The LipidWeb blank

Lipid Matters - Archive of Older Blogs - 2019

This Blog is an occasional series of notes on publications or other items dealing with lipid science that seem to be of particular interest to the editor Bill Christie. Inevitably, the selection is highly personal and subjective. In this web page, the blogs for 2019 are archived, while those for other years can be accessed from the foot of the current blog page.

December 30th, 2019

Scottish thistleLipids are essential components of bacterial cell walls. If we are to defeat pathogenic Gram-negative bacteria, we must understand how their anatomy (for want of a better word) and how it functions. I imagine that most microbiologists are familiar with the nature of the cell envelope, but I was ignorant of it until I decided that my Lipid Essentials section would be incomplete without a web page on lipid A. In fact, the cell wall consists of two bilayer membranes, separated by an aqueous phase, the periplasm, which contains a layer of peptidoglycan molecules. Lipid A is a multi-acylated disaccharide that serves to anchor a complex polysaccharide component to the outer leaflet of the outer membrane, so that the latter acts as an interface or barrier to the environment including the immune system of host animals including us. One of the most interesting aspects of the biochemistry is how the organism manages to construct and then transport such a large amphiphilic molecule across two bilayer membranes plus an aqueous phase and insert it correctly into the outer membrane. The answer is that it uses a kind of protein bridge made up of seven distinct proteins. A new review describes this in some detail but illustrates it with a superb diagrammatic representation, which greatly clarified the process for me (Sperandeo, P. et al. The Lpt ABC transporter for lipopolysaccharide export to the cell surface. Res. Microbiol., 170, 17981-17990 (2019);  DOI). I am envious of modern authors who have access to such artistic abilities.

The cell envelope of Mycobacterium tuberculosis is even more complex and includes a range of unique lipids that include mycolic acids, sulfoglycolipids, lipoarabinomannans and phosphatidylinositol mannosides. According to a new review, it has a sneaky habit of changing to accommodate different conditions, i.e. "to manipulate the human immune system, tolerate antibiotic treatment and adapt to the variable host environment" (Dulberger, C.L. et al. The mycobacterial cell envelope - a moving target. Nature Rev. Microbiol., 18, 47-59 (2020);  DOI). Again, this has a superb diagrammatic illustration of the cell wall that greatly aided my understanding.

December 18th, 2019

Every year at this time, I look over the LipidWeb to try to work out which areas have seen the most changes over the year as assessed by my log of daily updates, especially in the Lipid Essentials section. Often, the web pages on phosphatidylinositol and sphingosine-1-phosphate appear to be the most dynamic, and again both have been prominent in this regard but not as much as in past years. The clear winner this year as last has been my web page on mono-oxygenated eicosanoids (HETE), closely followed by the pages dealing with prostaglandins, and those of some of the other oxylipins. In comparison to previous years, I suspect that if I could break down these updates further across the relevant web pages, a much higher proportion would have been concerned with esterified oxylipins in relation both to signalling and lipoxidation reactions (for which two major review volumes have been published), as opposed to those in unesterified form. Indeed, my web page dealing with Bioactive aldehydes and oxidized phospholipids has probably seen the most substantial updates (and I am still working on it). As to other lipid classes, web pages on proteolipids and lipoproteins have seen numerous updates, but my sphingolipid pages do not seem to have developed as quickly as in past years, especially those dealing with the more complex glycosphingolipids. These comments always come with the caveat that the literature surveys on which my updates are based are highly subjective. I try to take a broad view, but my personal interests always emerge.

Formula of N-palmitoyl-O-phosphocholineserineMy selection for the novel lipid of the year is N-palmitoyl-O-phosphocholineserine (the most abundant species in its class), which has been found in patients with the genetic disorder Niemann-Pick disease type C1 (DOI) and was highlighted in one of my July blogs. A second group has now confirmed the structure (DOI - open access).

May I wish all my readers a very happy Christmas and good health and happiness in the New Year!

December 11th, 2019

Since the discovery of prostaglandins, thousands of papers have appeared on the chemistry and biochemistry of eicosanoids and docosanoids, but relatively few on the octadecanoids (C18), i.e. the oxylipins derived from linoleic acid. Yet octadecanoids (HODE) are reported to be the most abundant oxylipins in human plasma. Now, a new report suggests that they are also the main components of the oxylipins in the brains of rat pups (Hennebelle, M. et al. Linoleic acid-derived metabolites constitute the majority of oxylipins in the rat pup brain and stimulate axonal growth in primary rat cortical neuron-glia co-cultures in a sex-dependent manner. J. Neurochem., in press (2019);  DOI). 13S-HODE in particular increased axonal outgrowth cortical neurons in male rat pups significantly, but not in female pups where linoleic acid per se displayed this activity. These data contrast with many more negative reports of the biological activities of octadecanoids, which may for example be inflammatory and atherogenic through the induction of pro-inflammatory cytokines.

α-Linolenic acid tends to be of low abundance in animal tissues and I have not been able to find anything in the literature on the occurrence of oxylipins derived from this precursor in animals. I guess the best place to look for them would be in vegans, or better in non-ruminant herbivores such as the horse. My understanding is that linoleic acid is now regarded as an essential fatty acid in its own right, not simply as a precursor of arachidonic acid and eicosanoids, because of its vital functions in skin lipids as well as its conversion to bioactive oxylipins. In contrast, α-linolenic acid may only be essential for conversion to EPA and DHA and their metabolites.

Last week, I discussed briefly the therapeutic properties of bile acids. This week, a new review discusses their potential role as anticancer drugs (Goossens, J.F. and Bailly, C. Ursodeoxycholic acid and cancer: From chemoprevention to chemotherapy. Pharmacol. Therapeut., 203, 107396 (2019);  DOI). Paradoxically, ursodeoxycholic acid inhibits apoptosis in epithelial cells while promoting it in cancer cells.

December 4th, 2019

For much of my research career, I have been hearing about how bad lipids are for health - total fat intake, saturated fats, trans-fatty acids, cholesterol and so forth - are all anathema to nutritionists. This is perhaps why I am always fascinated now to learn of the therapeutic applications of specific lipids. As a non-subscriber, it will be a year before I can read anything other than the abstract, but a new publication from Serhan's group suggests that a resolvin may be of value in the treatment of deep vein thrombosis (Cherpokova, D. et al. Resolvin D4 attenuates the severity of pathological thrombosis in mice. Blood, 134, 1458-1468 (2019);  DOI). It is reported that this specialized pro-resolving mediator not only has a direct effect by significantly reducing the thrombus burden, but it also promotes "the biosynthesis of other D-series resolvins involved in facilitating resolution of inflammation".

For 160 years after the discovery of cholic acid in 1838, bile acids were considered to be simply a form of detergent that functioned to solubilize dietary lipids to facilitate their absorption. That has changed, and there have been a number of useful reviews on their other biological properties in recent years. However, I was attracted by the opening sentence of the abstract of new review, which happily is open access, and to quote - "Of all the novel glucoregulatory molecules discovered in the past 20 years, bile acids are notable for the fact that they were hiding in plain sight" (Ahmad, T.R. and Haeusler, R.A. Bile acids in glucose metabolism and insulin signalling - mechanisms and research needs. Nature Rev. Endocrin., 15, 701-712 (2019);  DOI). Now they are known to act through the nuclear receptor FXR and many others, and to have appreciable therapeutic potential. In fact, the hydrophilic secondary bile acid ursodeoxycholic acid (3α,7β-dihydroxy-5β-cholan-24-oic acid) and its taurine conjugate are already used clinically for cholesterol gallstone dissolution and in the treatment of primary biliary cirrhosis. This particular review concentrates on the manner in which bile acids regulate glucose homeostasis. Incidentally, I was intrigued to read in the review that bile acids are important for the biosynthesis of anandamide and other bioactive amides.

November 27th, 2019

Scottish thistleThe journal Free Radical Biology & Medicine has devoted a special issue to the topic of "Redox lipidomics and adductomics - Advanced analytical strategies to study oxidized lipids and lipid-protein adducts" with more than 300 pages of articles. The editors have contributed a useful commentary, which is open access, with this title (Cruciani, G. et al. Free Rad. Biol. Med., 144, 1-5 (2019);  DOI). I have only had time to read of few of these, but my eye was drawn to a short series of papers on the sub-topic of "Advances in analysis of nitrated lipids". Nitro fatty acids are produced while in esterified form in lipids, but it is the unesterified acids that have attracted most of the attention, as they are believed to be important mediators in physiopathological processes such as inflammation. Research seems to be an early stage and mainly with model systems in vitro, but it would be not at all surprising if, after nitration, intact lipids were found to have significant biological activities as is now recognized for oxidized phospholipids. "Adductomics" is a new word for my omics collection.

Text books tend to discuss autoxidation as a product of two reactions, the Haber-Weiss and Fenton reactions. However, it appears that in terms of living systems at least, the Haber-Weiss reaction can be discounted as negligible, and I have to confess that I was in error in over emphasizing its importance in my web page on isoprostanes (see - Filipovic, M.R. and Koppenol, W.H. The Haber-Weiss reaction - The latest revival. Free Rad. Biol. Med., 145, 221-222 (2019);  DOI). Although I have now made an appropriate correction, I should have been aware of this earlier.

November 20th, 2019

Lipid A is the glycolipid component that serves as the anchor for the lipopolysaccharides that make up a large part of the external cell walls of Gram-negative bacteria, including a great number of human pathogens. Unfortunately for us, once inside a human host, lipid A is recognized as a pathogen-associated molecule by many different receptors on immune cells and stimulates a robust inflammatory response, which can cause tissue damage and in the worst scenario septic shock and death of the host. However, some bacteria produce lipid A forms that act as antagonists to the toxic molecules, and it is apparent that the gut microbiome may be a good source of these (Di Lorenzo, F. et al. Lipopolysaccharide structures of Gram-negative populations in the gut microbiota and effects on host interactions. FEMS Microbiol. Rev., 43, 257-272 (2019);   DOI). The immune system must be able "to distinguish the beneficial microbes from the pathogens, even if the commensal bacteria have molecular patterns resembling those of the pathogenic counterparts." Hopefully, a better understanding of the molecular mechanisms involved in these interactions will lead to a new approach to the treatment of bacterial infections.

