Structural Lipidomics


lipidomicsLipidomics is the part of metabolomics dedicated to lipids. It can be defined as the full molecular characterization of the lipid components in a defined system, as well as consideration of their function when available. The name lipidomics was used for the first time in titles of scientific articles in 2003, and found more than four hundred times as such during the next decade, with 15% in the last year.

Such a development has led experts in the field to distinguish between different subdomains, such as structural or mediator lipidomics, in an attempt to simplify the data and decrease the complexity of their interpretation. A way to keep an integrated lipidomics approach that includes the structures and functions of lipids in a particular field can be called targeted lipidomics.

lipidomicsIn the present essay, the authors present lipid molecular species which have been well defined for their biological activities, whatever the biological system concerned, with reference to the closely related structural lipids. A special emphasis will be given to bioactive lipids issued from membrane lipids, especially polyunsaturated fatty acid derivatives produced through various oxygenation processes. The most numerous bioactive lipids have been described in the frame of cell lipid signaling, so the enzymes associated with the production of these bioactive lipids and receptor proteins relating to their action are also reported.

As methodological aspects are crucial considerations in characterizing the various lipids, the most common methods in use will be presented, together with a dynamic approach of the fluxes relating to the bioactive molecules, trying to anticipate a true fluxolipidomics. An attempt to visualize the lipids in their membrane superstructures will also be reported as imaging lipids.

The readers addressed with this essay are Master and PhD students as well as scientists starting to be interested in lipids involved in cell signaling. Also, this essay may help medical doctors interested in pathophysiological molecular bases of diseases involving lipids.

Bioactive lipids and their precursors

The numerous bioactive lipids require a comprehensive view of their immediate precursors and the more stable components that are usually structural components of biological membranes.


Glycerolipids result from the esterification of the three alcohol functions of glycerol by fatty acids and/or phosphate. The common glycerol backbone residue is either linked to three fatty acyls, leading to the storage lipid class called triacylglycerols (trivial name: triglycerides) or linked to two fatty acyls and one phosphate that esterifies the third alcohol, one of the two primary alcohols present in glycerol (glycero-phospholipids). The third position/alcohol of glycerol may also be derived by carbohydrates with osidic or ether linkage. There is no asymmetric carbon in glycerol, but carbon number two becomes asymmetric in most glycerolipids as the chemical groups at position one and three (acyls or polar groups) are different, except for triacylglycerols that have the same acyl group at the external positions. Natural glycerolipids are usually defined as L with the S configuration for carbon number two (Fig. 1). This stereochemistry is taken into consideration with “stereo-chemically numbered” (sn) preceding the number, e.g. sn-2 for the asymmetric carbon and sn-1/3 for external positions.



As storage lipids, triacylglycerols (TAG) are both qualitatively and quantitatively important in plant seeds and adipose tissues of animals in the frame of further mobilization to provide energy-rich molecules. They also are substantial components of blood plasma lipoproteins, especially those called TAG- rich lipoproteins, namely chylomicrons and very low-density lipoproteins (VLDL) in which various types of lipids are non-covalently associated with specific proteins. Chylomicrons and VLDL are the privileged vehicles of TAG from the intestine and liver, respectively. When TAG are mobilized from storage tissues or blood plasma lipoproteins by TAG lipases, acyl residues at the sn-1 or sn-3 positions are hydrolyzed to release fatty acids (Fig. 1), that become available to other tissue via albumin transport within the blood stream. Saturated and monounsaturated fatty acids are mainly used for energy supply through beta-oxidation, but polyunsaturated fatty acids may contribute to cell signaling as described below in Fatty acids and derivatives.


They are the most abundant lipids in biological membranes in general, except in thylakoids of plant cells where galacto-lipids are major lipid components. Glycerophospholipids differ both in terms of polar heads at the sn-3 position, and fatty acyl moieties at the sn-1 and sn-2 positions. Having two fatty acyl residues per molecule, the number of phospholipid molecular species is quite high. In addition, ether phospholipids are glycerol-phos- pholipids that have an alkyl (saturated ether) or alkenyl (alpha unsaturated ether) chain at the sn-1 position. The general structure is described in Figure 2.

The group of diacylglycerophospho-X, with X corresponding to the residue of X-OH (e.g. X-OH: ethanolamine: HO-CH2-CH2-NH2; X: -CH2-CH2-NH2) after esterification by the phosphate group that also esterifies the sn-3 primary alcohol of glycerol, is the most abundant lipid form in biological membranes, notably in animal cells.


Classes, subclasses and molecular species of glycerophospholipids

The different classes of glycerophospholipids relate to X-OH, which can be:

choline, ethanolamine, L-serine, myo-inositol (possibly further phosphorylated once, twice, or three times), or glycerol (Fig. 3). X is then the only difference in the polar head group: phosphate-X. The corresponding glycerophospholipids are called: phosphatidylcholine (PC) or choline glycero-phospholipids because they may contain ether phospholipids, especially as an alkyl form (see below), phosphatidylethanolamine (PE) or ethanolamine glycerophospholipids as they may also contain an ether moiety, especially as an alkenyl or alpha-unsaturated alkyl form, and phosphatidylserine (PS). Glycerophospholipids also comprise phosphoinositides (PIs) that include the most common one called phospha- tidylinositol (PI), and the further phosphorylated derivatives phosphatidyli- nositol-4-phosphate (PIP) and phosphatidylinositol-4,5-bisphosphate (PIP2). A further phosphorylation on carbon 3 is possible in response to cell activation, leading to phosphatidylinositol-3,4,5-trisphosphate (PIP3). In contrast to the other phosphoinositides, PIP3 is a quite transient component of the membranes. Phosphatidylglycerol (PG) is also present, especially in prokaryotic membranes.

The relative abundance of these glycerophospholipids in animal cells varies according to the different membranes of the cell and even according to the different cell types. It can be stated that PC is predominant, followed by PE, then PS and finally PIs.


Among PIs, PIP and PIP2 are less present, reaching around 10% of total PIs. This class of phospholipid is then quantitatively minor, although it is considered as a major bioactive lipid in cell signaling in several ways. Among PIs, it is worth to point out the very minor component PIP3, which does not accumulate, as already mentioned above, but rises in response to activation of some tyrosine kinase receptors such as that of insulin, resulting in PI-3-kinase activation. PI-3-kinase is especially active upon PIP2, giving rise to PIP3 which then acts as a messenger.

Finally, it is also worth to mention two peculiar glycero-phospholipids that contain two acylated glycerol moieties. They are bisphosphatidyl-glycerol or cardiolipin (CL) and bis-monoacyl-glycerophosphate (BMP), a position isomer of PG.

• CL is especially rich in unsaturated fatty acyls (often at each sn position), mostly linoleoyls. CL is almost exclusively located within the inner membrane of mitochondria, where it plays an important structural role for respiratory chain cytochrome insertion. The “double” size of CL, compared to classic glycerophospholipids, is also believed to be responsible for the relative impermeability of the mitochondrial inner membrane.

• BMP is a quantitatively minor phospholipid (the most minor one) produced from PG by a complex transacylation process. BMP is quite specifically located in the luminal membranes of late endosomes where it seems to regulate the cholesterol homeostasis and glycosphingolipid degradation.


Extract from Structural and Mediator Lipidomics By Michel Lagarde Published by Presses Polytechniques et Universitaires Romandes (PPUR)

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