Phosphatidylcholine and Related Lipids

Phosphatidylcholine or 1,2-diacyl-sn-glycero-3-phosphocholine (once given the trivial name 'lecithin') is a neutral or zwitterionic phospholipid over a pH range from strongly acid to strongly alkaline. It is usually the most abundant phospholipid in animals and plants, often amounting to almost 50% of the total complex lipids, and as such it is obviously a key building block of membrane bilayers. In particular, it makes up a very high proportion (80 to 90%) of the lipids of the outer leaflet of the plasma membrane of nucleated cells, and virtually all the phosphatidylcholine in human erythrocyte membranes is present in the outer leaflet. Phosphatidylcholine is the main phospholipid circulating in plasma, where it is an integral component of the lipoproteins, especially the HDL. On the other hand, it is less often found in bacterial membranes, perhaps ~10% of species, and there is none in the 'model' organisms Escherichia coli and Bacillus subtilis. In animal tissues, some of its membrane functions appear to be shared with the structurally related sphingolipid, sphingomyelin, although the latter has many unique properties of its own.

Formula for phosphatidylcholine

Platelet-activating factor (PAF) or 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine is an ether analogue of phosphatidylcholine that has its own web page here because of its unique biological properties.

1.  Phosphatidylcholine - Structure and Occurrence

In animal tissues, phosphatidylcholine tends to exist in mainly in the diacyl form, and small proportions only (in comparison to phosphatidylethanolamine and phosphatidylserine) of alkylacyl and alkenylacyl forms may be present, and data for the compositions of these various forms from bovine heart muscle are listed in our web pages on ether lipids. As a generalization, animal diacyl phosphatidylcholine tends to contain lower proportions of arachidonic and docosahexaenoic acids and more of the C18 unsaturated fatty acids than the other zwitterionic phospholipid, phosphatidylethanolamine. Saturated fatty acids are most abundant in position sn-1, while polyunsaturated components are concentrated in position sn-2. Indeed, C20 and C22 polyenoic acids are exclusively in position sn-2, yet in brain and retina the minor uncommon very-long-chain polyunsaturated fatty acids (C30 to C38) of the n-6 and n-3 families occur in position sn‑1. Dietary factors obviously influence overall fatty acid compositions, but in comparing animal species, it would be expected that the structure of the phosphatidylcholine in comparable tissues would be somewhat similar in terms of the relative distributions of fatty acids between the two positions. Table 1 lists some representative data.

Table 1. Positional distribution of fatty acids in the phosphatidylcholine of some animal tissues.
Position Fatty acid
16:0 16:1 18:0 18:1 18:2 20:4 22:6
 
  Rat liver [1]
sn-1 23 1 65 7 1 trace
sn-2 6 1 4 13 23 39 7
 
  Rat heart [2]
sn-1 30 2 47 9 11 - -
sn-2 10 1 3 17 20 33 9
 
  Rat lung [3]
sn-1 72 4 15 7 3 - -
sn-2 54 7 2 12 11 10 1
 
  Human plasma [4]
sn-1 59 2 24 7 4 trace -
sn-2 3 1 1 26 32 18 5
 
  Human erythrocytes [4]
sn-1 66 1 22 7 2 - -
sn-2 5 1 1 35 30 16 4
 
  Bovine brain (grey matter) [5]
sn-1 38 5 32 21 1 - -
sn-2 33 4 trace 48 1 9 4
 
  Chicken egg [6]
sn-1 61 1 27 9 1 - -
sn-2 2 1 trace 52 33 7 4
1, Wood, R. and Harlow, R.D. Arch. Biochem. Biophys., 131, 495-501 (1969);  DOI.
2, Kuksis, A. et al. J. Lipid Res., 10, 25-32 (1969);  DOI.
3, Kuksis, A. et al. Can. J. Physiol. Pharm., 46, 511-524 (1968);  DOI.
4, Marai, L. and Kuksis, A. J. Lipid Res., 10, 141-152 (1969);  DOI.
5, Yabuuchi, H. and O'Brien, J.S. J. Lipid Res., 9, 65-67 (1968);  DOI.
6, Kuksis, A. and Marai, L. Lipids, 2, 217-224 (1967);  DOI.

There are some exceptions to the rule as the phosphatidylcholine in some tissues or organelles contains relatively high proportions of disaturated molecular species, and it is well known that lung phosphatidylcholine in most if not all animal species studied to date contains a high proportion (50% or more) of dipalmitoylphosphatidylcholine.

The positional distributions of fatty acids in phosphatidylcholine in representative plants and yeast are listed in Table 2. In the leaves of the model plant Arabidopsis thaliana, saturated fatty acids are concentrated in position sn-1, but monoenoic fatty acids are distributed approximately equally between the two positions, and there is a preponderance of di- and triunsaturated fatty acids in position sn-2; the same is true for soybean ‘lecithin’. In the yeast Lipomyces lipoferus, the pattern differs only in that much of the 16:1 is in position sn-1.

