The LipidWeb blank

Lipid Matters - A Personal Blog



Or "Lipids Matter". An occasional series of notes on publications or other items dealing with lipid science that seem to be of particular interest to the originator of this web page, Bill Christie. Inevitably, the selection is highly personal and subjective. Older entries are archived in separate web pages by year (see the foot of this page).


June 20th, 2018

Scottish thistleAn interesting review publication suggests that long-chain polyunsaturated fatty acids, as opposed to linoleic and linolenic acids, are the true essential fatty acids (Anez-Bustillos, L. et al. Redefining essential fatty acids in the era of novel intravenous lipid emulsions. Clin. Nutr., 37, 784-789 (2018);  DOI). Mice fed arachidonic and docosahexaenoic acids exclusively for five generations grew and reproduced normally, and these fatty acids are certainly vital for eicosanoid and docosanoid production and for innumerable other purposes when esterified to lipids in tissues. There is no doubt that we must have adequate amounts to ensure health. On the other hand, linoleic acid is required for skin ceramides and cardiolipin in heart mitochondria, for example. If the skin barrier integrity and energy production were less than optimal (if adequate for life) in the experimental animals, would this have been noticed? The authors suggest that linoleate could be supplied for other functions by retro-conversion of arachidonic acid, but this seems to me a circular argument - linoleate produces arachidonate produces linoleate - the chicken versus the egg. The debate is important in that alternative injectable lipid emulsions low in the C18 precursors are apparently being considered for clinical use. It seems to me that a sensible compromise would be to ensure that there are adequate amounts of all fatty acids that may have essential functions in any artificial feeding regime.

In my last blog, I urged other senior lipid experts to consider keeping active in or near retirement by writing for the web. My web career was initiated by a desire to see that the large repository of mass spectrometric information (electron impact) on fatty acids and other simple lipids, which I had accumulated, was preserved. There are now more than 2,100 spectra available in the LipidWeb. On the other hand, my former colleagues recently asked me to advise on an analytical problem involving plant sterols. As I did not have access to the Wiley Library and had only a few representative spectra of my own, this proved to be a time-consuming and rather tedious task to search the literature. Is there anyone out there who would consider producing a website akin to mine dealing with electron-impact mass spectra of sterols and their derivatives? You would do the lipid community a great service. Again, I would be happy to advise.

Although we are probably stuck with it, I don't particularly like the term "endocannabinoid", as to use yet another cliché - it is putting the cart before the horse. For example, anandamide does not mimic cannabinol, but rather cannabinol mimics anandamide. Whatever we call them, there is no doubt that endocannabinoids have profound biological effects in humans, and drugs that influence their metabolism are undergoing clinical trials. Therefore, it would not be surprising if cannabinoids per se have medicinal properties, although there is currently some controversy in the UK about such applications. It in no way endorses the use of cannabis for recreational purposes if we accept that drugs derived from it may have a legitimate place in pharmacopoeias. Few politicians appear to understand the difference between the two.

June 13th, 2018

Thioxo-arseno lipidI enjoy eating fish, and I am not going to be deterred by the findings that the arseno-hydrocarbons, which they contain albeit at very low levels, are highly toxic. From experiments with human cell lines in vitro, a new publication reports that arsenic-containing hydrocarbons influence gene expression and DNA methylation with the nature and magnitude of the effects dependent on the chain-length of the hydrocarbon (Müller, S.M. et al. Arsenic-containing hydrocarbons: effects on gene expression, epigenetics, and biotransformation in HepG2 cells. Arch. Toxicol., 92, 1751-1765 (2018);  DOI). One surprise was that high proportions of the starting compounds were transformed into thioxo analogues, i.e. with the oxygen atom replaced by sulfur, with trace levels as arseno-fatty acids and alcohols. Thioxo-arseno lipids might be expected to be more lipophilic than the parent compounds, but it is not yet known whether this transformation results in an increase in toxicity.

When I have what my wife calls "a senior moment", it seems that the fault may lie with my lipids and in particular my leukotrienes. Experiments with mice engineered genetically to have excess tau proteins, the second-most important lesion in the brain in patients with Alzheimer's disease, showed that they developed learning and memory problems as they aged. However, the effects were reversed by a drug that inhibits leukotriene formation by blocking the 5-lipoxygenase enzyme. There is a popular account of the work in Science Daily.

One of the main virtues of writing for the web is its immediacy. Not only do you see the results of your efforts at once, but you also have the opportunities to update anything you write whenever new information becomes available. For example, the figures and comments in this and last weeks' blogs were prepared not for the blog per se but initially for the essays on the appropriate topics in the Lipid Essentials section of this website. I make changes to one or other of these web pages nearly every day - sometimes simply to add or replace a reference and occasionally I regret to say to correct an error. Sometimes, I merely find a better way of explaining a point. If I had intended to use these figures in a review on one of these topics for a print publication, it might be a year before it appeared in a journal - not the same day - and then there would be no opportunities for correction or updating. There are hundreds of senior scientists out there with a wealth of knowledge on lipid science who I am sure would find some fulfillment by setting up their own web sites and writing for the web. It is so easy to do - why not give it a go? I will be happy to offer advice to anyone who wants to try.

June 6th, 2018

Plasmalogen catabolismI have been enjoying the sunshine of Gran Canaria for the last week, and lipid science has not been at the forefront of my thoughts. However, it took only a preliminary look at the literature on my return, to see that I had missed an important paper. The mechanism for the cleavage of the vinyl ether bond in plasmalogens has now been revealed as the result of a master class in elegant mass spectrometric experiments involving the use of stable isotopes (Jenkins, C.M. et al. Cytochrome c is an oxidative stress–activated plasmalogenase that cleaves plasmenylcholine and plasmenylethanolamine at the sn-1 vinyl ether linkage J. Biol. Chem., 293, 8693-8709 (2018);  DOI - open access as an editors' pick, as is an additional useful commentary by Howard Goldfine). Perhaps surprisingly, the key enzyme is cytochrome c, best known for its role in the respiratory chain of mitochondria. This must first be activated to produce peroxidase activity by an interaction with cardiolipin. After a complex series of reactions, the products are a lysophospholipid and an α-hydroxyaldehyde. The carbonyl oxygen is derived from water while that of the α-hydroxyl group comes from molecular oxygen (or possibly from oxidized cardiolipin). As the resulting lysophospholipid is usually enriched in arachidonic acid, this may have interesting implications for eicosanoid production. The findings are also relevant to Alzheimer's disease, as it has long been known that α-hydroxyaldehydes accumulate in the brains of affected patients.

