 | |
 | |
| Names | |
|---|---|
| IUPAC name 2-Hydroxyethyl(trimethyl)azanium[1] | |
| Preferred IUPAC name 2-Hydroxy-N,N,N-trimethylethan-1-aminium | |
Other names
| |
| Identifiers | |
| |
3D model (JSmol) | |
| 1736748 | |
| ChEBI | |
| ChEMBL | |
| ChemSpider |
|
| DrugBank |
|
| ECHA InfoCard | 100.000.487 |
| EC Number |
|
| E number | E1001(additional chemicals) |
| 324597 | |
| KEGG |
|
| UNII | |
| |
| |
| Properties | |
| [(CH3)3NCH2CH2OH]+ | |
| Molar mass | 104.173 g·mol−1 |
| Structure | |
| Tetrahedral at thenitrogen atom | |
| Hazards | |
| Occupational safety and health (OHS/OSH): | |
Main hazards | Corrosive |
| GHS labelling: | |
 | |
| Danger | |
| H314 | |
| P260,P264,P280,P301+P330+P331,P303+P361+P353,P304+P340,P305+P351+P338,P310,P321,P363,P405,P501 | |
| NFPA 704 (fire diamond) | |
| Lethal dose or concentration (LD, LC): | |
LD50 (median dose) | 3–6 g/kg (rat, oral)[2] |
| Safety data sheet (SDS) | 4 |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Choline is acation with thechemical formula[(CH3)3NCH2CH2OH]+.[1][2][3] Choline forms varioussalts, such ascholine chloride andcholine bitartrate. Anessential nutrient for animals, it is a structural component ofphospholipids andcell membranes.[2][3]
Choline is used to synthesizeacetylcholine, aneurotransmitter involved in muscle control and numerous functions of the nervous system.[2][3] Choline is involved in early development of the brain,gene expression, cell membranesignaling, and brain metabolism.[3]
Although humans synthesize choline in theliver, the amount produced naturally is insufficient to meet cellular functions, requiring that some choline be obtained from foods ordietary supplements.[3] Foods rich in choline include meats, poultry, eggs, and other animal-based products,cruciferous vegetables, beans, nuts, andwhole grains.[3] Choline is present in breast milk and is commonly added as aningredient tobaby foods.[3]
Choline is aquaternary ammonium cation. The cholines are a family of water-solublequaternary ammonium compounds.[2] Choline is the parent compound of the choline class, consisting ofethanolamine residue having threemethyl groups attached to the samenitrogen atom.[1][2]Choline hydroxide is known as choline base. It ishygroscopic and thus often encountered as a colorlessviscous hydrated syrup that smells oftrimethylamine (TMA). Aqueous solutions of choline are stable, but the compound slowly breaks down toethylene glycol,polyethylene glycols, and TMA.[2]
Choline chloride can be prepared by treating TMA with2-chloroethanol:[2]
Choline has historically been produced from natural sources, such as viahydrolysis oflecithin.[2]
Choline is widespread in living beings. In most animals, choline phospholipids are necessary components incell membranes, in the membranes of cellorganelles, and invery low-density lipoproteins.[2]
Choline is anessential nutrient for humans and many other animals.[2] Humans are capable of somede 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 cholinephospholipids, such asphosphatidylcholine.[2] Choline is not formally classified as avitamin despite being an essential nutrient with anamino acid–like structure and metabolism.[4]
Choline is required to produceacetylcholine – aneurotransmitter – andS-adenosylmethionine (SAM), a universalmethyl donor. Upon methylation SAM is transformed intoS-adenosyl homocysteine.[2]
Symptomatic choline deficiency causesnon-alcoholic fatty liver disease and muscle damage.[2][5] Excessive consumption of choline (greater than 7.5 grams per day) can causelow blood pressure,sweating,diarrhea, andfish-like body smell due totrimethylamine, which forms in the metabolism of choline.[2][6] Rich dietary sources of choline and choline phospholipids includeorgan meats,egg yolks,dairy products,peanuts, certainbeans,nuts andseeds.Vegetables withpasta andrice also contribute to choline intake in theAmerican diet.[2][3]