Table 2. Composition of fatty acids (mol %) in positions sn-1 and sn-2 in the phosphatidylcholine from plants and yeast.
Position Fatty acid
16:0 16:1 18:0 18:1 18:2 18:3
 
   Arabidopsis thaliana (leaves) [1]
sn-1 42   4 5 23 26
sn-2 1   trace 5 47 47
 
   Soybean 'lecithin' [2]
sn-1 24   9 14 47 4
sn-2 5   1 13 75 6
 
   Lipomyces lipoferus [3]
sn-1 24 18 trace 37 16 4
sn-2 4 5 trace 39 31 19
1, Browse, J., Warwick, N., Somerville, C.R. and Slack, C.R. Biochem. J., 235, 25-31 (1986);  DOI.
2, Blank, M.L., Nutter, L.J. and Privett, O.S. Lipids, 1, 132-135 (1966);  DOI.
3, Haley, J.E. and Jack, R.C. Lipids, 9, 679-681 (1974);  DOI.

2.  Phosphatidylcholine – Biosynthesis

There are several mechanisms for the biosynthesis of phosphatidylcholine in animals, plants and micro-organisms. Choline itself is not synthesised as such by animal cells and is an essential nutrient, not only for phospholipid synthesis but also for cholinergic neurotransmission (acetylcholine synthesis) and as a source of methyl groups for numerous other metabolites. It must be obtained from dietary sources or by degradation of existing choline-containing lipids, for example those produced by the second pathway described below. Once taken across membranes and into cells by the transporters feline leukemia virus subgroup C cellular receptors 1 and 2 (FLVCR1/2), choline is immediately phosphorylated by choline kinase (two isoforms) (1) in the cytoplasm of the cell to produce phosphocholine, which is reacted with cytidine triphosphate (CTP) by the enzyme CTP:phosphocholine cytidylyltransferase (2) to form cytidine diphosphocholine (CDP-choline). The latter enzyme exists in two isoforms of which CCTα is the more important and is a soluble protein found first in the nucleoplasm and then in the cytoplasm, while CCTβ is a cytoplasmic enzyme, but both are activated upon reversible binding to membranes of the endoplasmic reticulum or nuclei. This is the rate-limiting step in phosphatidylcholine biosynthesis, and the enzyme is regulated by signals from a sensor in the membrane that reports on the relative abundance of the final product. To add to its role in lipid synthesis, choline kinase (ChoKα) has regulatory functions.

In plants, nematodes and certain parasites, most phosphocholine is synthesised by sequential methylation of phosphoethanolamine by phospho-base N‑methyltransferases, while free choline and betaine are synthesised by analogous routes in plants.

In the main pathway for the synthesis of phosphatidylcholine in animals and plants, the CDP-choline produced is reacted with sn-1,2-diacylglycerols in the endoplasmic reticulum and nuclei (CEPT1) by the membrane-spanning enzyme CDP-choline:1,2-diacylglycerol choline/ethanolamine-phosphotransferase, which is a dimer with ten transmembrane segments in each protomer and an interior hydrophobic chamber that coordinates the acyl tails during the catalytic process to form phosphatidylcholine (3); there is a related choline phosphotransferase 1 (CPT1) in the trans-Golgi. The first of these is responsible for most phosphatidylcholine biosynthesis but with a somewhat different molecular species composition from the second, which prefers 1-alkyl precursors. This mechanism is present in a few bacterial species only and is analogous to that for a major route to phosphatidylethanolamine. Phosphatidylcholine in mitochondria is obtained by transfer from the endoplasmic reticulum, probably at membrane contact sites.

Main pathway for the biosynthesis of phosphatidylcholine
Figure 1. Main pathway for the biosynthesis of phosphatidylcholine

The discovery of this pathway depended a little on serendipity in that in experiments in the laboratory of Professor Eugene Kennedy, samples of adenosine triphosphate (ATP) contained some cytidine triphosphate (CTP) as an impurity. Luck is of little value without receptive minds, and Kennedy and co-workers demonstrated that the impurity was essential for the formation of phosphatidylcholine.

The above reaction, together with the biosynthetic mechanism for phosphatidylethanolamine, is significantly different from that for phosphatidylglycerol, phosphatidylinositol and cardiolipin. Although both make use of nucleotides, with the latter, the nucleotide is covalently linked directly to the lipid intermediate, i.e., cytidine diphosphate diacylglycerol. A comparable pathway to this for biosynthesis of phosphatidylcholine occurs in some bacteria (see below).

The source of the sn-1,2-diacylglycerol precursor, which is likewise an intermediate in the formation of phosphatidylethanolamine, phosphatidylserine and triacylglycerols, is phosphatidic acid. In this instance, the main enzyme is phosphatidic acid phosphatase (sometimes termed ‘lipin’ or ‘phosphatidate phosphatase’ or ‘lipid phosphate phosphatase’ or ‘phosphatidate phosphohydrolase’).