The gut microbiome is now known to be the source of a further health-promoting lipid, i.e. α-galactosylceramide (normally present in tissues with a β-anomeric linkage), which activates invariant natural killer T cells with benefits against viral as well as bacterial infections (see a research publication and commentary in the November issue of the Journal of Lipid Research, for example). Perhaps I am naive, but I hope that such findings for these lipid classes could be utilized to produce nutraceuticals containing appropriate bacteria that are analogous to those containing Lactobacillus casei and are already available commercially. Anything that reduces the demand for antibiotics must be good.

November 13th, 2019

It is almost an axiom among nutritionists that dietary palmitic acid is bad for you, and I can even remember a newspaper headline 30 years ago to the effect that palmitic acid was "a poison produced by cows". Palm oil is widely derided in Western countries for its high content of palmitate and for the destruction of so many tropical habitats for palm plantations. Why then should plant biochemists strive to increase the content of palmitic acid in position sn-2 of triacylglycerols in seed oils as described in a new paper (van Erp, H. et al. Engineering the stereoisomeric structure of seed oil to mimic human milk fat. PNAS, 116, 20947-20952 (2019);  DOI). The title of the paper gives the game away, as human milk fat (and that of many other species) has a high content of palmitic acid in position 2. It appears that during digestion in the human infant, 2-palmitoylglycerols are produced that are absorbed in the intestines with relative ease. Infant formulae are now produced by technological means to have this distinctive structure, so the intention is to avoid chemicals in producing milk fat substitutes. On the other hand, I can imagine there will be howls of indignation in some quarters about the use of genetically modified crops for this purpose and the phrase "Frankenstein foods" will be used.

While palmitic acid has many essential functions in animal tissues, not least for the synthesis of sphingoid bases, there seems to be little doubt that dietary palmitic acid in excess is undesirable. In particular, it has inflammatory properties as discussed in a new review (Korbecki, J. and Bajdak-Rusinek, K. The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms. Inflam. Res., 68, 915-932 (2019);  DOI).

November 6th, 2019

From time to time, I enjoy reading a review that challenges accepted dogma, and one such discusses the biosynthesis of polyunsaturated fatty acids of the omega-3 family (Metherel, A.H. and Bazine, R.P. Updates to the n-3 polyunsaturated fatty acid biosynthesis pathway: DHA synthesis rates, tetracosahexaenoic acid and (minimal) retroconversion. Prog. Lipid Res., 76, 101008 (2019);  DOI). The measured rates of DHA biosynthesis in animals are very low, but the authors argue that this cannot be true. Among the authors' explanations are that DHA is used as quickly as it is produced for purposes other than for incorporation into membranes. They also have questions regarding the role of EPA in DHA synthesis and the proposed retroconversion mechanisms, and they point out that DHA is both a product and a precursor to tetracosahexaenoic acid (24:6(n-3)).

The same journal provided further food for thought with an intriguing article on the role of dietary C18 trans fatty acids in heart disease (Valenzuela, C.A. et al. Eighteen-carbon trans fatty acids and inflammation in the context of atherosclerosis. Prog. Lipid Res., 76, 101009 (2019);  DOI). I have always been sceptical of the suggestion that trans fatty acids of industrial origin are harmful, although those in dairy products are not - could it be fear of offending the massive dairy farming lobby? However, the authors accept that differences do indeed exist, which may be related to differences in the composition of the different isomers (and I bow to their superior knowledge). Dairy products have relatively high concentrations of trans-11-18:1 (vaccenic acid) in comparison to products of industrial hydrogenation, and importantly of conjugated linoleic acid (cis-9, trans-11-18:2 or CLA). The latter can also be produced in animal tissues by desaturation of ingested vaccenic acid, as can trans-11,cis-13-18:2. While the authors consider that CLA may be a cause of the perceived differences, one possible mechanism that they do not mention is that CLA is the preferred substrate for the formation of nitro fatty acids, which have pronounced anti-inflammatory effects.

October 30th, 2019

Scottish thistleA recent publication caused me to look up what I had written on lipoxygenase metabolites of eicosapentaenoic acid (EPA or 20:3(n-3)) in my web page here - to find not a word - and I soon found that I was not alone in this regard, as they are not mentioned in several major reviews on the topic, other than that 18-HEPE is a precursor for the E-series resolvins. A quick and relatively superficial survey found several brief mentions in the literature but only a little substantive information. It will be a year before I have access, but the paper that provoked my interest is by Leiria, L.O. et al. (12-Lipoxygenase regulates cold adaptation and glucose metabolism by producing the omega-3 lipid 12-HEPE from brown fat. Cell Metab., 30, 768-783.e7 (2019);  DOI). To quote from the abstract "The cold-induced 12-LOX product 12-HEPE was found to be a batokine that improves glucose metabolism by promoting glucose uptake into adipocytes and skeletal muscle through activation of an insulin-like intracellular signaling pathway".

I have now partially rectified my omissions, but I need to do more work on the topic. For example, it appears that 18-HEPE per se has cardioprotective properties and inhibits metastasis in a cancer model, while 5-HEPE enhances the induction of regulatory T cells (Tregs) that modulate the immune system and prevent autoimmune diseases. Fortuitously, the September issue of the journal International Immunology contains some relevant reviews in an open-access series on the theme of "Lipids in Inflammation". Perhaps surprisingly, I found more in my brief survey on the functions of lipoxygenase metabolites of EPA as plant oxylipins, as they are produced by marine algae as defense compounds against bacteria and other predators.

October 23rd, 2019

It is not at all easy to find data on the composition of cytidine diphosphate diacylglycerol (CDP-DAG) in animal tissues although it is a key intermediate in the biosynthesis of many complex glycerolipids, and I have to list data from a 1976 paper in my contribution on the topic here. I guess that it turns over so quickly that the levels in tissues remain too low to be easily detected by lipidomics methodology. It is relatively uncommon to even find this lipid as the major topic of a research publication. Mitochondria have their own unique CDP-diacylglycerol synthase (translocator assembly and maintenance protein 41 or Tam41), first characterized in yeast, and this is of course a key enzyme in the biosynthesis of cardiolipin with its myriad of essential functions. Although I will have to wait a year to read the paper, the structure of this enzyme has now been published and should help us understand how the enzyme functions (Jiao, H.Z. et al. Structures of the mitochondrial CDP-DAG synthase Tam41 suggest a potential lipid substrate pathway from membrane to the active site. Structure, 27, 1258-1269e4 (2019);  DOI). It appears that a binding pocket for the precursor/product has been identified in the structure, where phosphatidic acid may enter and CDP-DAG may exit, while the C-terminal region is crucial for membrane association.

In considering the metabolism of arachidonic acid and thence of the eicosanoids, one enzyme that has been somewhat neglected is the acyl-coenzyme A synthetase 4, which preferentially converts unesterified arachidonic acid to its CoA ester for incorporation into phospholipids when remodelling occurs. This enzyme is important in the earliest stages that might ultimately lead to the eicosanoid cascade, and a new study describes how it is required to maintain the content of highly unsaturated fatty acids to aid the inflammatory response (Kuwata, H. et al. Long-chain acyl-CoA synthetase 4 participates in the formation of highly unsaturated fatty acid-containing phospholipids in murine macrophages. Biochim. Biophys. Acta, 1864, 1606-1618 (2019);  DOI).

October 16th, 2019

Milk is fascinating stuff as the only animal food designed by evolution for oral consumption by other animals. It is not only nutritious but dairy products taste good. Of course, cow's milk is ideal food for calves, but it has its drawbacks for human nutrition, especially because of the low content of essential fatty acids. I can't comment on the taste of human milk (it is a long time since I was a baby!), but it obviously contains the perfect balance of nutrients for human infants. The lipids from the two sources are very different in composition, and both must be among the most studied of all natural products. However, surprises still occur. Now the emphasis is not on the bulk constituents, but on minor lipids that may be biologically active and perhaps should be added to infant formulae.

The nature of the specialized proresolving mediators in human milk, were the subject of my blog 2-3 years ago. Now a new paper discusses the properties of glycerol monolaurate in milk (Schlievert, P.M. et al. Glycerol monolaurate contributes to the antimicrobial and anti-inflammatory activity of human milk. Sci. Rep., 9, 14550 (2019);  DOI - open access). This lipid occurs at a concentration twenty times greater in milk of humans (3000μg/ml) compared to cows (and not at all in infant formulae) and has antimicrobial activity against a number of common bacteria. A second paper reports the presence of side-chain oxysterols in human milk, i.e. 24-, 25- and 27-hydroxycholesterol, throughout lactation with the last of these especially abundant in colostrum (Civra, A. et al. Antiviral oxysterols are present in human milk at diverse stages of lactation. J. Steroid Biochem. Mol. Biol., 193, 105424 (2019);  DOI). This was shown to be active against the pathogenic human rotavirus and rhinovirus of importance in pediatrics. What next for milk lipids?