Incidentally, a further new publication is relevant to the suggestion that oxidized cardiolipin may be involved in the reaction (Vähäheikkilä, M. et al. How cardiolipin peroxidation alters the properties of the inner mitochondrial membrane? Chem. Phys. Lipids, 214, 15-23 (2018);  DOI).

May 23rd, 2018

Scottish thistleIt is very rare to see a statue raised to commemorate a scientist, but I was pleased to see that Stephen Hawking was honoured at his death by being interred in Westminster Abbey. I only know of one lipid scientist who has been commemorated by a statue, and that is the great French chemist Michel Chevreul of whom there is a bronze statue in the Jardin des Plantes d'Angers in Paris. Of course that great stalwart of lipid research, the laboratory mouse, is commemorated by a bronze statue in a park in front of the Institute of Cytology and Genetics of the Russian Academy of Sciences in the city of Novosibirsk in Siberia, Russia. He/she is depicted knitting DNA (see the Wikipedia entry). In the main city square here in Dundee, we have a statue of Desperate Dan, a character from children's comics and a superhero of my own childhood. Our priorities must be different.

A candidate for the most unusual new lipid of the year is 1-phosphatidyl-2-acyl-glycero-3-phosphoethanolamine from a Gram-negative bacterial species; the structure has been tentatively identified by tandem mass spectrometric analysis (Luo, Y. et al. Nutrient depletion-induced production of tri-acylated glycerophospholipids in Acinetobacter radioresistens. Sci. Rep., 8, 7470 (2018);  DOI - open access). It is produced together with cardiolipin and lysocardiolipin, presumably from a common intermediate, only in the stationary phase of growth of the organism.

Structure of 1-phosphatidyl-2-acyl-glycero-3-phosphoethanolamine

Issue 8 (Volume 592, April 2018) of FEBS Letters contains a number of review articles on the theme of "Focus on… Yeast Lipid Biochemistry", all of which are open access.

May 16th, 2018

α-D-Galactosylceramides, i.e. cerebrosides with an α-D- rather than the usual β-D-linkage between galactose and ceramide, are present in trace amounts only in human tissues but they have profound biological effects. For example, studies with animal models have suggested that treatment with α-D-galactosylceramides may be effective against lung and colorectal cancers, melanomas and leukemia. Now, a phase I trial with high-risk melanoma patients has given promising preliminary results (Gasser, O. and 19 others. A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients. Cancer Immunology, Immunotherapy, 67, 285-298 (2018);  DOI). It is always pleasing to see that the potential of lipids in therapy is being realized. Unfortunately, not all glycosphingolipids are beneficial and a new short review of the influence of glycosphingolipids on cancer has been published (Zhuo, D.H. et al. Biological roles of aberrantly expressed glycosphingolipids and related enzymes in human cancer development and progression. Front. Physiol., 9, 466 (2018);  DOI - open access).

The bargain of the week is an open access review of triacylglycerol metabolism (Alves-Bezerra, M. and Cohen, D.E. Triglyceride metabolism in the liver. Comprehensive Physiology, 8, 1-22 (2018);  DOI). There are nearly 300 references, it is very well illustrated and it should be especially useful for teaching purposes. My only caveat is the use of the term 'triglyceride' instead of 'triacylglycerol', which has been recommended by IUPAC-IUB for more than 50 years. Two generations of biochemists have been taught the recommended nomenclature, so I am surprised to find the old used here. At least the authors did not use the hybrid term 'triacylglycerides', which I find much too often in the lipid literature. Am I being pedantic?

May 9th, 2018

In my blog of March 14th, I discussed a paper describing the synthesis of linoleic acid in primitive invertebrates, including insects, nematodes and snails. Hot on its heels, a new paper has just been published demonstrating that a large number of aquatic invertebrates possess the gene for a Δ15-desaturase and so can synthesise α-linolenic acid and polyunsaturated fatty acids of the omega-3 family (Kabeya, N. et al. Genes for de novo biosynthesis of omega-3 polyunsaturated fatty acids are widespread in animals. Science Advances, 4, eaar684902 (2018);  DOI - open access). It was pleasing to see that some of the authors were from the University of Stirling in Scotland. Until now, it had been believed that microorganisms were the main producers of polyunsaturated fatty acids of omega-3 fatty acids in the marine food web, but now it appears that animal species may make a significant contribution. In addition to adding the new information, I have had to make a small but important change to my web page on polyunsaturated fatty acids, by changing phrases such as "animals cannot produce essential fatty acids" to "higher animals cannot, etc".

It is 40 years since, the discovery of glycosylphosphatidylinositol (GPI)-anchored proteins, and thirty since the first complete structure was determined for the parasitic organism Trypanosoma brucei, and it since then it has become evident how important these are for so many aspects of metabolism in Eukaryotes. In their functional site on the outer leaflet of the plasma membrane, the flexible carbohydrate linkage provides GPI-proteins with a much higher degree of rotational freedom than is available to most other membrane proteins, facilitating their functions as signal receptors and host-recognition molecules. They have essential functions in the interaction of cells with their external environment by enabling the receipt of signals and the response to challenges as well as mediating adhesion of extracellular compounds to the cell surface. In parasitic protozoa, yeasts and fungi, GPI-proteins also participate in the structural integrity of the cell wall and with other complex glycans provide a layer of protection to the organisms. A new review is a valuable guide to the latter (Komath, S.S. et al. Generating anchors only to lose them: the unusual story of glycosylphosphatidylinositol anchor biosynthesis and remodeling in yeast and fungi. IUBMB Life, 70, 355-383 (2018);  DOI).