Conversion of phosphatidic acid to diacylglycerol
Figure 2. Biosynthesis of the diacylglycerol precursor

Yeasts contain two such enzymes, one of which is Mg2+-dependent (PAP1) and the other Mg2+-independent (PAP2). In mammals, there are three cytoplasmic phosphatidic acid phosphatases, termed lipins-1 to 3 (see our web page on triacylglycerol biosynthesis for further discussion). Lipin-1 is found mainly in adipose tissue, while lipin-2 is present mainly in liver, and they are unique among biosynthetic enzymes for glycerolipids in that they can transit between cellular membranes rather than remain tethered to membranes. Of these, lipin-1 is most important and exists in three isoforms, lipin-1α, lipin-1β and lipin-1γ with lipin-1α located mainly in the nucleus and lipin-1β in the cytoplasm, while lipin-1γ is present in brain primarily.

In the second pathway for biosynthesis of phosphatidylcholine, sequential methylation of phosphatidylethanolamine occurs with S‑adenosylmethionine (SAM) as the source of methyl groups and mono- and dimethylphosphatidylethanolamine as intermediates in reactions catalysed by the enzyme phosphatidylethanolamine N‑methyltransferase. A single enzyme (~20 KDa) in two isoforms catalyses all three reactions in hepatocytes; the main form (PEMT1) is located in the endoplasmic reticulum (ER) where it spans the membrane, while the second (PEMT2) is found in the mitochondria-associated ER membrane. Both are a product of the same gene and are similar in structure but generate molecular species with somewhat different compositions. This is a major pathway in the liver, generating one third of the phosphatidylcholine in this organ, but in brain, testis, heart and skeletal muscle, it is a minor pathway only. When choline is deficient in the diet, this is the main liver pathway, and it is in effect an endogenous route to choline biosynthesis. In yeasts, at least two N-methyltransferases are present, and this may be the main route to phosphatidylcholine (and in those bacterial species that produce this lipid), but it appears to operate in only a few species of higher plants.

Second biosynthetic route to phosphatidylcholine
Figure 3. Biosynthesis of phosphatidylcholine by methylation of phosphatidylethanolamine.

Dysregulation of this process can lead to an imbalance of phospholipid metabolism with health consequences. For example, a by-product of the biosynthesis of phosphatidylcholine from phosphatidylethanolamine is the conversion of S‑adenosylmethionine to S‑adenosylhomocysteine, which is hydrolysed in the liver to adenosine and homocysteine. An elevated level of the latter in plasma is a risk factor for cardiovascular disease, myocardial infarction and metabolic diseases that include diabetes and obesity. Knock-out of the PEMT enzymes in laboratory animals is reported to have potential health benefits.

Phosphatidylcholine biosynthesis by both pathways in the liver is necessary for normal secretion of the plasma lipoproteins (VLDL and HDL), and it is relevant to several human physiological conditions. It should be noted that all of these pathways for the biosynthesis of diacylphosphatidylcholine are very different and are separated spatially from that producing alkylacyl- and alkenylacyl-phosphatidylcholines de novo. Synthesis of phosphatidylcholine does not occur uniformly throughout the endoplasmic reticulum but is located at membrane interfaces or where it meets other organelles and when the membrane is expanding dynamically.

The enzymes in the endoplasmic reticulum responsible for the synthesis of all phospholipids are orientated in such a manner that their catalytic sites are exclusively facing the cytosol. Problems would arise if there were a rapid expansion of the cytosolic leaflet while the luminal leaflet did not change, but a phospholipid transporter known as a scramblase enables a rapid bidirectional flip-flop of phospholipids between leaflets of the bilayer in an energy-independent manner. Compositional asymmetry in first seen in the trans-Golgi and is completed before the plasma membrane is formed with phosphatidylcholine and sphingolipids present mainly in the exofacial (outer) leaflet while phosphatidylethanolamine and phosphatidylserine are enriched in the cytosolic leaflet.

Phosphorylcholine is produced by many bacteria, but they use it mainly as an attachment to a glycan structure or as a post-translational modification to proteins where it can be a factor in bacterial pathogenesis. In one bacterial species symbiotic with plants (Sinorhizobium meliloti), a third pathway for phosphatidylcholine biosynthesis has been identified that is now known to occur more widely. In this instance, the lipid is formed in one step via condensation of choline directly with CDP-diacylglycerol, with cytidine monophosphate (CMP) formed as a by-product; the choline comes from the host plant. In Agrobacterium species and some other bacteria, both this route and that via phosphatidylethanolamine operate.

Phosphatidylcholine biosynthesis via a bacterial pathway
Figure 4. Phosphatidylcholine biosynthesis in Sinorhizobium meliloti

In plant cells, phosphatidylcholine biosynthesis occurs mainly in the endoplasmic reticulum, and it is a major component of most membranes other than the internal membranes of plastids; it is absent from the thylakoids and the inner envelope membrane, but it is the main glycerolipid of the outer monolayer of the outer envelope membrane. Further complications arise in plants in that turnover or partial synthesis via lysophosphatidylcholine occurs in different organelles from separate fatty acid pools or by enzymes with differing specificities, and because fatty acids esterified to phosphatidylcholine serve as substrates for desaturases. The result is that an appreciable pool of the diacylglycerols for the biosynthesis of triacylglycerols, galactosyldiacylglycerols and other glycerolipids pass through phosphatidylcholine as an intermediate, so that the fatty acid compositions in different membranes change after the initial synthetic process. This mechanism has obvious differences from the remodelling of molecular species in animal tissues discussed next, although a comparable exchange of acyl groups does occur in part catalysed by acyl transferases (see next section). Some transfer of phosphatidylcholine per se from the endoplasmic reticulum to plastids may occur via contact points between the two membranes or may be facilitated by transport proteins.