In plants, the first step inde novo biosynthesis of choline is thedecarboxylation ofserine intoethanolamine, which is catalyzed by aserine decarboxylase.[7] The synthesis of choline from ethanolamine may take place in three parallel pathways, where three consecutiveN-methylation steps catalyzed by amethyl transferase are carried out on either the free-base,[8] phospho-bases,[9] or phosphatidyl-bases.[10] The source of the methyl group isS-adenosyl-L-methionine andS-adenosyl-L-homocysteine is generated as a side product.[11]
In humans and most other animals, de novo synthesis of choline proceeds via thephosphatidylethanolamine N-methyltransferase (PEMT) pathway,[6] but biosynthesis is not enough to meet human requirements.[12] In the hepatic PEMT route,3-phosphoglycerate (3PG) receives 2acyl groups fromacyl-CoA forming aphosphatidic acid. It reacts withcytidine triphosphate to form cytidine diphosphate-diacylglycerol. Itshydroxyl group reacts with serine to formphosphatidylserine, whichdecarboxylates to ethanolamine andphosphatidylethanolamine (PE) forms. A PEMT enzyme moves threemethyl groups from threeS-adenosyl methionines (SAM) donors to the ethanolamine group of the phosphatidylethanolamine to form choline in the form of a phosphatidylcholine. ThreeS-adenosylhomocysteines (SAHs) are formed as a byproduct.[6]
Choline can also be released from more complex precursors. For example,phosphatidylcholines (PC) can be hydrolyzed to choline (Chol) in most cell types. Choline can also be produced by the CDP-choline route,cytosoliccholine kinases (CK) phosphorylate choline withATP tophosphocholine (PChol).[4] This happens in some cell types like liver and kidney.Choline-phosphate cytidylyltransferases (CPCT) transform PChol toCDP-choline (CDP-Chol) with cytidine triphosphate (CTP). CDP-choline anddiglyceride are transformed to PC bydiacylglycerol cholinephosphotransferase (CPT).[6]
In humans, certain PEMT-enzymemutations andestrogen deficiency (often due tomenopause) 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.[6] Inknockout mice, PEMT inactivation makes them completely dependent on dietary choline.[4]
In humans, choline is absorbed from theintestines via theSLC44A1 (CTL1)membrane protein viafacilitated diffusion governed by the choline concentration gradient and the electrical potential across theenterocyte membranes. SLC44A1 has limited ability to transport choline: at high concentrations part of it is left unabsorbed. Absorbed choline leaves the enterocytes via theportal vein, passes the liver and enterssystemic circulation.Gut microbes degrade the unabsorbed choline to trimethylamine, which is oxidized in the liver totrimethylamineN-oxide.[6]
Phosphocholine andglycerophosphocholines are hydrolyzed viaphospholipases 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 andsphingomyelins) are either hydrolyzed by phospholipases or enter thelymph incorporated intochylomicrons.[6]
In humans, choline is transported as a free ion in blood. Choline–containingphospholipids and other substances, like glycerophosphocholines, are transported in bloodlipoproteins.Blood plasma choline levels in healthyfasting adults is 7–20 micromoles per liter (μmol/L) and 10 μmol/L on average. Levels are regulated, but choline intake and deficiency alter these levels. Levels are elevated for about 3 hours after choline consumption. Phosphatidylcholine levels in the plasma of fasting adults is 1.5–2.5 mmol/L. Its consumption elevates the free choline levels for about 8–12 hours, but does not affect phosphatidylcholine levels significantly.[6]
Choline is a water-solubleion and thus requires transporters to pass through fat-solublecell membranes. Three types of choline transporters are known:[13]