May 2nd, 2018

There has been no shortage of publications dealing with the molecular species of mitochondrial cardiolipin in recent years, but a new publication suggests that most of them suffer from a flaw in that they do not allow sufficiently for overlap with isobaric species (Oemer, G. et al. Molecular structural diversity of mitochondrial cardiolipins. Proc. Natl. Acad. Sci. USA, 115, 4158-4163 (2018);  DOI). I have been too long from the bench to fully comprehend the arguments, but the authors use a combination of HPLC-mass spectral data and a mathematical structural modeling approach to overcome the problems. The data are presented elegantly in graphical form for many different organisms and tissues, but I wish the authors had used the opportunities offered by having appendices to tabulate data at least for the major species, as they have done for fatty acid compositions. I would love to be able to list tabulated data from a modern paper in my web page on this lipid class to replace that from a 25 year old publication.

Do we now fully comprehend the structures of natural cardiolipins? Unfortunately, the answer is no because we know little or nothing about the positional distributions of fatty acids in the molecule. Cardiolipin has two chiral centres, one in each outer glycerol group, and this means that the four positions to which fatty acids are esterified are each metabolically distinct and can have different fatty acid compositions. As far as I am aware, no one has attempted to tackle the problem, which is unlikely to be solved by mass spectrometry. Analysts may have to resurrect enzymatic hydrolysis methods, which are stereo-selective but have been sadly neglected.

An interesting new paper (though I have only seen the abstract) suggests a close relationship between plasmalogen and cardiolipin biosynthesis (Kimura, T. et al. Substantial decrease in plasmalogen in the heart associated with tafazzin deficiency. Biochemistry, 57, 2162-2175 (2018);  DOI)). The authors establish that plasmenylcholine, which is abundant in linoleoyl species in heart mitochondria, is a substrate for tafazzin and may be important for the remodelling of cardiolipin. This may be especially relevant to the debilitating genetic disease Barth syndrome.

April 25th, 2018

Scottish thistleNew biological functions for lipids and new lipids per se continue to be found, and I have just caught up on one concerning the model nematode Caenorhabditis elegans. This contains a novel glucosylceramide with phosphoethanolamine or its monomethylated form attached to carbon 6 of the glucose moiety (Boland, S. et al. Phosphorylated glycosphingolipids essential for cholesterol mobilization in Caenorhabditis elegans. Nature Chem. Biol., 13, 647-654 (2017);  DOI) The ceramide moiety contained an iso-branched C17 sphingoid base of the phytosphinganine type (i.e. with a 4-hydroxyl group - normally considered a plant product) and amide-linked 2-hydroxy long-chain fatty acids with variable chain lengths (C22, C23 and C24). This lipid is shown to be essential for the development of C. elegans through its regulation of sterol mobilization (the organism requires an exogenous source of cholesterol). It is able to rescue larval arrest that has been induced by sterol starvation.

Formula of phosphoethanolamine-glucosylceramide

Related lipids had been reported earlier from a species of earth worm and from a marine worm, but with galactose as the carbohydrate moiety and with phosphocholine as the attachment, while phosphono analogues have been recorded from marine invertebrates (see my web page on glycosylceramides). However, the functions of these lipids have not been explored. Note that these lipids should be termed "phosphoglycosphingolipids", not "glycophosphosphingolipids", an important distinction that is explained for the glycerolipid equivalents here...

April 18th, 2018

Concerns over the nutritional effects of fatty acids with trans double bonds have created a need for methodologies that enable analysts to determine the nature and amounts of the trans isomers of polyunsaturated fatty acids that may be generated in the refining process of commercial oils. Two papers have just appeared on the topic. The first looks at geometric isomers of stearidonic acid (18:4(n-3)), which are isolated by silver ion chromatography and then subjected to structural analysis to determine the order of elution by GC (Delmonte, P. et al. Structural determination and occurrence in ahiflower oil of stearidonic acid trans fatty acids. Lipids, 53, 255-266 (2018);  DOI). The second is even more daunting technically as it involves docosahexaenoic acid isomers. I don't have access to the original publication, but from the abstract the authors use a very different approach involving epoxide intermediates (Menounou, G. et al. Trans lipid library: synthesis of docosahexaenoic acid (DHA) monotrans isomers and regioisomer identification in DHA-containing supplements. Chem. Res. Toxicol., 31, 191-200 (2018);  DOI).

I have seen (and cited in my literature survey pages for 2016) two publications dealing with the use of gas chromatography linked to vacuum ultraviolet spectroscopy as a means of identifying and quantifying trans-fatty acids in samples. Now a new publication describes an application of the technique to a much wider range of fatty acid types including those with branched-chains, cyclopropane rings and hydroxyl groups (Santos, I.C. et al. Analysis of bacterial FAMEs using gas chromatography-vacuum ultraviolet spectroscopy for the identification and discrimination of bacteria. Talanta, 182, 536-543 (2018);  DOI). I don't see such equipment supplanting GC-MS, but it may compliment it well.

I have just read a report that the owner of the Web of Science has purchased a software company that has a web-browser extension to simplify the process of finding and legally downloading scholarly publications. This will be incorporated as a tool that offers one-click access to journal articles to which we may have legal access without having to sign into the journal or go through an Institution's account. When it is implemented, it will make my weekly literature searches much easier.

April 11th, 2018

The Journal of Experimental Biology has published a special issue (March, 2018 vol. 221 (Suppl. 1) - open access) on the theme of "The biology of fat" with guest editors Raul K. Suarez and Hans H. Hoppeler. There is an eclectic array of topics, with brown fat, adipose tissue metabolism and the metabolic syndrome well to the fore. However, there are a number of interesting papers dealing with aspects of the subject less often encountered in main-stream publications, for example adipogenesis in fish and energy metabolism in migrating birds. I am always fascinated by novel functions of lipids, so I can recommend a paper on fats in over-wintering insects. Did you know that some insects can tolerate being completely frozen thanks to the presence of triacylglycerols containing acetate that remain liquid well below 0°C, while others contain glycolipids that serve as anti-freeze agents? An older story but one well worth recalling is the observation that dolphins and toothed whales have an organ in the head with mixtures of wax esters and triacylglycerols so arranged that they serve to focus sound during echolocation and hearing.