While phosphatidylcholine is a major lipid in yeasts, recent work suggests that it is not essential if suitable alternative growth substrates are available, unlike higher organisms where perturbation of phosphatidylcholine synthesis can lead to inhibition of growth or even cell death.

3.  Remodelling of Phosphatidylcholine - the Lands' cycle

Whatever the mechanism of biosynthesis of phosphatidylcholine in animal tissues, it is apparent that the fatty acid and molecular species compositions and positional distributions on the glycerol moiety are determined post synthesis by extensive re-modelling via orchestrated reactions of hydrolysis (phospholipase A2 mainly) to lysophosphatidylcholine (or lysophospholipids in general), acyl-CoA synthesis and re-acylation by lysophospholipid acyltransferases or transacylases, a series of reactions that is sometimes termed the 'Lands' Cycle' after its discoverer W.E.M. (Bill) Lands. Similar processes occur with all glycerophospholipid classes and can utilize all types of fatty acyl groups, including oxylipins where the products are the biologically active oxidized phospholipids. This cycle of reactions generates the selective molecular species compositions seen in each tissue that must contribute to vital functions and ultimately health.

The final composition of the lipid is achieved by a mixture of synthesis de novo and the remodelling pathway. In the main remodelling pathway, lysophosphatidylcholine is generated by the action of phospholipase A2 in the first step. There are at least fifteen different groups of enzymes in the phospholipase A2 super-family, which differ in calcium dependence, cellular location and structure (discussed on another web page in greater detail in relation to eicosanoid production). All hydrolyse the sn-2 ester bond of phospholipids only to generate a lysophospholipid and an unesterified fatty acid, both can be used for other purposes that add to their role in the Lands cycle. While there is a phospholipase A1 family of enzymes, which are esterases that can cleave the sn-1 ester bond, these are less relevant in this context.

The Lands' cycle - 1
Figure 5. Remodelling of phosphatidylcholine in the Lands' cycle - main mechanism in animals.

The re-acylation step with a new acyl-CoA is catalysed by membrane-bound coenzyme A-dependent lysophospholipid acyltransferases (15 family members are known) such as LPLAT3 (or ‘LPCAT3’ or ‘MBOAT5’ - nomenclature changes can cause confusion). These are located chiefly within the endoplasmic reticulum but also in mitochondria and the plasma membrane in organs such as the liver, adipose tissue and pancreas. Re-acylation with LPLAT3 maintains systemic lipid homeostasis by regulating lipid absorption and composition in the intestines, the secretion of lipoproteins and lipogenesis de novo in liver and is notable in that it incorporates linoleoyl and arachidonoyl chains specifically into lysophosphatidylcholine (as does a related enzyme LPLAT2). While LPLAT3 prefers 1-acyl lysophosphatidylcholine as an acyl acceptor, LPLAT2 utilizes both 1-acyl and 1‑alkyl precursors and is highly expressed in inflammatory cells such as macrophages and neutrophils, which contain ether-phospholipids, where it contributes to the production of oxylipin precursors.

With phosphatidylcholine and phosphatidylethanolamine, an sn-1 acyltransferase (lysophosphatidylglycerol acyltransferase 1 or LPGAT1/LPLAT7) controls the stearate/palmitate ratio with a preference for stearate. The highly saturated molecular species of phosphatidylcholine found in lung surfactant are formed from species with a more conventional composition by remodelling by an acyltransferase with a high specificity for palmitoyl-CoA acid (LPLAT1). In other tissues, those species containing high proportions of polyunsaturated fatty acids depend more on synthesis de novo. These and further related enzymes take part in remodelling of all other phospholipids. Over-expression of the genes for these enzymes is associated with the progression of many different cancers and may be involved in other pathological conditions.

In inflammatory cells, there are mechanisms to transfer arachidonic acid from phosphatidylcholine to lysophosphatidylethanolamine, i.e., between phospholipid classes, and this can occur by reaction with both CoA-dependent and CoA-independent acyltransferases. Further, in other cells and tissues, a lysophospholipase/transacylase transfers the fatty acyl moiety from lysophosphatidylcholine to lysophosphatidylethanolamine to form phosphatidylethanolamine and glycerophosphorylcholine. In activated human monocytes, palmitoleic acid is transferred from phosphatidylcholine to phosphatidylinositol by this mechanism with possible signalling consequences. It is noteworthy that lysophospholipid intermediates or end-products of these reactions have their own biological properties.