October 9th, 2019

Carnivorous plants are fascinating biological oddities to botanists and laymen alike, and I suppose that many of us have wondered how they could have evolved to use insects as a source of nutrients - even plants don't have to be vegans! The answer it seems is to do with their lipids, as the capacity to induce digestive enzymes uses a form of the same signalling machinery as that for plant defence against insect predators, i.e. jasmonates (Pavlovič, A. and Mithöfer, A. Jasmonate signalling in carnivorous plants: copycat of plant defence mechanisms. J. Exp. Botany, 70, 3379-3389 (2019);  DOI). In addition, it appears that jasmonate signalling is connected to the electrical signals that induce plants such as the Venus fly trap to close and trap their prey. There are further valuable review articles on jasmonates in the same journal issue, and if you need a brief introduction I can recommend the editorial to the topic (Farmer, E.E. and Goossens, A. What allene oxide synthase does for plants. J. Exp. Botany, 70, 3373–3378 (2019):  DOI - open access). It is the oddities that fascinate a dilettante such as myself, but jasmonates are fascinating oxylipins with structural similarities to the prostaglandins that are presumably of evolutionary significance.

Up until now, jasmonoyl-L-isoleucine was the only metabolite known to be an endogenous ligand of the jasmonate co-receptor, but it has now been demonstrated that the omega-hydroxy analogue, hitherto thought to be inert, differentially activates a subset of the same receptor complex to modify particular jasmonate-dependent responses to improve plant resilience to stress (Jimenez-Alemana, G.H. et al. Omega hydroxylated JA-Ile is an endogenous bioactive jasmonate that signals through the canonical jasmonate signaling pathway. Biochim. Biophys. Acta, 1864, 158520 (2019);  DOI).

October 2nd, 2019

In all of my research career, I threw away the ganglioside fraction, because it remained in the aqueous rather than the organic component after Folch lipid extraction. However, I am grateful for those who have had the persistence to tackle ganglioside biochemistry and analysis as they are proving to have many vital functions in human metabolism. Increasingly, it has emerged that they can be important factors in the development of cancers, and specific gangliosides can have either positive or negative effects upon the regulation of the malignant properties of cancer cells as described in a recent review (Cavdarli, S. et al. Gangliosides: the double-edge sword of neuro-ectodermal derived tumors. Biomolecules, 9, 311 (2019);  DOI - open access). In regard to the latter, the good news is that antibodies to specific gangliosides are proving to be a useful element in therapy for specific cancers, with some current interest focussed upon O-acetylated GD2 (OAcGD2) in breast cancer. Incidentally, the ganglioside GM3 is elevated in the serum of patients with breast cancer and may be a marker for the disease (Li, Q.Y. et al. Gangliosides profiling in serum of breast cancer patient: GM3 as a potential diagnostic biomarker. Glycoconjugate J., 36, 419-428 (2019);  DOI).

Gangliosides are also involved in the action of interactions between microbes and host cells during infections, and cholera toxin, which is an enterotoxin produced by Vibrio cholerae, is a much studied example. The five B-chains of cholera toxin each bind one molecule of ganglioside GM1 and this enables it to enter cells to exert its dire effects. Now it has been established that the botulinus toxin binds to a complex of a polysialoganglioside with the protein synaptotagmin, which together act as a high-affinity receptor complex to enable the neurotoxic effects (Flores, A. et al. Gangliosides interact with synaptotagmin to form the high-affinity receptor complex for botulinum neurotoxin B. PNAS, 116, 18098-18108 (2019);  DOI). Of course, the better we understand these mechanisms, the more likely are we to be able to counter the ill effects. While these make the news, it should not be forgotten that gangliosides have innumerable beneficial functions.

September 25th, 2019

Scottish thistleThe word "thraustochytrid" hardly trips off the tongue and I must confess that I was unaware of it until a new review appeared (Morabito, C. et al. The lipid metabolism in thraustochytrids. Prog. Lipid Res., 76, 101007 (2019);  DOI). Apparently, they are a group of unicellular marine organisms, which are considered to be non-photosynthetic microalgae (I rapidly got lost trying to understand their phylogeny). They are distinctively metabolically in that they produce a high proportion of their fatty acids as docosahexaenoic acid (DHA), as much as 20-25% of the dry weight, with most of the remainder as palmitic. We all know that DHA is a vital component of membrane lipids in animals, especially in brain, the eye and reproductive tissues, as well as being an essential precursor of the oxylipins resolvins, protectins and maresins - the specialized pro-resolving mediators (SPMs). But why is it so essential to this family of algae that it has evolved a distinctive mechanism for its synthesis, i.e. the anaerobic or polyketide pathway, which coexists in the organisms with a type 1 fatty acid synthase? Presumably the DHA is a component of the membrane lipids, but is it also a precursor for oxylipins and are there any other distinctive functions? It seems the answers to these questions are not known.

I have reached an age where I no longer worry about owning things, so instead I collect novel lipids and their functions (as computer files). I have long been aware of ascarosides, the complex glycolipids that protect the cell walls of the eggs of nematodes, but I was less aware of their functions as pheromones. A new review discusses them at length (Park, J.Y. et al. Ascaroside pheromones: chemical biology and pleiotropic neuronal functions. Int. J. Mol. Sci., 20, 3898 (2019);  DOI - open access). I have also been collecting mass spectra to add to the various Archive pages in the Mass Spectrometry section of these web pages, and I have recently added a further 21 to bring the total to 2128. However, these may be my last as my access to novel samples and mass spectrometry is diminishing.

September 11th, 2019

In my long-departed research career, I made good use of the evaporative light-scattering detector (ELSD) for HPLC. For those of you unfamiliar with the instrument, the principle involves evaporation of the mobile phase in a stream of air with lipid molecules forming an aerosol of minute droplets, which are passed through a light source and scatter the light in a manner that reflects the amount of sample. The proportionality of the response was always questionable, especially with minor components, and I made best use of it for micro-preparative purposes with a stream-splitter to divert a proportion of each peak for collection and further analysis. In this mode, the instrument is robust and very easy to use. I can't comment on any current models.

I have had high hopes for the Charged Aerosol Detector (CAD) in which aerosol particles are created in the same way, but then given an electrical charge for detection using an electrometer. Linearity of response is greatly improved over the ELSD, but I have not seen the numbers of published applications that I expected. Of course, I have no personal experience, but I have heard that minor impurities in the mobile phase can affect the response appreciably. That said, a few interesting applications to lipids have appeared, notably a recent one in which supercritical fluid chromatography rather than HPLC is used (Takeda, H. et al. Improved quantitation of lipid classes using supercritical fluid chromatography with a charged aerosol detector. J. Lipid Res., 60, 1465-1474 (2019);  DOI). Perhaps the greater availability of lower-cost bench-top mass spectrometers has dampened the interest in other HPLC detectors.

The Web of Science is now listing papers that appear online before being assigned a volume or page numbers. In many ways, this is useful in informing us of the latest developments, but it does cause a minor headache in recording the data. If this is inserted into a database, it will be necessary to return to journals from time-to-time to check not only on the eventual page numbers but also on the actual year of formal publication - a chore that I for one could do without for my Literature survey pages here. The DOI addresses remain constant at least.

September 4th, 2019

Bacteria tend to lack sphingolipids of their own so it is perhaps surprising that they have evolved to make use of host sphingolipids and sphingolipid enzymes to promote cellular colonization. In particular, they target the acid sphingomyelinase, leading to an increase of the levels of ceramide in membranes and resulting in the formation of ceramide-enriched membrane domains (rafts). This reorganization of membrane structure facilitates entry of bacteria into cells. There are also effects upon signalling and autophagy that benefit the invader. A new open-access review on the topic is worth a read (Rolando, M. and Buchrieser, C. A comprehensive review on the manipulation of the sphingolipid pathway by pathogenic bacteria. Front. Cell Develop. Biol., 7, 168 (2019);  DOI).

In this blog, I have frequently cited the work done by lipid scientists to discover and exploit lipopeptides derived from microorganisms as antibiotics for use against pathogenic bacteria, which are becoming resistant (see my blog of July 31st). Professor Dame Sally Davies, Chief Medical Adviser to the UK government, has just stated to the UK press that antibiotic resistance is a major threat that "could kill us before climate change does" and "at least 10 million could die every year if we don't get on top of this". Currently, around 70% of the world's antibiotics are given to farm animals (including farmed shrimp) - not for human welfare! I have not read any reports of politicians taking her seriously - but then Professor Davies is not a 16-year old Swedish girl. Please do not think that I am not concerned with climate change, as I applaud relevant work in lipid laboratories in relation to tolerance of plants to drought and excessive heat, for example. We do need to have a sense of perspective sometimes.

A phenomenon known as the "curse of the commentator" occurs when one states that a certain football team is sure to win, followed seconds later by a goal for the other side. I feel that I am suffering from this after my comments on the apparent demise of the sphingomyelin-cholesterol model of raft formation last week, only to find that it is alive and well in a new review just accepted by the Journal of Lipid Research (Morgan, P.K. et al. Hematopoiesis is regulated by cholesterol efflux pathways and lipid rafts: connections with cardiovascular diseases.  DOI). A thematic series on rafts is in the works in this journal.

August 28th, 2019

Scottish thistleIn updating my web pages in the Lipid Essentials section of the LipidWeb, I try to keep the big picture in mind rather than concentrating on the minutiae of a subject. From time to time, there is a substantial change in how a topic is viewed in the lipid community, and I at least have the chance to rectify matters here. I am thinking now of my web page dealing with rafts, the transient nano-domains reportedly present in cell membranes. This has always been a controversial subject, for example whether "detergent-resistant membranes" are truly representative of rafts, or indeed whether rafts do indeed exist. When I first prepared a web page on this subject, it was based entirely on the premise that there was a specific interaction between sphingolipids, especially sphingomyelin, and cholesterol in membranes that determined the existence and function of rafts. This premise now seems out-of-date to say the least. I have been prompted to these thoughts by a review to which I have just received access (Lu, S.M. and Fairn, G.D. Mesoscale organization of domains in the plasma membrane - beyond the lipid raft. Crit. Rev. Biochem. Mol. Biol., 53, 192-207 (2018);  DOI). The authors state - "At this time, we cannot find unequivocal evidence that the classic cholesterol-sphingolipid driven raft does not exist" - hardly a ringing endorsement. Instead, if I understand correctly, the prevailing belief is that there may be a number of factors involved in formation of nano-domains, not merely the miscibility of different lipids and this is especially true for protein-rich domains, where trans-membrane proteins may link to the underlying cortical actin cytoskeleton. Cholesterol and sphingomyelin may both be important, but not necessarily in combination. I was aware of some aspects of this view from earlier publications, but my web page did not reflect this adequately.