A cliché that I dislike intensely is "thinking outside the box", so I will refrain from using it when citing a new publication that makes use of clever chemistry in a procedure for isolating sphingoid bases (Gowda, S.G.B. et al. Facile chemoselective strategy toward capturing sphingoid bases by a unique glutaraldehyde-functionalized resin. ACS Omega, 3, 753-759 (2018);  DOI - open access). The authors utilize the selective but reversible reaction of glutaraldehyde with the 1,3-diol groups in sphingoid bases. By employing the functional groups bonded to a resin, they were able to develop a relatively simple procedure to concentrate a clean fraction of sphingoid bases for further analysis.

The journal Bioanalysis has devoted an issue (March, 2018) to the topic of "Bioanalytical techniques in lipidomics" (edited by D. Vuckovic). Some of the articles are open access.

Nature News reports that the EU is proposing a change in copyright law that might make life difficult for scientists in general and websites like this in particular. For example, publishers could demand a fee from any publication that quotes them in any way, including listing tabulated data. Although it is unlikely to be enforced, they could even demand a royalty for citing a paper. It would also "compel repositories of research articles to prevent uploads of copyrighted papers and other content" (this direct quotation could require a fee). Fortunately, any new law must be approved by the EU parliament and by member states before it can be enacted (here I have been careful to paraphrase the original). Not surprisingly, publishers are in favour of the proposals.

April 4th, 2018

Formula of jasmonoylisoleucinePlant oxylipins have been the subject of intensive study in recent years, and the jasmonates are especially important as the title of a new review makes clear (Koo, A.J. Metabolism of the plant hormone jasmonate: a sentinel for tissue damage and master regulator of stress response. Phytochem. Rev., 17, 51-80 (2018);  DOI). (+)-7-Jasmonoyl-isoleucine appears to be the key molecule as this is the only one known to have a specific receptor, although it is the precursor of at least 11 known metabolites many of which have biological activities in their own right. Jasmonic acid per se is a 12-carbon cyclic fatty acid derived from α-linolenic acid and with a cyclopentanone ring resembling that in mammalian prostaglandins (surely no coincidence) as a key structural feature. Together with the other plant oxylipins, jasmonates are an essential part of a complex interactive network of phytohormones that controls all aspects of plant growth and development and the manner in which plants adapt to the environment. As an example, next time you enjoy a plate of chips (French fries) you may care to recall that the glucopyranosyl derivative of tuberonic acid, derived from jasmonic acid after hydroxylation at C-12, induces tuber formation in potato plants through its influence upon gibberellic acid signalling. Jasmonates even enable plant to talk to each other, and when one is damaged by insect attack, volatile methyl jasmonate is released to be taken up by neighboring plants to stimulate them to set their own defence mechanisms in action.

Seed oil triacylglycerols have been the subject of intensive study because of their importance in commerce. Their biological role to supply energy and structural components to the developing plant embryo has not been neglected, and it has generally been assumed that the small concentrations of triacylglycerols in lipid droplets in vegetative tissues serve a similar purpose. However, a new review suggests that the latter may have many more dynamic functions (Yang, Y. and Benning, C. Functions of triacylglycerols during plant development and stress. Curr. Opinion Biotechn., 49, 191-198 (2018);  DOI). The authors discuss how triacylglycerol metabolism is involved in cell division and expansion, stomatal opening, and membrane lipid remodeling, while in reproductive tissues, they are important for organ formation and successful pollination.

In most plants and algae under phosphate deprivation, phosphatidylcholine in membranes is exchanged for digalactosyldiacylglycerols and/or betaine lipids. However, in a model marine diatom, it is replaced in part by a diglycosylceramide, suggesting that sphingolipids may be more important in these organisms than has been believed hitherto (Hunter, J.E. et al. Lipidomics of Thalassiosira pseudonana under phosphorus stress reveal underlying phospholipid substitution dynamics and novel diglycosylceramide substitutes. Appl. Environm. Microbiol., 84, UNSP e02034-17 (2018);  DOI).

Staying on a botanical theme, several correspondents have admired the Scottish thistles that adorn these web pages. My intention is merely to provide something appropriate, decorative and not too intrusive to brighten large areas of text and not simply to illuminate my origins. In fact, it does not always do to cast light on your ancestry as a family legend has it that about six generations back, an ancestor of mine was hung for piracy in Cornwall. We are quite proud of having a pirate in the family, but it is worrisome that he may have been an Englishman.

March 28th, 2018

Scottish thistleEarly in my career, an ozone generator was essential equipment in all major chemistry laboratories. They were bulky and expensive pieces of kit that had to reside in fume hood for safety reasons - partly because of the toxic nature of ozone and partly because there was a risk of explosions. The main application in lipid chemistry was for oxidation of double bonds as a means of determining their positions in fatty acyl chains. This seems to be still an important technique, except that it is now applied to intact lipids prior to analysis by mass spectrometry. A new publication shows that rather than using a purpose-built generator for the purpose, it is possible to carry out the reaction simply using a UV lamp and dissolved oxygen (Stinson, C.A. et al. UV lamp as a facile ozone source for structural analysis of unsaturated lipids via electrospray ionization-mass spectrometry. J. Am. Soc. Mass Spectrom., 29, 481-489 (2018);  DOI). I enjoy seeing clever thinking of this kind, although I have never really been convinced of the need for this and related methodologies other than when sample size is truly limiting. If this is not the case, it is much simpler and much better resolution is possible when the structures of fatty acids are determined separately by GC-MS using the methods described in my mass spectrometry pages.

Perhaps it is my Scottish Calvinistic heritage, but readers of this blog may have noticed that I enjoy freebies in the form of open access publications. The latest to reach my computer deals with ether lipids (Dean, J.M. and Lodhi, I.J. Structural and functional roles of ether lipids. Protein Cell, 9, 196-206 (2018);  DOI). In addition to its virtue of being open access, this is a useful and readable account of the subject. Incidentally, I now know that the term “plasmalogens” comes from the discovery back in 1924 that acid staining of tissues released aldehydes in the cytoplasm, although the origin of these was not then known. The same journal issue contains a further open access article dealing with carboxylesterases in lipid metabolism.