The Lands' cycle - 2
Figure 6. Alternative mechanisms for remodelling of phosphatidylcholine in the Lands' cycle in animals.

Plants and yeasts: Phosphatidylcholine has a central role in glycerolipid metabolism in plants and remodelling occurs for reasons and by mechanisms that are rather different from those in animal cells. There is extensive remodelling of this lipid as a substrate for fatty acid desaturation (see our web page on polyunsaturated fatty acids) and as the main entry point for acyl groups exported from the plastid into the endoplasmic reticulum. Remodelling of phosphatidylcholine provides fatty acids for triacylglycerol synthesis in developing seeds and for diacylglycerols for the synthesis of thylakoid lipids such as galactosyldiacylglycerols. In Arabidopsis, two lysophosphatidylcholine acyltransferases, LPCAT1 and LPCAT2, are used for remodelling in developing seeds and leaves, with some preference for position sn-2 using fatty acids exported from the plastid. In some plant species, there is a strong preference for C18‑unsaturated acyl chains over 16:0, but the lipases that generate lysophosphatidylcholine from phosphatidylcholine for this purpose are not yet known. Some remodelling in plant membranes occurs in response to abiotic stresses.

The yeast Saccharomyces cerevisiae is able to reacylate glycerophosphocholine generated endogenously by the action of phospholipase B (an enzyme that is both a phospholipase A1 and a phospholipase A2) on phosphatidylcholine with acyl-CoA in the microsomal membranes by means of a glycerophosphocholine acyltransferase (Gpc1) to produces lysophosphatidylcholine, which can be converted back to phosphatidylcholine by the lysophospholipid acyltransferase (Ale1) with appreciable changes in the molecular species composition. The process is regulated in coordination with the other main lipid pathways and affects growth, but the enzyme Gpc1 does not act upon other phospholipids in yeasts. A comparable mechanism appears to operate in some plant species.

Remodelling of phosphatidylcholine species in yeasts
Figure 7. Remodelling of phosphatidylcholine species in yeasts.

4.  Catabolism

Phosphatidylcholine (and most other glycerophospholipids) in membranes can be metabolized by lipolytic enzymes, i.e., phospholipases, some isoforms of which are selective for particular lipid classes in humans (the action of phospholipase A is discussed above). Phospholipase C (six families in mammals differing in expression and subcellular distribution) yields diacylglycerols together with phosphocholine by hydrolysing glycerophospholipids at the phosphodiester bond; one form of the enzyme utilizes phosphatidylcholine only and generates diacylglycerols for signalling purposes. Other enzymes in this family are of greater significance in relation to phosphoinositide metabolism. In the absence of ceramide, the sphingomyelin synthases can act as phospholipase Cs. Phospholipase D generates phosphatidic acid and choline, while phospholipase B removes both fatty acids to yield glycerophosphocholine.

Hydrolysis of phosphatidylcholine by phospholipases B, C and D
Figure 8. Hydrolysis of phosphatidylcholine by phospholipases B, C and D.

Dietary phosphatidylcholine is rapidly hydrolysed in the proximal small intestine by pancreatic enzymes with formation of lysophosphatidylcholine (and free fatty acids). Further hydrolysis can occur in the jejuno-ileal brush-border by the action of the membrane phospholipases, with the release of glycerophosphocholine, but much of the lysophosphatidylcholine is reacylated by the lyso-PC-acyl-CoA-acyltransferase 3 for export in chylomicrons.

After catabolism by these enzymes, the lipid components are recycled, or they may act in signalling, while much of the choline is re-used for phosphatidylcholine biosynthesis, often after being returned to the liver (the CDP-choline cycle). Lysophosphatidylcholine and lysophosphatidylethanolamine formed by degradation in lysosomes are exported into the cytosol by a transporter Spns1 for recycling. Some choline is oxidized in the kidney and liver to betaine, which serves as a donor of methyl groups for S‑adenosylmethionine production, and some is used in nervous tissues for production of acetylcholine, a neurotransmitter of importance to learning, memory and sleep, while some is lost through excretion of phosphatidylcholine in bile. Phosphatidylcholine in the high-density lipoproteins of plasma is taken up by the liver, and perhaps surprisingly, a high proportion of this is eventually converted to triacylglycerols via diacylglycerol intermediates.

5.  Phosphatidylcholine – Functions in Tissues

Because of the generally cylindrical shape of the molecule, phosphatidylcholine organizes spontaneously into bilayers, so it is ideally suited to serve as the bulk structural element of cell membranes, and as outlined above, it makes up a high proportion of the lipids in the outer leaflet of the plasma membrane. The unsaturated acyl chains are kinked and confer fluidity on the membrane. Such properties are necessary to act as a balance to those lipids that do not form bilayers or that form the micro-domains such as rafts. While phosphatidylcholine does not induce curvature of membranes, as may be required for membrane transport and fusion processes, it can be metabolized to form lipids that do.