I am not an expert on the subject, merely a populariser of lipid science, so I sit on the fence and spectate until hopefully a consensus emerges. So far, I have simply tinkered with my web page to reflect the controversy, but have been watching closely to see what develops. It now appears that I will have to undertake a more substantial revision to reflect current views, but at what point do I discount the earlier concepts entirely?

August 21st, 2019

It has long been known that many marine invertebrates produce prostaglandins, often in amounts that seem far in excess of what is required simply for signalling purposes. It is presumed that they have a defensive role of some kind, perhaps against predators. This may include human predators, as marine prostaglandins are believed to be responsible for some poisoning events in Japan. In addition to the conventional mammalian prostaglandins, there is an astonishing array of different structures, and as well as being in the free acid form they can be esterified, even as methyl esters, and acetylated. More surprising perhaps is the discovery of prostaglandins and the relevant biosynthetic enzymes in brown algae (seaweeds), diatoms and micro-algae. As some of these may have useful pharmaceutical properties, for example as anti-cancer and anti-inflammatory agents, they are attracting increasing interest. A new open access review is a valuable update on the topic (Di Costanzo, F. et al. Prostaglandins in marine organisms: a review. Marine Drugs, 17, 428 (2019);  DOI).

Prostaglandins have also been reported from a few higher plants (as opposed to ferns, lichen, algae, etc), though in the past I have been sceptical about whether some of them they do indeed possess the precursor arachidonic acid. Some years ago with a colleague, we established the presence of arachidonic acid in a gymnosperm, Agathis robusta, by GC-mass spectrometry of the 3-pyridylcarbinol (picolinyl) ester and dimethyloxazoline derivatives. There had indeed been a few earlier reports in the literature, but then solely on the basis of relative retention times on GC columns - hence my doubts. As I no longer keep up with this aspect of the literature, I can't comment on more recent publications.

August 14th, 2019

Bis(monoacylglycero)phosphate (BMP) is a fascinating lipid in many ways. It is a minor component of most animal tissues but has a number of important functions. As such, it would be expected that we would know a great deal about its nature and biosynthesis, but there are some surprising gaps in our knowledge. For example, while we know that it has unique stereochemistry in that the phosphodiester moiety is linked only to positions sn-1 and sn-1' of glycerol, rather than to positions sn-3 and sn-3', we are unsure of the positional distributions of the fatty acid components. After isolation from tissues by standard solvent extraction conditions, the fatty acids are in the sn-3 and sn-3' positions, but it is argued from biosynthesis studies that they are in the sn-2 and sn-2' positions when the lipid is first formed. They would be expected to migrate from these to the primary positions under the acidic conditions of the lysosomal compartment of cells or during solvent extraction on analysis. However, the information on biosynthesis is far from complete and the mechanism reported in many publications (including here) is based to some extent on conjecture, especially as to how its ultimate stereochemical configuration is attained. We continue to learn more of its function, so hopefully someone out there is planning to have another attempt to fill in the details of its biosynthesis.

Plant sphingolipids are very different in their structures and functions from those in animal tissues, but as in the latter they are "involved in multiple cellular and regulatory processes including vesicle trafficking, plant development and defence". I can recommend a new open access review on the topic (Huby, E. et al. Sphingolipids: towards an integrated view of metabolism during the plant stress response. New Phytologist, 15597 (2019);  DOI).

August 7th, 2019

Among the more unpleasant lipid classes as far as humans are concerned are the chlorosulfolipids, which were first found and characterized from the phytoflagellate Ochromonas danica, but are now known to occur in marine algae and other organisms. Those isolated from the digestive glands of toxic mussels are causative agents of diarrhetic shellfish poisonings, which tend to be associated with marine algal blooms. For example, mytilipin B isolated from the culinary mussel Mytilus galloprovincialis contains an ester-linked fatty acid in addition to eleven chlorine atoms, six hydroxyls and a sulfate group on a long-chain alkyl moiety. The stereochemistry of this molecule is obviously highly complex, and I have nothing but admiration for those with the courage and persistence to attack the problem (Sondermann, P. and Carreira, E.M. Stereochemical revision, total synthesis, and solution state conformation of the complex chlorosulfolipid mytilipin B. J. Am. Chem. Soc., 141, 10510-10519 (2019);  DOI).

Further novel lipids from an unpleasant source are 6-phosphatidyltrehalose and 6,6'-diphosphatidyltrehalose, which consist of trehalose attached to one or two phosphatidic acid units. These glycophospholipids (not 'phosphoglycolipids - see this web page for an explanation) were isolated from the typhoid fever-causing, Gram-negative bacterium Salmonella Typhi. The positional distributions of the fatty acids have now been determined: long-chain saturated fatty acids in position sn-1 and cyclopropyl fatty acids in position sn-2 (Mishra, V.K. et al. Total synthesis of an immunogenic trehalose phospholipid from Salmonella Typhi and elucidation of its sn-regiochemistry by mass spectrometry. Org. Letts, 21, 5126-5131 (2019);  DOI - open access). As these lipids are potent immunostimulants in an important pathogen, I am sure we will be learning more about them. They also reveal a functional convergence with mycobacteria, which produce a range of acyl trehaloses.

Glycophospholipids of this type, i.e. diacylglycerol-phosphate-carbohydrate, are relatively rare in nature, and the only other direct analogue that comes to mind is phosphatidylglucoside, a minor brain component. Most comparable lipids are derived from phosphatidylglycerol rather than phosphatidic acid. Incidentally, the experts in the field use the term 'phosphatidylglucoside', but I have never been sure why 'phosphatidylglucose' is not correct. Over to you LipidMaps or anyone else who cares to comment!

July 31th, 2019

Scottish thistleAlthough they may be outside the mainstream of lipid research, I like to keep abreast of what is happening in the world of bacterial lipopeptides, as these appear to be one of our best hopes for the discovery of novel antibiotics to combat the development of resistance of bacterial pathogens to the current spectrum of antibiotics. A new review has helped to clarify my understanding of how these molecules work (Balleza, D. et al. Role of lipid composition, physicochemical interactions, and membrane mechanics in the molecular actions of microbial cyclic lipopeptides. J. Membrane Biol., 252, 131-157 (2019);  DOI). It appears that variety of different mechanisms may be involved, and this will hopefully be advantageous therapeutically. Bacterial lipopeptides, both linear and cyclic constitute a diverse range of amphiphilic agents that not only interact electrostatically with the charged head groups of membrane lipids, but also with the hydrophobic region of lipid bilayers. This can result in electrostatic and mechanical changes, reduction in surface tension, promotion of metal ion sequestration, and a disturbance of the structures of lipid bilayers in bacterial and fungal membranes. Often, there appears to be a general tendency to induce pore formation. As I understand it, toxicity problems remain that limit therapeutic use at present, but hopefully time and hard work will reduce these. It is noteworthy that surfactins kill the larval and pupal stages of mosquito species and even have anti-viral properties; some have already reached commercial application as biocontrol agents in agriculture.

July 24th, 2019

Leukotriene B4 is usually considered one of the harmful inflammatory oxylipins, but it also has its good points, for example by triggering functional responses important for host defence including the elimination of certain pathogens. A new publication reports that a single dose ameliorates the symptoms of influenza and improve tolerance to the disease in mice by limiting the accumulation of inflammatory monocyte-derived macrophages, controlling tissue damage and increasing survival (Pernet, E. et al. Leukotriene B4-type I interferon axis regulates macrophage-mediated disease tolerance to influenza infection. Nature Microbiol., 4, 1389–1400 (2019);  DOI). More than 300 died from the disease in the U.K. in the winter of 2017, so anything that may help will be welcome.

The definition of what constitutes an endocannabinoid is looking rather tenuous. Usually the term is taken to mean those lipids that function as agonists for the two primary G protein-coupled receptors for the plant cannabinoids, i.e. those designated CB1 and CB2, but it is now recognized that other receptors may be involved in their functions. Some N-acylethanolamides interact with the other receptors but not with CB1 or CB2, or they may interact with only one of them. The picture is complicated increasingly by findings that derivatives of polyunsaturated fatty acids of the n-3 family are also endocannabinoids or endocannabinoid-like, and then there are the forms that are enzymatically oxidized. For example, some epoxy-endocannabinoids interact much more strongly with the endocannabinoid receptors than does anandamide per se. Two new reviews in this area from different stand-points have helped me to update my web pages here (Watson, J.E. et al. Emerging class of omega-3 fatty acid endocannabinoids and their derivatives. Prostaglandins Other Lipid Mediators, 143, 10633 (2019);  DOI, and de Bus, I. et al. The role of n-3 PUFA-derived fatty acid derivatives and their oxygenated metabolites in the modulation of inflammation. Prostaglandins Other Lipid Mediators, 144, 106351 (2019);  DOI).

July 17th, 2019

Some amazing results can now be obtained by modern mass spectrometric methods, and in particular it is possible to determine double bond positions in the fatty acid components and positional distributions on the glycerolipid backbone for phospholipids. I have been impressed by a new review dealing with what can now be accomplished by such techniques with minute amounts of sample (Siegel, T.P. et al. Reshaping lipid biochemistry by pushing barriers in structural lipidomics. Angew. Chem.-Int. Ed., 58, 6492-6501 (2019);  DOI - open access). For example, it seems to be possible to determine the ratio of n‑9 to n‑7 monoenes in a lipid class, or the ratio of the 16:0/18:1 to 18:1/16:0 species. On the other hand, it does seems that the correct choice of instrumentation may be critical, and that not every system bought off the shelf is suitable for such analyses. If you are planning a purchase, this review will be essential reading.