March 21st, 2018

In recent years, any number of review publications have appeared on the subject of lipidomics, many dealing with technical aspects, others with applications to mammalian lipids and then often to various disease states. I have cited most of these in my literature survey pages on this website, and I have read them with great interest. However, a new review has caught my eye that is somewhat different from the others (Řezanka, T. et al. Lipidomic analysis: from archaea to mammals. Lipids, 53, 5-25 (2018);  DOI). Only one page is devoted to animal lipidomics and the rest to the many fascinating lipids that have been found in archaebacteria, bacteria, yeast, fungi, algae and plants thanks to the new technology. Incidentally, I note that the authors cite my web page on lipid definitions and nomenclature, which you can read here.., as well as my more extensive discussion of what constitutes a lipid - A Lipid Primer. These express my personal opinions, which some may find idiosyncratic.

I am grateful to a friend who made available to me a new review on protein-lipid modifications (Jiang, H. et al. Protein lipidation: occurrence, mechanisms, biological functions, and enabling technologies. Chem. Rev., 118, 43-112 (2018);  DOI). I can't imagine a more substantial review on the subject and it has been a great help in updating my web page on proteolipids. Returning to the subject of lipid nomenclature, I suggest in this web page that that the term 'proteolipid', which was used in the first paper on the topic in 1971, should be used for those molecules in which the two components are linked covalently, while the term 'lipoprotein' should be reserved for the relatively loose protein-lipid complexes of plasma. Unfortunately, the latter term is also used and almost universally for the covalent lipid-protein complexes present in bacteria.

March 14th, 2018

Following on from my discussion of 16:1 isomers in my last blog, a new review of the biological effects of palmitoleic acid (9-16:1), sometimes termed a lipokine, has been published (de Souza, C.O. et al. Is palmitoleic acid a plausible nonpharmacological strategy to prevent or control chronic metabolic and inflammatory disorders? Mol. Nutr. Food Res., 62, 1700504 (2018);  DOI). After a thorough review of the evidence, the answer to the question posed in the title seems to be that we do not yet know, although the results with animal studies are promising, and that further human-based research is required. This publication and those for the next two topics are open access.

I also mentioned the essential fatty acids last week, and a new review discusses the evolutionary significance of the biosynthesis of linoleate in primitive invertebrates, including some species of insects, nematodes and pulmonates (air-breathing slugs and snails) (Malcicka, M. et al. An evolutionary perspective on linoleic acid synthesis in animals. Evol. Biol., 45, 15-26 (2018);  DOI). It appears that there is no consistent lineage in the occurrence of the ability to produce linoleate, not even within any given family, and that this ability was lost and repeatedly gained during the evolution of distinct invertebrate groups. One key factor may have been the development of bifunctionality in desaturase enzymes (Δ12/Δ15). Much of the information was new to me, and my first thought was for endosymbiont-mediated linoleate synthesis, but it seems that no examples of this have yet been discovered. Of course, much of the discussion is of necessity speculative, but the paper is certainly thought-provoking.

I suppose that few of us have given much thought to the function of butyric acid in animal metabolism. From my years in an animal research institute, I was well aware of its importance in the metabolism of ruminant animals, and of course it is an important component of the triacylglycerols of cow's milk, where it is located specifically in position sn-3. However, it is also produced in significant amounts by microbial fermentation of dietary fibers in the lower intestinal tract of all animals, and a new review describes its many functions within the tissues of the host animal (Liu, H. et al. Butyrate: a double-edged sword for health? Adv. Nutr., 9, 21-29 (2018);  DOI).

While I am on the subject of bioactive fatty acids, the first report of the occurrence of resolvins in a non-mammalian tissue (marine diatoms) has just appeared (Rettner, J. et al. Survey of the C20 and C22 oxylipin family in marine diatoms. Tetrahedron Letts., 59, 828-831 (2018);  DOI).

March 7th, 2018

The essential nature of linoleic acid in the diet was first reported in 1929 by George and Mildred Burr, although it was many years before this was recognized by the scientific community at large. It was much later in the last century before many other vital functions of specific fatty acids were recognized, for example palmitic and myristic acids as covalent conjugates with proteins to target them to membranes or octanoic acid that is required for grehlin activation. Three 16:1 isomers are known in human tissues with double bonds in the 6, 7 and 9 positions. Of these, 9-16:1 or palmitoleate is best known and has been termed a 'lipokine', i.e. it is an adipose tissue-derived hormone, which amongst other effects stimulates the action of insulin in muscle; it is linked very specifically to a conserved serine residue in the Wtn family of proteins (O-acylated proteolipids) involved in adipose tissue development, and it is essential for their function. 7-16:1 has some biological functions in common with 9-16:1, and it is regarded as an anti-inflammatory molecule, while 6-16:1 or sapienic acid is found mainly in human skin and has biocidal properties. Now all three isomers have been detected in macrophages both from mice and humans (Astudillo, A.M. et al. Occurrence and biological activity of palmitoleic acid isomers in phagocytic cells. J. Lipid Res., 59, 237-249 (2018);  DOI)). However, in contrast to the other two isomers, the levels of 6-16:1 were not regulated by the activation state of the cell, and it appears that we do not yet know its function in these cells. Incidentally, it seems that the trivial name 'sapienic' from Homo sapiens is now a misnomer as it is now shown to be present in mice - brings to mind the John Steinbeck novel - "Of Mice and Men" (I may be showing my age again).

I can recommend an authoritative review of sphingolipid biosynthesis and function that has just been published (Hannun, Y.A. and Obeid, L.M. Sphingolipids and their metabolism in physiology and disease. Nature Rev. Mol. Cell Biol., 19, 175-191 (2018);  DOI).

February 28th, 2018

Scottish thistleWhen I do my weekly literature search, I have to scan lists of around 400 references to select those that are useful to me or should appear in my literature survey section, and then transfer them to my data base in an appropriate format. I can only spare about 20 minutes for the selection phase and I have to rely on the clarity of the titles, so inevitably I miss some important papers; also, the search algorithm I use is less than perfect. I am therefore grateful when correspondents point out items that I have missed. For example, two publications from 2016 dealing with novel methodology for the determination of trans fatty acids involving gas chromatography-vacuum ultraviolet spectroscopy have just been drawn to my attention, and they are listed in my current monthly analysis list (and will appear subsequently in that for 2016).