In contrast, in human lung surfactant, dipalmitoyl phosphatidylcholine is the main surface-active component, although in other animals the lung surfactant can be enriched in some combination of short-chain disaturated and monounsaturated species, mainly palmitoylmyristoyl- and palmitoylpalmitoleoyl- in addition to the dipalmitoyl-lipid. This is believed to provide alveolar stability by decreasing the surface tension at the alveolar surface to a very low level during inspiration while preventing alveolar collapse at the end of expiration. Also, the internal lipids of the animal cell nucleus (after the external membrane has been removed) contain a high proportion of disaturated phosphatidylcholine, which is synthesised entirely within the nucleus, unlike phosphatidylinositol for example, and in contrast to other cellular lipids, its composition cannot be changed by extreme dietary manipulation. It has been suggested that it may have a role in stabilizing or regulating the structure of the chromatin, as well as being a source of signalling diacylglycerols. A further unique molecular species, 1-oleoyl-2-palmitoyl-phosphatidylcholine, is located at the protrusion tips of neuronal cells and appears to be required for their function, while 1‑palmitoyl-2-arachidonoyl-phosphatidylcholine is necessary for the regulation of the progression of the cell cycle and cell proliferation, processes that are independent of eicosanoid production.

Phosphatidylcholine is present bound non-covalently in the crystal structures of several membrane proteins, including cytochrome c oxidase and yeast cytochrome bc1, and depending on the protein, both the head group and the acyl chains may take part in the interactions. The ADP/ATP carrier protein has two binding sites for phosphatidylcholine, one on each side, while the enzyme 3‑hydroxybutyrate dehydrogenase must be bound to phosphatidylcholine before it can operate optimally.

Scottish thistleAs noted above, phosphatidylcholine is by far the most abundant phospholipid component in plasma and in all plasma lipoprotein classes. Although it is most abundant in high density lipoproteins (HDL), it strongly influences the levels of all circulating lipoproteins, including the very-low-density lipoproteins (VLDL), which are surrounded by a phospholipid monolayer. Indeed, phosphatidylcholine with polyunsaturated fatty acids in position sn-2 is indispensable for the assembly and secretion of VLDLs and chylomicrons in liver and the intestines, and it must be synthesised de novo in the latter. Phosphatidylcholine synthesis is required to stabilize the surface of lipid droplets in tissues where triacylglycerols are stored.

Some of the phosphatidylcholine synthesised in the liver is secreted into bile by a flippase together with bile acids where it assists in the emulsification of dietary triacylglycerols in the intestinal lumen to facilitate their hydrolysis and uptake. Eventually, it is absorbed across the intestinal brush border membrane after hydrolysis to lysophosphatidylcholine, which may then assist in the initiation of chylomicron formation in the endoplasmic reticulum of enterocytes by stimulation of a protein kinase. Phosphatidylcholine produced in enterocytes is secreted into the intestinal lumen and forms part of the hydrophobic mucus layer that protects the intestinal surface.

The plasmalogen form of phosphatidylcholine may be a signalling mediator, as thrombin treatment of endothelial cells initiates a selective hydrolysis (phospholipase A2) of molecular species containing arachidonic acid in the sn-2 position, releasing this fatty acid for eicosanoid production, while the diacyl form of phosphatidylcholine acts in signal transduction in other tissues. Phosphatidic acid generated by the action of phospholipase D from phosphatidylcholine in animals is a factor in the metabolism and signalling functions of phosphoinositides by its action upon phosphatidylinositol 4-phosphate 5-kinase, the main enzyme generating the lipid second messenger phosphatidylinositol-4,5-bisphosphate. Phosphatidylcholine may have a further role in signalling via the generation of diacylglycerols by phospholipase C. Although the pool of the precursor is so great in many tissues that turnover is not easily measured, the presence of phospholipases C and D that are specific for phosphatidylcholine and are induced by several agonists suggests such a function in the cell nucleus, although diacylglycerols formed in this way would be much more saturated than those derived from phosphatidylinositol and would not be expected to serve as efficiently.

Phosphatidylcholine is the biosynthetic precursor of sphingomyelin and as such must have some influence on the many metabolic pathways that constitute the sphingomyelin cycle. It is also a precursor for phosphatidic acid, lysophosphatidylcholine and platelet-activating factor, each with distinctive signalling functions, and of phosphatidylserine.

Because of the increased demand for membrane constituents, there is enhanced synthesis of phosphatidylcholine in cancer cells and solid tumours, so the various biosynthetic and catabolic enzymes, and especially the lysophospholipid acyltransferase LPLAT3, are seen as potential targets for the development of new therapeutic agents. Impaired phosphatidylcholine biosynthesis has been observed in many pathological conditions in the liver in humans, including the development of non-alcoholic fatty liver disease, liver failure and impaired liver regeneration, while a deficiency in phosphatidylcholine or an imbalance in the ratio of phosphatidylcholine to phosphatidylethanolamine has negative effects upon insulin sensitivity and glucose homeostasis in skeletal muscle.

