also store choline as phospholipids in their cell membranes for the production of acetylcholine.
Source of trimethylglycine In humans, choline is oxidized irreversibly in liver mitochondria to glycine betaine aldehyde by choline oxidases. This is oxidized by mitochondrial or cytosolic betaine-aldehyde dehydrogenases to trimethylglycine. Trimethylglycine is a necessary osmoregulator. It also acts as a substrate for the BHMT enzyme, which methylates homocysteine to methionine. This is a S-adenosylmethionine (SAM) precursor. SAM is a common reagent in biological methylation reactions. For example, it methylates guanidines of DNA and certain lysines of histones. Thus, it is part of gene expression and epigenetic regulation. Choline deficiency thus leads to elevated homocysteine levels and decreased SAM levels in blood.
Content in foods