The Lipid Maps "Lipid Of the month" for February (see their home page) was another novelty for me, i.e. the elovanoids - C32 and C34 analogues of the protectins, which have been found in retinal cells. I presumably missed these because my weekly search did not contain suitable key words. Again, I have gone back to the Web of Science, to recover the relevant references which are now in my new monthly list for "Lipid essentials". What intrigued me especially, when I read the original papers was the fact that the protectins per se are derived from DHA in position sn-2 of phospholipids, while the precursors of the elovanoids are in position sn-1. This implies that the enzymes involved in the release of the two classes of fatty acid substrates are very different and so must be the stimulatory and regulatory mechanisms. There is a comparable difference for eicosanoid and anandamide biosynthesis; the arachidonic acid for the former comes from position sn-2 of phospholipids, while that for the latter comes from position sn-1.

This brings me back to an old theme of mine that in the world of lipidomics positional distributions are not given sufficient weight in comparison to molecular species analyses. I am sure that positional distributions obtained by mass spectrometry offer nothing near the precision of the older methods using selective lipases, but I would like to see an experimental comparison.

February 21st, 2018

As I have mentioned from time to time in this blog, I am an armchair analyst these days so I am reluctant to endorse what seems novel methodology. I do read and I can comment, however, and others can correct me if they wish. For example, a major problem with HPLC of all polar lipids has always been adsorption on columns. It is usually necessary to add ionic species to the mobile phase to get sharp peaks, and these can cause detection problems or degrade stationary phases. I never attempted to analyse CoA esters in my research days, but I am aware of some of the technical difficulties and I found a new publication had some interesting ideas to eliminate adsorption effects (Abranko et al. Comprehensive quantitative analysis of fatty-acyl-Coenzyme A species in biological samples by ultra-high performance liquid chromatography-tandem mass spectrometry harmonizing hydrophilic interaction and reversed phase chromatography. J. Chromatogr. A, 1534, 111-122 (2018);   DOI); the paper is open access. The authors tested various ammonium salts in the mobile phase and found that ammonium bicarbonate (10 mM adjusted to pH 8.5) was much the best over the whole range of chain-lengths, aided appreciably by the incorporation of a 0.1% phosphoric acid wash step between injections. Of course, the nature of the stationary phase is also important, and I have complained in the blog from time to time of the use of the term 'HILIC chromatography', which tells us nothing about the mode of interaction with analytes, adsorption, ion-exchange, etc. In this work, a Waters BEH HILIC column was used in part; it took me an age to find what 'BEH' implied, although I am little further forward in my understanding.

An interesting article by a young scientist was published in the Guardian newspaper last week complaining about the inappropriate use of metrics to evaluate scientific research. During much of my career, the pressures were different and I did not have to pay too much attention to this aspect of publication; my usual philosophy in selecting a particular journal for a new publication was whether it would reach the intended audience. The important objective was to see that any new information I had uncovered was disseminated - not how. It is a different world now and I recognize that young scientists starting on their careers face real difficulties. Many of the best papers I read have multiple authors (often into double figures) because multiple technologies and expertise may be required to provide answers. At the start of their careers, scientists working on their own can only hope to make incremental progress in their chosen fields, and I would hope that this would be recognized by scientific administrators. In my later years of research, my pet hate was projected 'milestones' - if I knew where the results were going to lead 2-3 years ahead, the work was not worth doing.

What really worries me now having just reviewed the above comments, is that I am beginning to sound like my father (no disrespect intended) in his later years - "when I was a boy, etc., etc.!" It is bad enough that I now look like he did. I will have to try to resurrect the youthful inner me.

February 14th, 2018

In plants,glycerolipid biosynthesis in chloroplasts has long been termed the "prokaryotic pathway", and it produces galactosyldiacylglycerols and phosphatidylglycerol with C18 acids in position sn-1 and C16 acids in position sn-2. This pattern is seen in cyanobacteria and it has been assumed that the similarity was a consequence of endosymbiosis during evolution. A new study demonstrates that this is not true (Sato, N. and Awai, K. "Prokaryotic Pathway" is not prokaryotic: noncyanobacterial origin of the chloroplast lipid biosynthetic pathway revealed by comprehensive phylogenomic analysis. Genome Biol. Evolution, 9, 3162-3178 (2017);  DOI); the paper is open access. It is now evident that the two steps of acylation in cyanobacteria and chloroplasts utilize enzymes that have no phylogenetic relationship. The structural differences in the diacylglycerol moieties of galactolipids from various species of algae and higher plants originate in fact in compartmentalization of the biosynthetic pathways or precursors in cells, especially between the chloroplasts and endoplasmic reticulum, each compartment having its own distinctive enzymes with characteristic specificities (see my web page on galactosyldiacylglycerols for further discussion).

My prize for the most unusual new lipid that I have encountered this year so far goes to a novel arsenolipid. The unicellular marine alga Dunaliella tertiolecta contains phytyl 5‑dimethylarsinoyl-2-O-methyl-ribofuranoside as 35 to 65% of the total arsenolipids. Apart from its arsenic content, this lipid is unique in containing both an ether-linked phytyl group and a 2‑O‑methylriboside of a type normally found only in RNA. (Glabonjat, R.A. et al. A 2-O-methylriboside unknown outside the RNA world contains arsenic. Angew. Chem.-Int. Ed., 56, 11963–11965 (2017);  DOI.

Formula of phytyl 5-dimethylarsinoyl-2-O-methyl-ribofuranoside

There is an interesting article in Nature on the importance of scientific blogs. Regretfully, they missed this one!

February 7th, 2018

In my blog of two weeks ago, I discussed the therapeutic potential of nitro fatty acids and in particular how subcutaneous injection of nitro-oleic acid suppressed allergic contact dermatitis in mice. Alas, a new publication from the same research group reports that topical applications have the opposite effect (Mathers, A.R. et al. Topical electrophilic nitro-fatty acids potentiate cutaneous inflammation. Free Rad. Biol. Med., 115, 31-42 (2018);  DOI). The problem appears to lie in the finding that nitro-conjugated linoleate is formed naturally "in the skin microenvironment as products of cutaneous inflammatory responses and, in high local concentrations, may exacerbate inflammatory skin diseases".