Plants and bacteria: In addition to its structural role in plant membranes, phosphatidylcholine levels at the shoot apex correlate with flowering time, and this lipid is believed to bind to the Flowering Locus T, a master regulator of flowering. Molecular species containing relatively low levels of α-linolenic acid are involved. Diacylglycerols formed by the action of a family of enzymes of the phospholipase C type on phosphatidylcholine, as opposed to phosphatidylinositol, may be more important in plants during phosphate deprivation for the generation of precursors for galactolipid biosynthesis and perhaps for lipid re-modelling more generally. Phosphatidic acid generated from phosphatidylcholine by the action of phospholipase D in plants has key signalling functions.

In prokaryotes, phosphatidylcholine is crucial for certain symbiotic and pathogenic microbe-host interactions, and in human pathogens such as Brucella abortus and Legionella pneumophila, it is necessary for full virulence. The same is true for plant pathogens, such as Agrobacterium tumefaciens, while bacteria symbiotic with plants, e.g., the rhizobial bacterium Bradyrhizobium japonicum, require it to establish efficient symbiosis and root nodule formation.

6.  Lysophosphatidylcholine

Formula of lysophosphatidylcholineLysophosphatidylcholine (LPC), with one mole of fatty acid per mole of lipid in position sn-1, is found in trace amounts in most animal tissues, although there are relatively high concentrations in plasma (150 to 500µM). It is produced by hydrolysis of dietary and biliary phosphatidylcholine and is absorbed as such in the intestines, but it is re-esterified before being exported in the lymph. Most tissues produce it by hydrolysis by the superfamily of phospholipase A2 enzymes as part of the de-acylation/re-acylation cycle that controls the overall molecular species composition of the latter, as discussed above. Much of the LPC in the plasma of animal species is secreted by hepatocytes into plasma in a complex with albumin, but an appreciable amount is formed within plasma by the action of the enzyme lecithin:cholesterol acyltransferase (LCAT), which is secreted from the liver. This catalyses the transfer of fatty acids from position sn-2 of phosphatidylcholine to free cholesterol, with formation of cholesterol esters and of course of lysophosphatidylcholine, which consists of a mixture of molecular species with predominately saturated and mono- and dienoic fatty acid constituents (see our web page on lipoproteins). Some LPC is formed by the action of an endothelial lipase on phosphatidylcholine in HDL.

At high concentrations, lysophosphatidylcholine has detergent properties that can disrupt membranes, while at low concentrations it may affect the properties of membrane proteins indirectly simply by its ability to diffuse readily into membranes to alter their curvature. In plasma, it is bound to albumin and lipoproteins so that its effective concentration is reduced to a safe level.

Lysophosphatidylcholine is a factor in cardiovascular and neurodegenerative diseases. It is usually considered to have pro-inflammatory properties, and it is known to be a pathological component of oxidized lipoproteins (LDL) in plasma and atherosclerotic lesions when it is generated by overexpression or enhanced activity of phospholipase A2. Its concentration is elevated in joint fluids from patients with rheumatoid arthritis. As a major component of platelet-derived microvesicles, it activates a receptor in platelets that ultimately leads to vascular inflammation, increasing the instability of atherosclerotic plaques. The intracellular acyltransferase LPLAT cannot remove lysophosphatidylcholine directly from plasma or lipoproteins, nor do there appear to be any enzymes of a lysophospholipase A1 type in the circulation. Among many other effects, lysophosphatidylcholine blocks the formation of early hemifusion intermediates required for cell-cell fusions that in insect bites attracts inflammatory cells to the site, enhances parasite invasion, and inhibits the production of nitric oxide as in Chagas disease. Elevated levels of 26:0‑lysophosphatidylcholine in blood are reported to be characteristic of Zellweger spectrum disorders such as X-linked adrenoleukodystrophy, which is caused by pathogenic variants in the ABCD1 gene encoding an ATP-binding cassette membrane protein that transports very-long-chain saturated fatty acids (≥C22:0) into peroxisomes for β-oxidation.

Scottish thistleHigh levels of lysophosphatidylcholine have been identified in cervical cancer and may be diagnostic for the disease. On the other hand, reduced concentrations of lysophosphatidylcholine are observed in some malignant cancers, and it is protective in patients undergoing chemotherapy. Stearoyl-lysophosphatidylcholine has an anti-inflammatory role in that it is protective against lethal sepsis in experimental animals by various mechanisms, including stimulation of neutrophils to eliminate invading pathogens through a peroxide-dependent reaction, and there are reports that lysophosphatidylcholine may be beneficial in some other diseases. However, there are suggestions that some experimental studies in vitro of lysophosphatidylcholines may be flawed because insufficient levels of carrier proteins were used. A further point for consideration is that lysophosphatidylcholine is the precursor of the lipid mediator lysophosphatidic acid via the action of the enzyme autotaxin in plasma, and this may be the true source of some of the effects described for the former on cell migration and survival.