SLC5A7s aresodium- (Na+) and ATP-dependent transporters.[13][6] They have highbinding affinity for choline, transport it primarily toneurons and are indirectly associated with theacetylcholine production.[6] Their deficient function causeshereditary weakness in the pulmonary and other muscles in humans via acetylcholine deficiency. Inknockout mice, their dysfunction results easily in death withcyanosis andparalysis.[14]
CTL1s have moderate affinity for choline and transport it in almost all tissues, including the intestines, liver, kidneys,placenta, andmitochondria. CTL1s supply choline for phosphatidylcholine andtrimethylglycine production.[6] CTL2s occur especially in the mitochondria in the tongue, kidneys, muscles, and heart. They are associated with the mitochondrialoxidation of choline to trimethylglycine. CTL1s and CTL2s are not associated with acetylcholine production, but transport choline together via theblood–brain barrier. Only CTL2s occur on the brain side of the barrier. They also remove excess choline from the neurons back to the blood. CTL1s occur only on the blood side of the barrier, but also on the membranes ofastrocytes and neurons.[13]
OCT1s and OCT2s are not associated with acetylcholine production.[6] 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.[13]
Choline is stored in the cell membranes andorganelles as phospholipids, and inside cells as phosphatidylcholines and glycerophosphocholines.[6]
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 (seetransport). Trimethylglycine is demethylated in the liver and kidneys todimethylglycine (tetrahydrofolate receives one of the methyl groups).Methylglycine forms are excreted into urine or are demethylated toglycine.[6]
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, theneurotransmitter acetylcholine, and theosmoregulatortrimethylglycine (betaine). Trimethylglycine in turn serves as a source ofmethyl groups by participating in the biosynthesis ofS-adenosylmethionine.[15][16]
Choline is transformed into diverse phospholipids, like phosphatidylcholines and sphingomyelins.[2][3] These are found in all cell membranes and the membranes of most cell organelles.[4] Phosphatidylcholines are a structurally important part of the cell membranes. In humans, 40–50% of their phospholipids are phosphatidylcholines.[6]
Choline phospholipids also formlipid rafts in the cell membranes along withcholesterol.[2] The rafts are centers, for example forcholinergicreceptors and receptorsignal transduction enzymes.[2][4]
Phosphatidylcholines are needed for the synthesis ofVLDLs: 70–95% of their phospholipids are phosphatidylcholines in humans.[6]
Choline is also needed for the synthesis ofpulmonary 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 toacute respiratory distress syndrome.[17]
Phosphatidylcholines are excreted intobile and work together withbile acid salts assurfactants in it, thus helping with theintestinal absorption oflipids.[4]
Choline is a precursor toacetylcholine, a neurotransmitter that plays a necessary role inmuscle contraction, memory, andneural development.[2][3][6][5] Nonetheless, there is little acetylcholine in the human body relative to other forms of choline.[4] Neurons also store choline in the form of phospholipids in their cell membranes for the production of acetylcholine.[6]
In humans, choline isoxidized irreversibly in liver mitochondria toglycine betaine aldehyde bycholine oxidases. This is oxidized by mitochondrial or cytosolicbetaine-aldehyde dehydrogenases to trimethylglycine.[6] Trimethylglycine is a necessary osmoregulator. It also works as a substrate for theBHMT-enzyme, which methylateshomocysteine tomethionine. This is aS-adenosylmethionine (SAM) precursor. SAM is a common reagent in biologicalmethylation reactions. For example, it methylatesguanidines ofDNA and certainlysines ofhistones. Thus, it is part ofgene expression andepigenetic regulation. Choline deficiency thus leads to elevated homocysteine levels and decreased SAM levels in blood.[6]