I couldn't have put better the philosophy implied in the title to an editorial contribution to a Nature journal (Marx, V. Fats add structure, they signal, they interact. In the lab, lipids are tough to work with but worth the challenge. Nature Methods, 15, 35-38 (2018);  DOI).

I always enjoy reading the personal reminiscences of lipid scientists and that by Dennis E. Vance was no exception, and it has a title that recalls my previous paragraph (From masochistic enzymology to mechanistic physiology and disease. J. Biol. Chem., 292, 17169-17177 (2017);  DOI). However, it also served to remind me that a new edition of one of the most valued books in my personal library was now available, but with new editors (Ridgway, N.D. and McLeod, R.S. Biochemistry of Lipids, Lipoproteins and Membranes, 6th Edition. (Elsevier, Amsterdam) (2016) - see Science Direct) - and prompted recourse to Amazon. It covers much the same range of topics as in previous editions, but often with replacement authors, and I expect to make good use of it. As expected with modern textbooks it is very well produced from a technical standpoint. Comparison with the book by Gurr et al. (Lipids: Biochemistry, Biotechnology and Health, 6th Edition), which I reviewed some months ago is probably unfair, as they probably aim at different audiences. My superficial first impression is that the new book goes into the subjects in greater depth but the coverage is not so exhaustive. For example, it was of great help to me in updating my web page on proteolipids, but there is no mention of "endocannabinoids" or "lipid sulfates" in the index.

January 31st, 2018

Scottish thistleIt has been a puzzle to me how the endocannabinoids, anandamide and 2-arachidonoylglycerol, can have so many different functions in a given tissue while operating through a single G protein receptor. A new review illustrates how this happens using brain as the model (Busquets-Garcia, A. et al. CB1 receptor signaling in the brain: extracting specificity from ubiquity. Neuropsychopharmacology, 43, 4-20 (2018);  DOI). It seems that endocannabinoid receptors exert their wide variety of different cellular effects by specific interactions with many other G proteins and that this is dependent on such factors as cell type, subcellular location and cellular functional state. Within a given tissue, expression of a receptor can vary between different locations. For example, in brain some types of neuron contain very high levels of CB1 receptor protein, whereas others have much lower levels; there are even lower levels in some regions of the hypothalamus and astroglial cells. In turn, variation in the location of CB1-interacting proteins may have a role in the cell-specific modulation of endocannabinoid signalling. This paper is part of a special issues on "Cannabinoids and endocannabinoids" and the only one to be open access. However, most of the other contributions appear to be more suitable for specialists.

The number of different molecular species of lipids in a given cell is astonishing (at least 1,000). Yet it is surprising how often only a single molecular species of a given lipid is required for optimum activity in a specific function. Cardiolipin in heart muscle is a prime example. If it had say 10 different fatty acid components, as is usual in most glycerolipids, together with the four different positions for acylation, there could in theory be 104 different molecular species. Instead, as is well known, linoleic acid is by far the most abundant fatty acid (as much as 80%) and the tetralinoleoyl species amounts to at least half the total. Many have speculated as to why this should be so, but a new publication demonstrates that if linoleate is displaced by docosahexaenoate in mitochondrial cardiolipin in the rat then the enzyme activities of the respiratory complexes are greatly reduced, apparently by preventing the formation of phospholipid domains that regulate enzyme activity (Sullivan, E.M. et al. Docosahexaenoic acid lowers cardiac mitochondrial enzyme activity by replacing linoleic acid in the phospholipidome. J. Biol. Chem., 293, 466-483 (2013);  DOI). I wonder what would be the result if they tried to displace linoleate with palmitate as this is the most abundant fatty acid in testis cardiolipin and has a much less mobile conformation than DHA.

January 24th, 2018

Nitro fatty acids are fascinating 21st Century molecules with important anti-inflammatory properties (they were first recognized as natural lipid components in 1999). In tissues, they occur in the free form, bound reversibly to thiol-containing proteins and glutathione, and as esters in triacylglycerols and phospholipids. In human serum in addition to non-covalent binding with albumin, nitro-conjugated linoleic acid has been shown to form covalent adducts at Cys-34 (Michael reaction), suggesting that this may be a means of systemic distribution. The effective concentrations of nitro fatty acids in tissues are reduced by this means, but a mechanism for the reversal of the reaction has been revealed under conditions of oxidative stress in vitro in plants at least. Reactive oxygen and nitrogen species, as represented by hydrogen peroxide and peroxynitrite, respectively, have the ability to oxidize cysteine-adducted nitro fatty acids with the release of free nitroalkenes, which can presumably then exert their anti-inflammatory effects (Padilla, M.N. et al. In vitro nitro-fatty acid release from Cys-NO2-fatty acid adducts under nitro-oxidative conditions. Nitric Oxide, Biol. Chem., 68, 14-22 (2017); DOI). Incidentally, nitro fatty acids are present in olives and virgin olive oil at concentrations that may be significant biologically, and it has been argued that they could be one reason for the beneficial effects of the Mediterranean diet. Their clinical potential is under active investigation, for example to inhibit cutaneous inflammation (Mathers, A.R. et al. Electrophilic nitro-fatty acids suppress allergic contact dermatitis in mice. Allergy, 72, 656-664 (2017); DOI).

The concept of lipid rafts in membranes, i.e. laterally segregated domains usually enriched in sphingolipids and cholesterol that provide platforms for signalling proteins, is now well established in the scientific literature. The terms termed 'membrane rafts', 'nanodomains' and 'microdomains' tend to be used interchangeably, but a new review suggests that in plants at least, different types of domain exist with differing compositions and functions so more precise definitions are required (Ott, T. Membrane nanodomains and microdomains in plant-microbe interactions. Curr. Opinion Plant. Biol., 40, 82-88 (2017); DOI).

