Severe deficiency causes muscle damage and non-alcoholic fatty liver disease, which may develop into cirrhosis.Besides humans, fatty liver is also a typical sign of choline deficiency in other animals. Bleeding in the kidneys can also occur in some species. This is suspected to be due to deficiency of choline derived trimethylglycine, which functions as an osmoregulator. Causes and mechanisms
Estrogen production is a relevant factor which predisposes individuals to deficiency along with low dietary choline intake. Estrogens activate phosphatidylcholine producing PEMT enzymes. Women before menopause have lower dietary need for choline than men due to womens higher estrogen production. Without estrogen therapy, the choline needs of post-menopausal women are similar to mens. Some single-nucleotide polymorphisms (genetic factors) affecting choline and folate metabolism are also relevant. Certain gut microbes also degrade choline more efficiently than others, so they are also relevant.In deficiency, availability of phosphatidylcholines in the liver are decreased – these are needed for formation of VLDLs. Thus VLDL-mediated fatty acid transport out of the liver decreases leading to fat accumulation in the liver. Other simultaneously occurring mechanisms explaining the observed liver damage have also been suggested. For example, choline phospholipids are also needed in mitochondrial membranes. Their inavailability leads to the inability of mitochondrial membranes to maintain proper electrochemical gradient, which, among other things, is needed for degrading fatty acids via β-oxidation. Fat metabolism within liver therefore decreases. Excess intake
Excessive doses of choline can have adverse effects.
It is hygroscopic and thus often encountered as a colorless viscous hydrated syrup that smells of trimethylamine (TMA). Aqueous solutions of choline are stable, but the compound slowly breaks down to ethylene glycol, polyethylene glycols, and TMA.Choline chloride can be made by treating TMA with 2-chloroethanol:
(CH3)3N + ClCH2CH2OH → (CH3)3N+CH2CH2OH · Cl–The 2-chloroethanol can be generated from ethylene oxide. Choline has historically been produced from natural sources, such as via hydrolysis of lecithin. 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-L-methionine and S-adenosyl-L-homocysteine is generated as a side product. In humans and most other animals, de novo synthesis of choline is 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 a phosphatidylcholine.