Choline occurs in foods as a free cation and in the form of phospholipids, especially as phosphatidylcholines. Choline is highest inorgan meats andegg yolks, though it is found to a lesser degree in non-organ meats, grains, vegetables, fruit, anddairy products.[3]Cooking oils and other food fats have about 5 mg/100 g of total choline.[6] In the United States,food labels express the amount of choline in a serving as a percentage ofDaily Value (%DV) based on theAdequate Intake of 550 mg/day. 100% of the daily value means that a serving of food has 550 mg of choline.[3] "Total choline" is defined as the sum of free choline and choline-containing phospholipids, without accounting for mass fraction.[3][18]
Human breast milk is rich in choline.[2][3] Exclusivebreastfeeding corresponds to about 120 mg of choline per day for the baby. An increase in a mother's choline intake raises the choline content of breast milk, and a low intake decreases it.[6]Infant formulas may or may not contain enough choline. In the EU and the US, it is mandatory to add at least 7 mg of choline per 100 kilocalories (kcal) to every infant formula. In the EU, levels above 50 mg/100 kcal are not allowed.[6][19]
Trimethylglycine is a functionalmetabolite of choline. It substitutes for choline nutritionally, but only partially.[4] High amounts of trimethylglycine occur inwheat bran (1,339 mg/100 g), toastedwheat germ (1,240 mg/100 g) andspinach (600–645 mg/100 g), for example.[18]
| Meats | Vegetables | ||
|---|---|---|---|
| Bacon, cooked | 124.89 | Bean, snap | 13.46 |
| Beef, trim-cut, cooked | 78.15 | Beetroot | 6.01 |
| Beef liver, pan fried | 418.22 | Broccoli | 40.06 |
| Chicken, roasted, with skin | 65.83 | Brussels sprout | 40.61 |
| Chicken, roasted, no skin | 78.74 | Cabbage | 15.45 |
| Chicken liver | 290.03 | Carrot | 8.79 |
| Cod, atlantic | 83.63 | Cauliflower | 39.10 |
| Ground beef, 75–85% lean, broiled | 79.32–82.35 | Sweetcorn, yellow | 21.95 |
| Pork loin cooked | 102.76 | Cucumber | 5.95 |
| Shrimp, canned | 70.60 | Lettuce, iceberg | 6.70 |
| Dairy products (cow) | Lettuce, romaine | 9.92 | |
| Butter, salted | 18.77 | Pea | 27.51 |
| Cheese | 16.50–27.21 | Sauerkraut | 10.39 |
| Cottage cheese | 18.42 | Spinach | 22.08 |
| Milk, whole/skimmed | 14.29–16.40 | Sweet potato | 13.11 |
| Sour cream | 20.33 | Tomato | 6.74 |
| Yogurt, plain | 15.20 | Zucchini | 9.36 |
| Grains | Fruits | ||
| Oatbran, raw | 58.57 | Apple | 3.44 |
| Oats, plain | 7.42 | Avocado | 14.18 |
| Rice, white | 2.08 | Banana | 9.76 |
| Rice, brown | 9.22 | Blueberry | 6.04 |
| Wheatbran | 74.39 | Cantaloupe | 7.58 |
| Wheat germ, toasted | 152.08 | Grape | 7.53 |
| Others | Grapefruit | 5.63 | |
| Bean, navy | 26.93 | Orange | 8.38 |
| Egg, chicken | 251.00 | Peach | 6.10 |
| Olive oil | 0.29 | Pear | 5.11 |
| Peanut | 52.47 | Prune | 9.66 |
| Soybean, raw | 115.87 | Strawberry | 5.65 |
| Tofu, soft | 27.37 | Watermelon | 4.07 |
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The following table contains updated sources of choline to reflect the new Daily Value and the new Nutrition Facts and Supplement Facts Labels.[3] It reflects data from the U.S. Department of Agriculture, Agricultural Research Service. FoodData Central, 2019.[3]
| Food | Milligrams (mg) per serving | Percent DV* |
| Beef liver, pan fried, 3 oz (85 g) | 356 | 65 |
| Egg, hard-boiled, 1 large egg | 147 | 27 |
| Beeftop round, separable lean only, braised, 3 oz (85 g) | 117 | 21 |
| Soybeans, roasted, 1/2 cup (~120 mL) | 107 | 19 |
| Chicken breast, roasted, 3 oz (85 g) | 72 | 13 |
| Beef, ground, 93% lean meat, broiled, 3 oz (85 g) | 72 | 13 |
| Cod, Atlantic, cooked, dry heat, 3 oz (85 g) | 71 | 13 |
| Mushrooms, shiitake, cooked, 1/2 cup (~120 mL) pieces | 58 | 11 |
| Potatoes, red, baked, flesh and skin, 1 large potato | 57 | 10 |