Two substantial review articles deal with the methodology of lipidomics (Rustam, Y.H. and Reid, G.E. Analytical challenges and recent advances in mass spectrometry based lipidomics. Anal. Chem., 90, 374-397 (2018); DOI. And - Hu, T. and Zhang, J.L. Mass-spectrometry-based lipidomics. J. Sep. Sci., 41, 351-372 (2018); DOI). The second of these is open access.

January 17th, 2018

In recent years, I have written to several journals, most recently two months ago, to point out major errors in the interpretation of mass spectra in published papers. On most occasions, the journal has replied promptly and has promised to publish a correction - I still have to see one. Usually, the problem lies in computerized identification of methyl esters of fatty acids, as computers don't recognize that they cannot distinguish between positional and geometrical isomers of monoenoic or dienoic fatty acids, but often the authors (and reviewers) have simply not done their homework. One example, was a report of iso-methyl branched fatty acids in higher plants on the basis of a large ion equivalent to m/z = M-43; it has been known since the 1950s that this is common to mass spectra of all straight-chain fatty acids as a result of a complex rearrangement involving expulsion of carbons 2 to 4.

Problems also arise with interpretation of mass spectra of dimethyloxazoline derivatives of fatty acids. The first authors described a simple rule for how to locate double bonds. However, lacking appropriate standards, they were not aware that the rule did not apply when the double bonds were close to either end of the molecule. In addition, 3-isomers isomerize to 2-isomers on derivatization. The answer is to compare with authentic spectra, such as those on this website. Unfortunately, in spite of my best efforts, there are many flawed publications out there.

The ISI Web of Science seems to be just catching up after the holiday, and my weekly literature seach has given me three special review volumes to digest. I will list selected individual papers in my next literature update, but many of you will wish to consult the original journals for the full list. The December issue of Current Opinion in Plant Biology (Volume 40, Pages 1-168 (2017)) is devoted to the topic of "Cell biology: Membrane dynamics - being at the right place at the right time" (edited by Eugenia Russinova and Karin Schumacher) and includes a number of reviews of interest to plant lipid biochemists. The open access journal Antioxidants (Volume 6, issue 4 (2017)) contains three review articles dealing with tocopherols, including their biosynthesis in plants and their metabolism in humans. The journal Prostaglandins & Other Lipid Mediators (Volume 133, November (2017)) is a special issue from the "6th European Workshop on Lipid Mediators" (edited by Bannenberg, G. et al.) with a number of review articles on polyunsaturated fatty acids and oxylipins (eicosanoids and docosanoids).

January 10th, 2018

Although the most important aspect of any new publication is its content, the manner of presentation can make a big difference to how well the message gets across. Text books have lead the way in this regard, but the ability to use colour in diagrams now afforded by many journals has been a considerable step forward, and as more journals go online only I am sure that this facility will be used increasingly. I am also rather envious of those authors who have access to design departments who produce figures and diagrams that are works of art. One new article that meets all these quality criteria deals with phosphoinositides (Choy, C.H. et al. Phosphoinositide diversity, distribution, and effector function: stepping out of the box. Bioessays, 39, 1700121 (2017); DOI). I found this review to be of considerable value in updating my web page here on the topic.

Some years ago, I was rather pleased with myself when my cholesterol level was measured and found to be in the bottom quartile for my age group, but a friend brought me down to earth by telling me that all this meant was that rather than having a heart attack I would probably die of cancer. The editors' selection (and therefore open access) in the latest issue of JBC explains how two isoforms of phospholipase A regulate the nature of the eicosanoids produced during a heart attack and thence the damage done. In non-failing human hearts, one isoform channels arachidonic acid into protective epoxyeicosatrienoic acids (EETs), whereas in failing hearts, activation of a second isoform channels arachidonic acid into toxic hydroxyeicosatetraenoic acids (HETEs) (Moon, S.H. et al. Heart failure-induced activation of phospholipase iPLA2γ generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore. J. Biol. Chem., 293, 115-129 (2018); DOI). One way or another your lipids probably get you in the end!

January 3rd, 2018

As a New Year gift to lipid analysts, I draw your attention to a 72 page open access publication reviewing NMR spectroscopy (1H, 13C and 31P) of lipids (Alexandri, E. et al. High resolution NMR spectroscopy as a structural and analytical tool for unsaturated lipids in solution. Molecules, 22, 1663 (2017); DOI). It is a large file at 34Mb, so you may need a fast broadband connection.

The lipid A (endotoxin) component of bacterial lipopolysaccharides is a fascinating complex molecule that serves to protect the organism from attack from external agencies, including antibiotics, but is a major reason for the virulence of pathogenic bacteria. Many factors are involved, including the number and nature of the fatty acid constituents, but the general mechanism of the immune response is usually considered to be a binding to a large hydrophobic pocket in a receptor such as toll-like receptor 4 (TLR4) via the lipid chains, while the phosphate groups can interact directly with the receptor leading to formation of a heterodimer complex that is active in immune signalling. However, a new publication demonstrates that the TLR4 receptor does not recognize the endotoxin of a rather nasty pathogen, Francisella novicida, which is thus able to evade the host innate immune system. Instead, this stimulates the cyclooxygenase-2-dependent inflammatory pathway and is responsible for the lethality of such infections through overproduction of proinflammatory effectors such as prostaglandin E2 (Scott, A.J. et al. Host-based lipid inflammation drives pathogenesis in Francisella infection. PNAS, 114, 12596-12601 (2017); DOI).

The regulation of cholesterol levels in animal tissues is a complicated topic involving innumerable factors, and I struggle to come to grips with it. One novel feature that has just come to light is that the first 100 amino acid in a key enzyme in cholesterol biosynthesis, i.e. squalene monooxygenase, is a proteasomal degradation signal or 'degron'. This sequence attaches reversibly to the ER membrane, and in the presence of excessive cholesterol levels, it is ejected and unravels to expose a hydrophobic patch, which then says "eat me" (Chua, N.K. et al. A conserved degron containing an amphipathic helix regulates the cholesterol-mediated turnover of human squalene monooxygenase, a rate-limiting enzyme in cholesterol synthesis. J. Biol. Chem., 292, 19959-19973 (2017); DOI).


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Author: William W. Christie Updated: June 20th, 2018 Credits/disclaimer LipidWeb logo