My main worry as always is that older "classical" techniques may be forgotten. As I have pointed out before, I don't ever recall seeing a study in which positional distributions on the glycerol backbone obtained by mass spectrometry were compared with older methods using phospholipase methodology. It is possible that high precision is not always necessary, but it would be useful to know the potential error, and I suppose that the same may be true for fatty acid isomer distributions. I was once asked to adjudicate on a paper, where the method for methylation of GC analysis might introduce an error of 0.5% in one component of interest, but I pointed out that the standard of accuracy demanded by one referee was much higher than that expected in most fields of biochemistry.

If you would like to read of a further challenging aspect of lipidomics methodology, I can recommend a review that deals with structural analysis of Archaeal lipids. These have isoprenoid alkyl moieties linked by ether bonds to one or two glycerols of the "wrong" stereochemistry, often with ring structures in the alkyl chains and two polar head groups (Law, K.P. and Zhang, C.L.L. Current progress and future trends in mass spectrometry-based archaeal lipidomics. Org. Geochem., 134, 45-61 (2019);  DOI).

July 10th, 2019

A few years ago in this blog, I commented on discovery of 9-hydroxy-stearic acid its isomers with a free carboxyl group and a centrally located hydroxyl group to which a further fatty acid was linked as an estolide or 'FAHFA' (Fatty Acid ester of Hydroxy Fatty Acid). At the time, I thought it simply a novelty, but a number of publications since have demonstrated that these lipids are important anti-inflammatory mediators. The most recent has used the naturally occurring lipids of this type in oat oil to demonstrate that they suppress "lipopolysaccharide-stimulated secretion of cytokines and expression of pro-inflammatory genes. These studies identify LAHLAs as an evolutionarily conserved lipid with anti-inflammatory activity in mammalian cells" (Kolar, M.J. et al. Linoleic acid esters of hydroxy linoleic acids are anti-inflammatory lipids found in plants and mammals. J. Biol. Chem., 294, 10698-10707 (2019);  DOI). If the topic continues to expand, it may need its own web page on this site one day. Incidentally, many years ago I was involved in a minor collaboration with a company promoting the perceived benefits of oat oil as a nutraceutical, unaware of any special value in the estolide components (although we were aware of them).

By some calculations there can be as many as 1000 distinct molecular species of lipids in an animal membrane, so it is surprising that a single one of these can stand out from the rest. This seems to be true for the 18:0/18:1 species of phosphatidylserine in the inner leaflet of the membrane, which has a range of properties that enable transfer of signals to the cytosol. A new review suggests that the mechanism for this may be an interaction with the very-long chain acyl groups of sphingolipids (interdigitation or a "hand-shake") in the outer leaflet in raft-like domains. The result is an accumulation of the anionic phospholipid and negative surface charge to which specific poly-cationic proteins in the membranes can bind (Skotland, T. and Sandvig, K. The role of PS 18:0/18:1 in membrane function. Nature Commun., 10, 2752 (2019);  DOI - open access).

I hate to carp when the first author has such a fine surname, but in view of my recent comments on overuse of abbreviations was it really necessary to use "PS" instead of the full name in the title. Perhaps I am simply becoming a G.O.M. (Grumpy Old Man).

Acronyms may be used to spare embarrassment, and it seems that B.O. and the resulting local pollution is due to oxidation of skin lipids especially on clothing (Lakey, P.S.J. et al. The impact of clothing on ozone and squalene ozonolysis products in indoor environments. Commun. Chem., 2 (1)(2019);  DOI).

July 3rd, 2019

Of all the lipids that now appear to have therapeutic potential, I suspect that nitro fatty acids must be front runners in terms of reaching clinical acceptance. As they are formed relatively easily by non-enzymatic methods, their stereochemistry is relatively simple in comparison to say eicosanoids or docosanoids, so they can be produced on a relatively large scale as pharmaceuticals. They are known to exert protective effects against chronic unresolved inflammation in numerous pre-clinical animal models of disease including cardiovascular, pulmonary and renal fibrosis. A new brief review is worth a look (Khoo, N.K.H. and Schopfer, F.J. Nitrated fatty acids: from diet to disease. Curr. Opinion Physiol., 9, 67-72 (2019);  DOI). Nitrated conjugated linoleic acid is the most active form. In contrast to linoleic acid, α-linolenic acid (18:3(n-3)) is present at low levels only in human tissues, and conjugated forms are not usually detectable. However, naturally occurring conjugated C18 trienes found in certain seed oils are reported to be potent anticancer agents, so it would be interesting to know whether this activity is mediated via nitro adducts.

Another lipid with potential pharmaceutical value is N-oleoylethanolamide with beneficial effects towards non-alcoholic fatty liver disease (NAFLD), the most prevalent of chronic liver diseases. A new systematic review supports the claims and suggests that further clinical are warranted (Tutunchi, H. et al. The effects of oleoylethanolamide, an endogenous PPAR-α agonist, on risk factors for NAFLD: A systematic review. Obesity Rev., 20, 1057-1069 (2019);  DOI). Of course, it is also of interest as an endogenous regulator of food intake, where it is believed to act as a local satiety signal rather than as a blood-borne hormone.

The journal Trends in Analytical Chemistry has a virtual special section on "Ion Mobility Spectrometry" (Volume 116, July (2019) edited by Janusz Pawliszyn) in which many of the articles deal with lipids. The Springer book series Advances in Experimental Medicine and Biology (for those who have access) has two recent volumes dedicated to lipids - "Cholesterol Modulation Of Protein Function: Sterol Specificity And Indirect Mechanisms" and "Bioactive Lipids In Health And Disease".

June 26th, 2019

Scottish thistleThe most unusual lipid of the month and perhaps of the year is N-palmitoyl-O-phosphocholineserine (the most abundant species in its class), which has been found in patients with the genetic disorder Niemann-Pick disease type C1 (Sidhu, R. et al. N-Acyl-O-phosphocholineserines: structures of a novel class of lipids that are biomarkers for Niemann-Pick C1 disease. J. Lipid Res., in press (2019);  DOI). Nothing is yet reported of the biosynthesis and function of this novel lipid, and we do not even know whether it has any specific role in cells or is merely a byproduct, but no doubt we will learn more soon.

Formula of N-palmitoyl-O-phosphocholineserine

I tend to believe that all lipids have some distinctive function in tissues, if only as an intermediate in the deactivation of some more vital lipid. It is fun to speculate on biosynthesis and the obvious possibility is that it is produced by the promiscuous action of a sphingomyelin synthase upon N-acylserines, instead of upon ceramide, with phosphatidylcholine as the phosphocholine donor (speculations are not always a good idea, as I have on occasion seen them cited by others later as facts). N-Acylserines are known constituents of animal tissues, although N-arachidonoylserine has been most studied. However, N-palmitoylserine per se has been detected in brain, and it is reported to have neuroprotective effects against traumatic brain injury. LipidMaps will have to decide how they will classify this new phospholipid, but I have included a brief note in my web page on lipoamino acids on the assumption that it is derived biosynthetically from such lipids.

June 19th, 2019

From time to time I have a diatribe here about the excessive use of abbreviations in publications, and especially in their titles. In my weekly literature search, I have just come across the use of 'HETE' in the title of a paper, which every good lipid scientist knows means 'hydroxyeicosatetraenoic acid' - except that in this instance it apparently stood for 'hydroxyethylthioethyl'. Of course, we cannot control the use of acronyms in other disciplines. I understand that it is necessary to use acronyms for specific genes and proteins in publications, but more details in titles would be often be invaluable. For example, a title such as 'Activation of XYZ123 by abc789' may means something to an expert in a particular field, but to those of us who may be only peripherally involved it may be gobbledygook, and we may not know if it is even related to lipid science. Please give some thought to more explanatory titles for those of us who have difficulty remembering all the acronyms for lipids, never mind genes, enzymes, etc.

In my web pages on oxylipins, I concentrate on mammalian metabolism, although I do not overlook higher plants. However, it is easy to forget that some more primitive organisms produce oxylipins, including hydroperoxides, prostaglandins, and even resolvins, by utilizing enzymes that may only be distantly related in structure to those found in animals. It can be difficult to pull all this information together, so I was grateful for a new review on the topic (Niu, M.Y. and Keller, N.P. Co-opting oxylipin signals in microbial disease. Cell. Microbiol., 21, e13025 (2019);  DOI - open access)

The open access bargain of the week has a title that seems encompass the whole of the biochemistry of complex lipids, but in only 30 pages, they appear to make a creditable job of it (Casares, D. et al. Membrane lipid composition: effect on membrane and organelle structure, function and compartmentalization and therapeutic avenues. Int. J. Mol. Sci., 20, 2167 (2019);  DOI). Students and newcomers to the subject will find it especially useful, but those of us who are a bit more jaded may enjoy a refresher session.

June 12th, 2019

Formula of DiEpHEDEThree years ago in this blog, I highlighted a publication describing a novel eicosanoid with an unusual structure. It was termed dioxolane DXA3 and subsequently was found to have fascinating biological properties. The latter have not changed, but it appears that the structure proposed originally was wrong, and it has now been established that it is in fact a di-epoxide or 8,9‑11,12‑diepoxy-13-hydroxyeicosadienoic acid (8,9-11,12-DiEp-13-HEDE or DiEpHEDE). Of course, this is just as interesting from a biosynthetic standpoint as a dioxolane structure, especially as the cyclooxygenase 1 is the key biosynthetic enzyme (Kornilov, A. et al. Revising the structure of a new eicosanoid from human platelets to 8,9‑11,12-diepoxy-13-hydroxyeicosadienoic acid. J. Biol. Chem., 294, 9225-9238 (2019);  DOI - open access as author's choice).