| Wheat germ, toasted, 1 oz (28 g) | 51 | 9 |
| Beans, kidney, canned, 1/2 cup (~120 mL) | 45 | 8 |
| Quinoa, cooked, 1 cup (~240 mL) | 43 | 8 |
| Milk, 1% fat, 1 cup (~240 mL) | 43 | 8 |
| Yogurt, vanilla, nonfat, 1 cup (~240 mL) | 38 | 7 |
| Brussels sprouts, boiled, 1/2 cup (~120 mL) | 32 | 6 |
| Broccoli, chopped, boiled, drained, 1/2 cup (~120 mL) | 31 | 6 |
| Cottage cheese, nonfat, 1 cup (~240 mL) | 26 | 5 |
| Tuna, white, canned in water, drained in solids, 3 oz (85 g) | 25 | 5 |
| Peanuts, dry roasted, 1/4 cup (~60 mL) | 24 | 4 |
| Cauliflower, 1 in (2.5 cm) pieces, boiled, drained, 1/2 cup (~120 mL) | 24 | 4 |
| Peas, green, boiled, 1/2 cup (~120 mL) | 24 | 4 |
| Sunflower seeds, oil roasted, 1/4 cup (~60 mL) | 19 | 3 |
| Rice, brown, long-grain, cooked, 1 cup (~240 mL) | 19 | 3 |
| Bread, pita, whole wheat, 1 large (6+1⁄2 in or 17 cm diameter) | 17 | 3 |
| Cabbage, boiled, 1/2 cup (~120 mL) | 15 | 3 |
| Tangerine (mandarin orange), sections, 1/2 cup (~120 mL) | 10 | 2 |
| Beans, snap, raw, 1/2 cup (~120 mL) | 8 | 1 |
| Kiwifruit, raw, 1/2 cup (~120 mL) sliced | 7 | 1 |
| Carrots, raw, chopped, 1/2 cup (~120 mL) | 6 | 1 |
| Apples, raw, with skin, quartered or chopped, 1/2 cup (~120 mL) | 2 | 0 |
DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for choline is 550 mg for adults and children age 4 years and older.[20] The FDA does not require food labels to list choline content unless choline has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.[3]
The U.S. Department of Agriculture's (USDA's) FoodData Central lists the nutrient content of many foods and provides a comprehensive list of foods containing choline arranged by nutrient content.[3]
Insufficient data is available to establish an estimated average requirement (EAR) for choline, so the Food and Nutrition Board established adequate intakes (AIs).[3][21] For adults, the AI for choline was set at 550 mg/day for men and 425 mg/day for women.[3] These values have been shown to prevent hepatic alteration in men. However, the study used to derive these values did not evaluate whether less choline would be effective, as researchers only compared a choline-free diet to a diet containing 550 mg of choline per day. From this, the AIs for children and adolescents were extrapolated.[22][23]
Recommendations are in milligrams per day (mg/day). TheEuropean Food Safety Authority (EFSA) recommendations are general recommendations for theEU countries. The EFSA has not set any upper limits for intake.[6] Individual EU countries may have more specific recommendations. TheNational Academy of Medicine (NAM) recommendations apply in the United States,[3] Australia, and New Zealand.[24]
| Age | EFSAadequate intake[6] | US NAM adequate intake[3] | US NAMtolerable upper intake levels[3] |
|---|---|---|---|
| Infants and children | |||
| 0–6 months | Not established | 125 | Not established |
| 7–12 months | 160 | 150 | Not established |
| 1–3 years | 140 | 200 | 1,000 |
| 4–6 years | 170 | 250 | 1,000 |
| 7–8 years | 250 | 250 | 1,000 |
| 9–10 years | 250 | 375 | 1,000 |
| 11–13 years | 340 | 375 | 2,000 |
| Males | |||
| 14 years | 340 | 550 | 3,000 |
| 15–18 years | 400 | 550 | 3,000 |
| 19+ years | 400 | 550 | 3,500 |
| Females | |||
| 14 years | 340 | 400 | 3,000 |
| 15–18 years | 400 | 400 | 3,000 |
| 19+ y | 400 | 425 | 3,500 |
| If pregnant | 480 | 450 | 3,500 (3,000 if ≤18 y) |
| If breastfeeding | 520 | 550 | 3,500 (3,000 if ≤18 y) |
Twelve surveys undertaken in 9 EU countries between 2000 and 2011 estimated choline intake of adults in these countries to be 269–468 milligrams per day. Intake was 269–444 mg/day in adult women and 332–468 mg/day in adult men. Intake was 75–127 mg/day in infants, 151–210 mg/day in 1- to 3-year-olds, 177–304 mg/day in 3- to 10-year-olds, and 244–373 mg/day in 10- to 18-year-olds. The total choline intake mean estimate was 336 mg/day in pregnant adolescents and 356 mg/day in pregnant women.[6]