There is evidence to suggest that lysophosphatidylcholine containing docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, presumably in position sn-2, in plasma targets more of these essential fatty acids into the brain via a receptor/transporter at the blood-brain barrier known as the sodium-dependent LPC symporter 1 (MFSD2A), than occurs with these fatty acids in unesterified form. This finding is now being explored in relation to potential therapeutic applications for neurological diseases, cognitive decline and dementia, and for improvements to retinal function in Alzheimer disease-associated retinopathy. Hepatic lipase is the main source of these lipids in vivo. At the maternal plasma/placental interface, phosphatidylcholine is taken up and hydrolysed to sn‑2‑lysophosphatidylcholine, presumably by the endothelial lipase, to facilitate transfer of polyunsaturated fatty acids across the basal membrane into the foetal circulation with the aid of the same LPC transporter.

Lysophosphatidylcholine has been found to have serve in cell signalling, and receptors (coupled to G proteins) have been identified, i.e., GPR119, GPR40, GPR55 and G2A, in addition to Toll-like receptors and ion channels. It activates the specific phospholipase C that releases diacylglycerols and inositol triphosphate from phosphatidylinositol 4,5-bisphosphate with resultant increases in intracellular Ca2+ and activation of protein kinase C. By direct binding to GPR119, lysophosphatidylcholine regulates glucose-dependent insulin secretion. It stimulates the mitogen-activated protein kinase in certain cell types, and it promotes demyelination in the nervous system. By interacting with the TRPV4 ion channels of skin keratinocytes, it causes persistent itching and even chronic pain, and elevated levels of 18:0-lysophosphatidylcholine contribute to the development of pain in burn victims and increase the sensitivity to mechanical and heat stimuli. Identification of a phospholipase A2γ in peroxisomes that is unique in generating sn‑2‑arachidonoyl lysophosphatidylcholine suggests that this may be of relevance to eicosanoid generation and signalling, and there is reportedly an enrichment of 2-arachidonoyl-lysophosphatidylcholine in carotid atheroma plaque from type 2 diabetic patients. In vascular endothelial cells, it induces the pro-inflammatory enzyme cyclooxygenase-2 (COX-2), one of the prostaglandin synthases. On the other hand, it is beneficial towards the innate immune system as it can induce macrophages to increase phagocytosis in the presence of T lymphocytes.

As lysophospholipids in general and lysophosphatidylcholine especially are signalling molecules within mammalian cells, their levels are closely regulated, mainly by the action of the lysophospholipases A1 and A2 (LYPLA1 and LYPLA2), depending on the position to which the fatty acid is esterified; these are cytosolic serine hydrolases, which act as esterase and thioesterases. Glycerophosphocholine, the fully de-acylated molecule produced by these reactions can enter the Lands' cycle or be further degraded, but in the kidney, it is formed in response to high levels of sodium chloride and has osmoprotective properties. One further enzyme, alkaline sphingomyelinase, renders lysophosphatidylcholine inert but by removing the phosphocholine moiety to yield a monoalkylglycerol.

In relation to plants, amylose-rich starch granules of cereal grains contain lysophosphatidylcholine as virtually the only lipid in the form of inclusion complexes or lining channels in the starch macromolecules.

7.  Other Phosphatidylcholine Analogues and Metabolites

Formula of phosphatidylsulfocholineThe diatom Nitzschia alba contains a number of interesting sulfolipids, as membrane constituents, including phosphatidylsulfocholine (a sulfonium analogue of phosphatidylcholine, i.e., with two methyl groups attached to a terminal sulfur atom as opposed to three attached to nitrogen). This novel lipid completely replaces phosphatidylcholine in the organism, and it has now been found in some other marine diatoms and algae that contain phosphatidylcholine per se. Experiments with isotopically labelled substrates confirmed that both methyl groups and the sulfur atom are derived from methionine. A related lipid, phosphatidyl-S,S-dimethylpropanethiol, has been reported from several algal species.

Saturated and monoenoic alkylphosphocholines/ethanolamines (C15 to C25) together with related ubiquinol-containing metabolites (not fully characterized) accumulate in plasma and other tissues of patients with Sjögren-Larsson syndrome, a rare neurometabolic disorder caused by a deficiency of fatty aldehyde dehydrogenase. It is suggested that they may be formed from accumulating fatty alcohols by the action of sphingomyelin synthases and may be a diagnostic biomarker for the disease. Synthetic analogues of alkylphosphocholines have strong anti-cancer properties by triggering apoptosis of cancer cells, and they are used to treat parasitic infections such as leishmaniasis.

Formula of an alkylphosphocholine

Phosphatidylarsenocholine is a minor component of the lipids of a number of marine organisms and is discussed in the web page dealing with arsenolipids.

8.  Analysis

Analysis of phosphatidylcholine is straightforward, and it is readily isolated by thin-layer or high-performance liquid chromatography methods. Determination of the dipalmitoyl species in lung surfactant is more demanding, but suitable methods have been published, and modern mass spectrometry methodology has greatly simplified the task of molecular species determination in general. Phospholipase A2 from snake venom has been used in methods to determine the position of fatty acids on the glycerol moiety, although this can be accomplished now by mass spectrometry. Lysophosphatidylcholine can be formed inadvertently and over-estimated when there has been careless extraction of lipids from tissues.

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