A further open access bargain deals with the recent developments in oxysterol research (Griffiths, W.J. and Wang, Y.Q. Oxysterol research: a brief review. Biochem. Soc. Trans., 47, 517-526 (2019);  DOI). It has become apparent that these are intimately involved in innumerable biochemical processes of which many are relevant to human diseases, including neurodegenerative diseases and cancer. They are also important in tissue development through their involvement in the regulation of the activities of hedgehog proteolipids, among my favourite lipid molecules as they contain both cholesterol and palmitic acid, which are covalently bound. Technically, these oxysterols can be hard to study because they tend to be minor components in the presence of relatively large amounts of cholesterol, which is liable to autoxidation during processing. It may be a while before we can hand over their analysis to robots, so lipid analysts will continue to be gainfully employed.

June 5th, 2019

It has long been known that palmitoleic acid or cis-9-16:1 is a bit special and indeed has been termed a lipokine. For example, it is essential for the function of Wnt proteins in animal development. Now, another isomer, i.e. cis-10-16:1 isolated from a bacterial species, has been found to have distinctive anti-inflammatory properties (Smith, D.G. et al. Identification and characterization of a novel anti-inflammatory lipid isolated from Mycobacterium vaccae, a soil-derived bacterium with immunoregulatory and stress resilience properties. Psychopharmacology, in press (2019);  DOI). It is shown to upregulate many genes associated with signalling via its action upon peroxisome proliferator-activated receptor alpha (PPARα). Double bonds in even-numbered positions in monoenes are rather unusual, and one in position 10 may be unique (please correct me if I am wrong). Another interesting feature is that the fatty acid appears to be esterified into triacylglycerols as a single molecular species in the organism.

I mentioned a fascinating short review on aspirin in a recent blog, including its effects upon prostaglandin synthesis. It also a factor in the biosynthesis of the so-called aspirin-triggered specialized proresolving mediators produced from docosahexaenoic acid, i.e. the aspirin-triggered resolvins (AT-RvDs) and lipoxins (AT-LXs). It has now been demonstrated that AT-RvDs mediate the anti-tumour activity of aspirin. I can do no better than quote from the abstract - "Thus, the pro-resolution activity of AT-resolvins and AT-lipoxins may explain some of aspirin's broad anticancer activity. These AT-SPMs are active at considerably lower concentrations than aspirin, and thus may provide a nontoxic approach to harnessing aspirin's anticancer activity" (Gilligan, M.M. et al. Aspirin-triggered proresolving mediators stimulate resolution in cancer. PNAS, 116, 6292-6297 (2019);  DOI). We can but hope that clinical studies will soon prove their efficacy.

The British Journal of Pharmacology, Volume 176, Issue 8 has a themed Section: "Eicosanoids 35 years from the 1982 Nobel: where are we now?" with guest editors: Roderick J. Flower and Timothy D Warner.

May 29th, 2019

Scottish thistleMy recent blog-free holiday in Gran Canaria has provoked some reflection. When I started writing for the WWW in my supposedly retirement years, my first task was to set up my mass spectrometry pages. Then, I was aware that at the time (pre Lipid Maps) there was little else of value to students of lipid science - chemistry, biochemistry, physiology - that was open access. I had written a review of triacylglycerol composition and metabolism some years earlier, so it was not difficult to update and reformat this in a manner suited to the internet, and I hoped to make a small contribution in this way. However, on reflection, I thought that this should be balanced by a similar web page on a phospholipid, so I produced a similar web page on phosphatidylcholine. I was clear at the outset that I was aiming to help students and young scientists - not experts in the field - though I hoped that the reading list provided would assist the latter.

The Lipid Essentials section of the web site came into existence then in a relatively unplanned way as I continued to tackle individual lipid classes one at a time over a number of years. Of course, I was not omniscient then (or now), so I learned a great deal myself during this process. Writing for the WWW turned out to be an iterative process, as it is so easy to update web pages as I become aware of further information or new publications on my topics, or simply find a better way to explain some aspect. Nearly 20 years into my task, I continue to find stimulation in this activity, and I still have plenty of time for my family, garden, etc.

My background in lipid chemistry governed my approach, but I occasionally look back to consider whether I could have tackled it in a different way. For example, it is evident that there is a complex interplay among the innumerable lipid species in cells, and it can be difficult to convey this adequately in a web page devoted largely to a single lipid class, even with the use of hyperlinks between pages. While this is especially true for the oxylipins, it is also relevant for all complex lipids in membranes. These thoughts were stimulated in part by a review dealing with lipids as cells divide (Storck, E.M. et al. Lipid cell biology: a focus on lipids in cell division. Annu. Rev. Biochem., 87, 839-869 (2018);  DOI). In this process, a host of different lipids with different functions are involved in an integrated manner, and I am somewhat at a loss to see how I can incorporate this information adequately into so many different web pages on this site. A further paper to show the complexity of lipid interactions that is difficult to fit into my approach deals with the sneaky way viruses hijack many aspects of cellular lipid metabolism for their own nefarious purposes (Vieyres, G. and Pietschmann, T. HCV pit stop at the lipid droplet: refuel lipids and put on a lipoprotein coat before exit. Cells, 8, 233 (2019);  DOI).

I am content to continue with my existing plan for this website, but there must be many scientists out there who are nearing retirement and might consider the production of complementary websites with deeper insights into aspects of lipid science or with a more integrated approach to the subject. Over to you!

May 8th, 2019

If I have to select a single lipid that is attracting particular interest at present, it would have to be the epoxides of polyunsaturated fatty acids, both eicosanoids and docosanoids. Any number of publications have crossed my desk in recent weeks, and the most recent is a review article (Sausville, L.N. et al. Cytochrome P450 epoxygenases and cancer: A genetic and a molecular perspective. Pharmacol. Therapeut., 196, 183-194 (2019);  DOI). In many of their functions, epoxy-eicosanoids derived from arachidonic acid are believed to be beneficial towards human health, but not in relation to cancer where they are pro-angiogenic and promote tumor development and growth. The dihydroxy acids formed by ring opening of such epoxides seem to be regarded universally as harmful. On the other hand, the epoxy-fatty acids derived from eicosapentaenoic and docosahexaenoic acids inhibit angiogenesis and are protective against certain pathological conditions that include cancer. Life is complicated.

Next, a publication in which the title contains the worst pun of the year (Dixit, D. et al. Secrets and lyase: Control of sphingosine 1-phosphate distribution. Immun. Rev., 289, 173-185 (2019);  DOI). All joking aside, this seems to be a fascinating approach to the understanding of the complex problem of the multiple functions of sphingosine 1-phosphate in tissues.

My last publication today is surely a sign of the times (Lee, C.W. et al. Lipidomic profiles disturbed by the internet gaming disorder in young Korean males. J. Chromatogr. B, 1114, 119-124 (2019);  DOI). While a companion study of cell phone addiction and plasma lipids might now be relevant, where would we get an appropriate control group? I am not sure of any real relevance to lipids, and I confess that I should not be flippant about what is obviously a real problem for some.

May 1st, 2019

There is an interesting exchange of letters between H.S. Hansen and W.L. Smith in the latest issue of the Journal of Biological Chemistry (Issue 17) on the essential functions of linoleic acid in its own right, as opposed to as a precursor of arachidonic acid, and thence of the prostaglandins and other eicosanoids. Both agree on the vital role of linoleic acid as a precursor of hepoxilin-like compounds in skin, though perhaps the role in the specific skin ceramides should also be mentioned. In addition, it perhaps should be noted that oxygenated linoleate metabolites are the most abundant oxylipins in plasma in both free and esterified forms, and these have a range of biological functions - mainly with negative implications as far as I can see. Similarly, nitro-metabolites of linoleate may have important biological functions, though most current research appears to be with oleate isomers as these are more readily accessible by chemical synthesis. Indeed, conjugated linoleate, probably derived from linoleate per se, is by far the most active precursor for nitro fatty acids. N-linoleoyl ethanolamide is one of the main acylethanolamides in animal tissues; does it have any specific functions? All of these linoleate products may potentially be involved in its essentiality.

A subsidiary question is whether arachidonic acid has biological functions other than as a source of eicosanoids, and of course the endocannabinoids are important examples of this. Some years ago, A.R. Brash published a review on the topic (Brash, A.R. Arachidonic acid as a bioactive molecule. J. Clin. Invest., 107, 1339-1345 (2001);  DOI), and perhaps a revised and updated version might be timely (although it is quite possible that I have missed something). Finally, does α-linolenic acid have any essential functions in animal tissues other than as a precursor of long-chain polyunsaturated fatty acids of the n-3 family? As far as I understand it, the consensus at present appears to be no, but I await correction.

Dawn Cotter has been responsible for the weekly appearance of this blog on the LIPID MAPS® Lipidomics Gateway. Soon now, the complete LipidWeb will be duplicated there thanks to her efforts.

April 24th, 2019

Scottish thistleIt is not difficult to understand how so many of the oxylipins derived from essential fatty acids can interact physically with receptors, enzymes and other proteins with such specificity. After all, they contain double bonds, ring structures and/or oxygen molecules in highly stereospecific arrangements to favour specific interactions, and natural selection has designed them for such purposes. Even a relatively simple molecule, such as palmitoleic acid with only a single 9-cis double bond in the chain, is uniquely recognized by the enzymes involved in the function of Wtn proteins. However, when chain-length is the only structural feature of a fatty acid, it is sometimes harder to understand how specificity can be achieved.