A study based on theNHANES 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 period. Out of 2+ year olds, only15.6±0.8% of males and6.1±0.6% of females exceeded the adequate intake (AI). AI was exceeded by62.9±3.1% of 2- to 3-year-olds,45.4±1.6% of 4- to 8-year-olds,9.0±1.0% of 9- to 13-year-olds,1.8±0.4% of 14–18 and6.6±0.5% of 19+ year olds. The upper intake level was not exceeded in any subpopulations.[25]
A 2013–2014 NHANES study of the US population found the choline intake of 2- to 19-year-olds to be256±3.8 mg/day and339±3.9 mg/day in adults 20 and over. Intake was402±6.1 mg/d in men 20 and over and 278 mg/d in women 20 and over.[26]
Symptomatic choline deficiency is rare in humans. Most obtain sufficient amounts of it from the diet and can biosynthesize limited amounts of it viaPEMT.[4] Symptomatic deficiency is often caused by certain diseases or by other indirect causes. Severe deficiency causes muscle damage andnon-alcoholic fatty liver disease,[5] which may develop intocirrhosis.[27]
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 a deficiency of choline-derived trimethylglycine, which functions as an osmoregulator.[4]
Estrogen production is a relevant factor that predisposes individuals to deficiency, along with low dietary choline intake. Estrogens activate phosphatidylcholine-producing PEMT enzymes. Women before menopause have a lower dietary need for choline than men due to women's higher estrogen production. Withoutestrogen therapy, the choline needs of post-menopausal women are similar to men's. Somesingle-nucleotide polymorphisms (genetic factors) affecting choline andfolate metabolism are also relevant. Certain gut microbes also degrade choline more efficiently than others, so they are also relevant.[27]
In deficiency, the availability of phosphatidylcholines in the liver is decreased – these are needed for the formation of VLDLs. Thus, VLDL-mediatedfatty acid transport out of the liver decreases, leading to fat accumulation in the liver.[6] Other simultaneously occurring mechanisms explaining the observed liver damage have also been suggested. For example, choline phospholipids are also needed inmitochondrial membranes. Their unavailability leads to the inability of mitochondrial membranes to maintain properelectrochemical gradient, which, among other things, is needed for degrading fatty acids viaβ-oxidation. Fat metabolism within the liver therefore, decreases.[27]
Excessive doses of choline can have adverse effects. Daily 8–20 g doses of choline, for example, have been found to causelow blood pressure,nausea,diarrhea, andfish-like body odor. The odor is due to trimethylamine (TMA) formed by the gut microbes from the unabsorbed choline (seetrimethylaminuria).[6]
The liver oxidizes TMA to trimethylamineN-oxide (TMAO). Elevated levels of TMA and TMAO in the body have been linked to increased risk ofatherosclerosis and mortality. Thus, excessive choline intake has been hypothesized to increase these risks in addition tocarnitine, which also is formed into TMA and TMAO by gut bacteria. However, choline intake has not been shown to increase the risk of dying fromcardiovascular diseases.[28] 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 not have been properly accounted for in certain studies observing TMA and TMAO level-related mortality. Causality may be reversed or confounded, 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.[29]