The source of octanoic acid for its unique use for activation of ghrelin, has recently been identified as synthesis de novo from long-chain fatty acids by β-oxidation in ghrelin-producing cells, and proximity of the relevant enzymes may contribute to specificity. Then, we now have some understanding of distinctive acylations as in the N-myristoylation or S-palmitoylation of proteins, where it now seems that interactions between binding proteins and acyltransferases may provide an explanation for how these fatty acids are selected (see our web page on proteolipids). Of course, it has long been known how desaturases recognize saturated fatty acid precursors. Now a new, highly specific function for myristic acid has been described (Iwata, K. et al. Myristic acid specifically stabilizes diacylglycerol kinase δ protein in C2C12 skeletal muscle cells. Biochim. Biophys. Acta, 1864, 1031-1038 (2019);  DOI). Early biochemistry text books considered saturated fatty acids as dangerous in nutrition in excess, but otherwise as relatively inert molecules from a physiological standpoint; they were only present in tissues as a source of energy or as building blocks of membrane lipids. Those scientists with an interest in sphingolipids have always known better! I suspect that every fatty acid that we encounter in animal tissues has some vital biochemical function, although we may not yet know it.

April 17th, 2019

A few weeks ago, I expressed surprise that research on sphingosine-1-phosphate covered a span of 50 years. This now pales into insignificance with a new publication (Montinari, M.R. et al. The first 3500 years of aspirin history from its roots - A concise summary. Vasc. Pharm., 113, 1-8 (2019);  DOI). Of course there were no Proceedings of the Sumerian (or Egyptian) Academy of Sciences back then, but the Ebers Papyrus (1534BCE) apparently reports the use of willow bark as a painkiller and antipyretic. A mere 1000 years later, Hippocrates was aware of the medicinal properties of this plant family, but the true science of the salicylates began in the late 1700s. As the review recounts, we now know, thanks to the work of Sir John Vane and colleagues, that the mechanism of action of aspirin and other non-steroidal anti-inflammatory drugs is the dose-dependent inhibition of prostaglandin biosynthesis via its action upon cyclooxygenases. Why not put your feet up and read it during your next coffee break - at least it is a change from Brexit?

The effects of the Ebola virus on the lipid metabolism of patients with the disease was also mentioned in an earlier blog. Now a new review describes how this virus (and others) is able to take phosphatidylserine from the inner layer of the host plasma membrane and externalize it on the viral envelope to exploit the host apoptotic clearance machinery to enhance their entry into host cells (Nanbo, A. and Kawaoka, Y. Molecular mechanism of externalization of phosphatidylserine on the surface of Ebola virus particles. DNA Cell Biol., 38, 115-120 (2019);  DOI - open access).

There is currently great interest in oxidized phospholipids in animals, because of their influence on innumerable disease states. However, they are just as important in plants, in which both galactolipids and phospholipids are known to contain specific oxylipins, thanks largely to the marvels of modern mass spectrometry. The best known of these are the arabidopsides, which are formed in leaves upon wounding, but also in distant unstressed leaves so there must be some means of communication between them. A new review summarizes current knowledge (Genva, M. et al. New insights into the biosynthesis of esterified oxylipins and their involvement in plant defense and developmental mechanisms. Phytochem. Rev., 18, 343-358 (2019);  DOI.).

April 10th, 2019

There have been any number of excellent review articles on the topic of lipidomics in recent years that together cover most aspects of the techniques involved in some depth. However, if you are a complete novice to the subject where would you start? I can recommend a new review from the laboratory of Prof. Xianlin Han (Wang, J. et al. Tutorial on lipidomics. Anal. Chim. Acta, 1061, 28-41 (2019);  DOI). The text of the paper is simple, straight-forward and readable, and anything missing is covered by an extensive list of references.

This has been a good week for papers dealing with lipid methodology, and I suspect that one on the topic of oxylipins will prove to be seminal (Watrous, J.D. et al. Directed non-targeted mass spectrometry and chemical networking for discovery of eicosanoids and related oxylipins. Cell Chem. Biol., 26, 433-442 (2019);  DOI). I have yet to get hold of a copy, but from the abstract it appears that there are many more lipid mediators of this type in human plasma than have been adequately characterized to date. The authors are surely having fun exploring the chemistry of these now, especially to determine which are primary metabolites, with studies of the biological properties to follow. "Fun" is probably not the correct word, as I know how frustrating it can be to try to obtain the structures of fatty acid derivatives from minute amounts of material.

In addition, I was intrigued by a paper on derivatization reactions in the solid phase (Atapattu, S.N. and Rosenfeld, J.M. Micro scale analytical derivatizations on solid phase. Trends Anal. Chem., 113, 351-356 (2019);  DOI). There do not yet appear to be many applications to main-stream lipids as yet, but the potential is there. The same journal issue has two further reviews dealing with solid-phase methods for preparing lipid extracts.

The journal Biochimie has a special issue (Volume 159, Pages 1-122, April 2019) devoted to the topic of "Fatty acids and lipopolysaccharides from health to disease" edited by Michel Narce and Isabelle Niot. An eclectic range of topics is covered within the main subject areas.

April 3rd, 2019

It is almost 100 years since the discovery of vitamin E or tocopherol so it is appropriate to see a special journal issue devoted to review articles on the topic - "Vitamin E - Regulatory Roles" edited by A. Azzi and W.J. Whelan (IUBMB Life, Volume 71, Issue 4, Pages: 401-522, April 2019). In the early years, the function of tocopherol as an antioxidant was the focus of most research, then the signalling roles came to the fore, and now there are multiple avenues that are being explored. It seems that I am going to be rather busy now with updates to my tocopherol page, as even a cursory glance at the abstracts shows there is much that I have missed in the last year or two. In particular, I suspect that reading up on the biochemistry of the tocopherol metabolites is going to be a considerable task. For example, I was not aware until now of a publication describing how these interact with 5-lipoxygenase and thence interfere with leukotriene signalling (Pein, H. and 30 others. Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. Nat. Commun., 9, 3834 (2018);  DOI).

However, another important review is demanding my attention at the moment, and this requires updates to several of my web pages - two already (O’Donnell, V.B. et al. Enzymatically oxidized phospholipids assume center stage as essential regulators of innate immunity and cell death. Sci. Signal., 12, eaau2293 (2019);  DOI - open access). Amongst much of interest, it is suggested that the biosynthetic enzymes for free hydroxyeicosatetraenoic acids and their esterified products are colocalized and work cooperatively to the same time scale when cells are activated.

March 27th, 2019

Scottish thistleI had thought that sphingosine-1-phosphate biochemistry was largely a product of this century, so I was surprised to see the title of a new review (Saba, J.D. Fifty years of lyase and a moment of truth: sphingosine phosphate lyase from discovery to disease. J. Lipid Res., 60, 456-463 (2019);  DOI). However, it appears that the first work on this key enzyme of sphingolipid catabolism was published by Wilhelm Stoffel (who recently celebrated his 90th birthday) and colleagues in 1969. This work seems to have been ahead of its time and was largely forgotten until the late 1990s, when research was stimulated by the new findings on the biological activities of this lipid. Stoffel was also of course the key pioneer in the revealing the mechanism for the biosynthesis of sphingoid bases (see - Stoffel, W. Studies on the biosynthesis and degradation of sphingosine bases. Chem. Phys. Lipids, 5, 139-158 (1970);  DOI). Scientific historians may correct me, but I suspect that it was a further 20 years until the next important paper on the topic was published from Sarah Spiegel's laboratory (Zhang, H. et al. Sphingosine-1-phosphate, a novel lipid, involved in cellular proliferation. J. Cell Biol., 114, 155-167 (1991);  DOI).

phosphatidylmonogalactosyldiacylglycerolNature can confound the best lipid classification schemes. For example, is the lipid illustrated (phosphatidylmonogalactosyldiacylglycerol) a glycolipid, a phospholipid, a glycophospholipid or a phosphoglycolipid (there is a difference between the last two as described here..)? In essence, it is a monogalactosyldiacylglycerol linked by a phosphate bond to phosphatidic acid. It was first described from a bacterium some years ago, and there are glucosyl equivalents, but a new paper describes undoubtedly the best characterization, including the β-D-galactopyranosyl unit and polyunsaturated acyl groups, together with its biological properties (Manzo, E. et al. Immunostimulatory phosphatidylmonogalactosyldiacylglycerols (PGDG) from the marine diatom Thalassiosira weissflogii: inspiration for a novel synthetic toll-like receptor 4 agonist. Marine Drugs, 17, 103 (2019);  DOI). It is probably best considered as a phosphoglycolipid, as it is believed to be derived biosynthetically from monogalactosyldiacylglycerols by a transphosphatidylation reaction with phosphatidylglycerol.

Two weeks ago, I suggested that a review of the connections between glycerolipid and sphingolipid biochemistry might be timely. My apologies but I have been reminded that one exists and is well worth reading (Rodriguez-Cuenca, S. et al. Sphingolipids and glycerophospholipids - The "ying and yang" of lipotoxicity in metabolic diseases. Prog. Lipid Res., 66, 14-29 (2017);  DOI).

March 20th, 2019

There have been two substantial multi-author reviews in the last six months on the health value of plant sterols and stanols in the diet (Jones, P.J.H. and 24 others. Progress and perspectives in plant sterol and plant stanol research. Nutr. Rev., 76, 725-746 (2018);  DOI.   Plat, J. and 19 others. Plant-based sterols and stanols in health and disease: 'Consequences of human development in a plant-based environment?' Prog. Lipid Res., 74, 87-102 (2019);  DOI - the latter is open access). Both support the claims for the cholesterol lowering effects of such supplements, although there is as yet no direct evidence that there is an actual reduction in the risk of heart disease. Time only will tell, but my fingers are crossed that this does indeed work, as I have been encouraging my wife to consume one of the proprietary brands for some years. The other important information that I took from the reviews is that there may be many further benefits, and I quote from the second of these publications - "ranging from its presence and function intrauterine and in breast milk towards a potential role in the development of non-alcoholic steatohepatitis, cardiovascular disease, inflammatory bowel diseases and allergic asthma." The authors consider that these additional beneficial properties may even prove to be more important than the effects upon cholesterol lowering in the long term.