Low maternal intake of choline is associated with an increased risk ofneural tube defects (NTDs).[5] Higher maternal intake of choline is likely associated with better neurocognition/neurodevelopment in children.[30][2] Choline and folate, interacting withvitamin B12, act as methyl donors to homocysteine to form methionine, which can then go on to formS-adenosylmethionine (SAM).[2] SAM is the substrate for almost allmethylation reactions in mammals. It has been suggested that disturbed methylation via SAM could be responsible for the relation between folate and NTDs.[31] This may also apply to choline.[citation needed] Certainmutations that disturb choline metabolism increase the prevalence of NTDs in newborns, but the role of dietary choline deficiency remains unclear, as of 2015.[update][2]
Choline deficiency can causefatty liver, which increases cancer and cardiovascular disease risk. Choline deficiency also decreases SAM production, which is involved inDNA methylation – this decrease may also contribute tocarcinogenesis. Thus, deficiency and its association with such diseases have been studied.[6] However,observational studies of free populations have not convincingly shown an association between low choline intake and cardiovascular diseases or most cancers.[2][6] Studies onprostate cancer have been contradictory.[32][33]
Studies observing the effect of higher choline intake andcognition have been conducted in human adults, with contradictory results.[2][34] Similar studies on human infants and children have been contradictory and also limited.[2]
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Both pregnancy and lactation increase the demand for choline dramatically. This demand may be met by upregulation ofPEMT via increasingestrogen levels to produce more cholinede 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 thatPemt −/− mice (mice lacking functional PEMT) will abort at 9–10 days unless fed supplemental choline.[35]
While maternal stores of choline are depleted during pregnancy and lactation, the placenta accumulates choline by pumping choline against the concentration gradient into the tissue, where it is then stored in various forms, mostly as acetylcholine. Choline concentrations inamniotic fluid can be ten times higher than in maternal blood.[35]
Choline is in high demand during pregnancy as a substrate for buildingcellular membranes (rapid fetal and mother tissue expansion), increased need for one-carbonmoieties (a substrate for methylation of DNA and other functions), raising choline stores in fetal and placental tissues, and for increased production of lipoproteins (proteins containing "fat" portions).[36][37][38] In particular, there is interest in the impact of choline consumption on the brain. This stems from choline's use as a material for making cellular membranes (particularly in making phosphatidylcholine). Human brain growth is most rapid during thethird trimester of pregnancy and continues to be rapid until approximately five years of age.[39] During this time, the demand is high for sphingomyelin, which is made from phosphatidylcholine (and thus from choline), because this material is used tomyelinate (insulate)nerve fibers.[40] Choline is also in demand for the production of the neurotransmitter acetylcholine, which can influence the structure and organization of brain regions,neurogenesis, myelination, andsynapse formation. Acetylcholine is even present in the placenta and may help controlcell proliferation anddifferentiation (increases in cell number and changes of multiuse cells into dedicated cellular functions) andparturition.[41][42]
Choline uptake into the brain is controlled by a low-affinity transporter located at the blood–brain barrier.[43] Transport occurs when arterial blood plasma choline concentrations increase above 14 μmol/L, which can occur during a spike in choline concentration after consuming choline-rich foods. Neurons, conversely, acquire choline by both high- and low-affinity transporters. Choline is stored as membrane-bound phosphatidylcholine, which can then be used for acetylcholine neurotransmitter synthesis later. Acetylcholine is formed as needed, travels across the synapse, and transmits the signal to the following neuron. Afterwards,acetylcholinesterase degrades it, and the free choline is taken up by a high-affinity transporter into the neuron again.[44]
Cholinechloride and cholinebitartrate are used indietary supplements. Bitartrate is used more often due to its lower hygroscopicity.[4] Certain choline salts are used to supplement chicken, turkey, and some otheranimal feeds. Some salts are also used as industrial chemicals: for example, inphotolithography to removephotoresist.[2]Choline theophyllinate and cholinesalicylate are used as medicines,[2][45] as well asstructural analogs, likemethacholine andcarbachol.[46]Radiolabeled cholines, like11C-choline, are used inmedical imaging.[47] Other commercially used salts include tricholinecitrate and cholinebicarbonate.[2]
The most common forms of dietary choline supplements are shown in the following table:
| Supplement | weight (g/mol) | Choline content (%) |
|---|---|---|
| Αlpha-GPC (Choline alfoscerate) | 257.22 | 40.5% |
| Choline bitartrate | 253.25 | 41.13 |
| Choline citrate | 295.29 | 35.28% |
| Citicoline (CDP-choline) | 488.32 | 21.33% |
| Phosphatidylcholine (PC) | Varies | 14-29%[48] |
| Soy lecithin (12.69%–16.7% Phosphatidylcholine) | - | 1.67% – 2.20%[49] |
In 1849,Adolph Strecker was the first to isolate choline from pig bile.[50][51] In 1852, L. Babo and M. Hirschbrunn extracted choline fromwhite mustard seeds and named itsinkaline.[51] In 1862, Strecker repeated his experiment with pig and ox bile, calling the substancecholine for the first time after the Greek word for bile,chole, and identifying it with thechemical formula C5H13NO.[52][12] In 1850,Theodore Nicolas Gobley extracted from the brains androe ofcarps a substance he namedlecithin after the Greek word for eggyolk,lekithos, showing in 1874 that it was a mixture ofphosphatidylcholines.[53][54]
In 1865,Oscar Liebreich isolated "neurine" from animal brains.[55][12] Thestructural formulas of acetylcholine and Liebreich's "neurine" were resolved byAdolf von Baeyer in 1867.[56][51] 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.[57][58][51] The compound now known asneurine is unrelated to choline.[12]
In the early 1930s,Charles Best and colleagues noted that fatty liver in rats on a special diet anddiabetic dogs could be prevented by feeding them lecithin,[12] proving in 1932 that choline in lecithin was solely responsible for this preventive effect.[59] In 1998, the US National Academy of Medicine reported its first recommendations for choline in the human diet.[60]
Choline is a critical nutrient for development during gestation and early life, particularly for the formation and maturation of the nervous system. (...) gestational choline insufficiency is strongly associated with neural tube defects, notably mirroring the developmental pathologies observed in folate insufficiency. (...) additionally, been linked to non-neurological developmental abnormalities including cleft lip, hypospadias, heart abnormalities and congenital diaphragmatic hernia. (...) Choline intake was recently discovered to be a potential modifier of dementia risk in AD progression. (...) highlights the importance of the cholinergic neurotransmission in memory, learning, and, ultimately, in the development of AD pathology. (...) there is impressive plasticity in satisfying choline requirements at the organismal level as well. While a completely choline-free diet eventually results in NAFLD and muscle damage, diets that do not meet the NIH adequate intake are rarely associated with clinical symptoms in otherwise healthy adults, suggesting the human body is highly capable of adapting to reduced choline availability.
In this Opinion, the Panel considers dietary choline including choline compounds (e.g. glycerophosphocholine, phosphocholine, phosphatidylcholine, sphingomyelin).
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