Lipidomics studies are contributing substantially to our knowledge of the metabolic consequences of diseases states, including heart disease and cancer of course where lipids play an active part. It is perhaps more surprising that this can also be true of viral diseases, and a new study describes the changes in lipids brought about by the Ebola virus (Kyle, J.E. et al. Plasma lipidome reveals critical illness and recovery from human Ebola virus disease. PNAS, 116, 3919-3928 (2019);  DOI). It appears that the plasma lipidomes are profoundly altered in survivors and fatalities, and are related to the outcome and stage of the disease and recovery. Importantly, these changes in the lipidome suggest potential targets for therapy.

March 13th, 2019

A new review publication on sphingolipids is worth reading for a number of reasons, but I was intrigued by some fascinating data on how research on these lipids has expanded in recent years (Sahu, S.K. et al. Emergence of membrane sphingolipids as a potential therapeutic target. Biochimie, 158, 257-264 (2019);  DOI). The authors point out that in relation to sphingolipid metabolism their "extensive literature survey reveals a whopping 28-fold increase in the number of publications from the year 1999 onwards in comparison to papers from 1987 to 1998". I guess this has been fueled in part by the discovery of the signalling roles of lipids such as the ceramides and sphingosine-1-phosphate and in part by the development of new mass spectrometric methodologies, which have greatly simplified analysis.

It is not hard to understand why glycerolipid biochemistry and sphingolipid biochemistry are usually treated as separate subjects within lipid science. A few years ago, I was asked at a symposium whether I knew of any links between the two, and while I recalled the fact that phosphatidylcholine was an immediate precursor of sphingomyelin, my mind was a blank on other links. When I had time later, others did indeed come to mind and I began a list of additional connections, which I later incorporated into my introductory web page on sphingolipids. I continue to add to this and the most recent example is the generation of 1-O-acylceramides in skin and lipid droplets by the action of diacylglycerol acyltransferase 2 (DGAT2), a key enzyme in triacylglycerol biosynthesis. There must be more such links of which I am unaware, and I would be delighted to learn of further examples. As an alternative to my musings, perhaps someone (not me) could consider publishing a proper review on the topic!

March 6th, 2019

At first glance, the topic of prostaglandins in insects may not appear to be of special interest, but a new review has some fascinating information (Stanley, D. and Kim, Y. Prostaglandins and other eicosanoids in insects: biosynthesis and biological actions. Front. Physiol., 9, 1927 (2019);  DOI - open access). For example, it appears that there is very little arachidonic acid in insects, so the first step in prostaglandin synthesis seems to be release of linoleate from phospholipids by the action of phospholipase A2 for conversion to arachidonic acid. Then, insects do not possess cyclooxygenases but instead have a specific peroxidase termed 'peroxinectin', which produces PGH2. This is acted upon in turn by a PGE2 synthase. Thereafter, prostaglandins appear to have a similar innumerable range of functions in insects as in vertebrates, including hormone actions in the fat body and effects upon reproduction, fluid secretion, and the immune response.

I gather that it is easily possible to spend seven figure sums to purchase an NMR spectrometer these days, but I am intrigued by the possibilities for the use of low-cost bench-top instruments that do not require the use of cryogens in lipid analysis. I understand that they are relatively low field, up to about 80 Mhz, but early in my career 60Mhz was considered state of the art. These thoughts were stimulated by a paper on the analysis of phospholipids using 31P NMR with an instrument of this type (Gouilleux, B. et al. Analytical evaluation of low-field 31P NMR spectroscopy for lipid analysis. Anal. Chem., 91, 3035-3042 (2019);  DOI - open access). The results appear to show sufficient accuracy for many routine applications in food or clinical science, and certainly at least as good as alternative low-tech methods, such as thin-layer chromatography, while being much less labour intensive. I would love to drive a Ferrari, but I am content in general with my Ford Fiesta - perhaps it might be the same with NMR spectrometers?

My current moan concerning scientific publications is poor paragraph construction. I recently came across a review article in which a single paragraph extended over three pages.

February 27th, 2019

Scottish thistleHaving mentioned the need for good titles and abstracts in scientific publications in recent weeks, I should say something about the contents. I have been rather impressed by the use of colour and art work in some recent papers. When my grand-daughter was 5-6 years old, she asked me "what was life like in the black and white days?" - obviously under the impression from TV viewing that colour was a late 20th century invention. Colour in the world at large is one thing, but the world of scientific publication and presentation was largely monochromatic until well into my scientific career, although we may now take the use of colour for granted. That said, I must commend the authors of a review that has just been published for an outstanding example of the tasteful use of colour coupled with real artistic skill to complement the text and illustrate complex biological processes (Olzmann, J.A. and Carvalho, P. Dynamics and functions of lipid droplets. Nature Rev. Mol. Cell Biol., 20, 137-155 (2019);  DOI).

From time to time in this blog, I have mentioned the N-acylhomoserine lactones, which govern how many bacterial species interact with each other and with their environment. A new molecular species has just been isolated with the main fatty acid component being 2E,5Z-dodecadienoic acid. Locating double bonds close to the carboxyl group can be tricky, as they have a tendency to migrate under mild reaction conditions, so the authors had to synthesise various possibilities for comparison purposes (Ziesche, L. et al. An unprecedented medium-chain diunsaturated N-acylhomoserine lactone from marine Roseobacter group bacteria. Marine Drugs, 17, 20 (2019);  DOI). The references cited lead me to a publication that I had missed when it first appeared and contains an excellent review of the topic. It also introduced me to a whole new area (to me at least) of fatty acid biochemistry (Schulz, S. and Hötling, S. The use of the lactone motif in chemical communication. Nat. Prod. Rep., 32, 1042-1066 (2015);  DOI - open access).

February 20th, 2019

There is a new record for the most highly unsaturated natural fatty acid from a conventional source, i.e. tetratriacontadecaenoic acid or 34:10, from a fish oil supplement (Ozaki, H. et al. Basic eluent for rapid and comprehensive analysis of fatty acid isomers using reversed-phase high performance liquid chromatography/Fourier transform mass spectrometry. J. Chromatogr. A, 1585, 113-120 (2019);  DOI). The methodology used does not permit detailed determination of the structure, but that illustrated appears to be the most probable. The previous record for a normal tissue belonged to 28:8(n-3) from marine dinoflagellates, although fatty acids with an even higher degree of unsaturation have been isolated from the brains of patients with genetic impairments of peroxisome function.

34:0 fatty acid

It has long been known that aspirin inhibits the cyclooxygenase (COX) enzymes by transferring its acetyl group irreversibly to a specific serine residue, which then protrudes into the active site and obstructs the binding of arachidonate. However, COX-2 is not completely inhibited but there is shift in reaction specificity, converting the enzyme activity from that of a cyclooxygenase to a lipoxygenase, and resulting in the generation of 15(R)-hydroxy-5,8,11,13-eicosatetraenoic acid (15(R)-HETE), i.e. with the opposite chirality to that produced in the lipoxygenase reaction. Now a new publication demonstrates that some PGD2, but not PGE2, is formed also - again with the 15(R)-configuration (Giménez-Bastida, J.A. et al. Residual cyclooxygenase activity of aspirin-acetylated COX-2 forms 15R-prostaglandins that inhibit platelet aggregation. FASEB J., 33, 1033-1041 (2019);  DOI). This may contribute to the therapeutic effects of aspirin.

Two weeks ago, I commented on the need for care in preparing the title of their publications, and this is also true for the abstracts. As I will not have access to the above publication for a year, I was grateful that it had an accurate title and abstract - certainly enough for my diletante requirements. In contrast this week, I came across a paper in my literature search that claimed in the title to have discovered a novel keto fatty acid in a plant source, but with no structural information whatsoever in the abstract.

February 13th, 2019

The UK government recently announced that new funds (£30M) were being made available to universities for research into the discovery of new antibiotics, as pharmaceutical companies seem to believe that such research is not cost effective. I hope that some of this money will go to lipid biochemists, as bacterial lipopeptides are among our best hopes for success. Cyclic lipopeptides appear especially promising, and a new review discusses their biosynthesis by ribosomal and nonribosomal mechanisms as well as their therapeutic potential (Monaim, S.A.H.A. et al. Bacteria hunt bacteria through an intriguing cyclic peptide. Chemmedchem, 14, 24-51 (2019);  DOI). Although to date cyclic lipopeptides have greater antibacterial potency and greater oral bioavailability, linear lipopeptides have significant activity and cannot be neglected in that they are more accessible by chemical synthesis, so that modified forms can easily be produced in quantity (Moon, S.H. and Huang, E. Novel linear lipopeptide paenipeptin C binds to lipopolysaccharides and lipoteichoic acid and exerts bactericidal activity by the disruption of cytoplasmic membrane. BMC Microbiol., 19, 6 (2019);  DOI). The polymyxins have been around since the 1960s, but they were abandoned as systemic antibiotics because of nephrotoxicity. However, they have made something of a comeback as a drug of last resort against drug resistant Gram-negative bacterial strains, aided by the development of new derivatives. They have value also in that they damage the outer membranes of target bacteria and render them more permeable to other antibiotics (Vaara, M. Polymyxin derivatives that sensitize Gram-negative bacteria to other antibiotics. Molecules, 24, 249 (2019);  DOI).

It may seem surprising to some, but the essentiality of dietary α-linolenic acid (18:3(n-3)) was doubted by many in the lipid community until the 1970s, mainly it seems because it did not cure the dermal symptoms of EFA deficiency. The finding that docosahexaenoic acid (DHA) is necessary for optimum retinal function did not attract much attention, and the position only changed when it was observed that Greenland Eskimos had a low incidence of atherosclerotic coronary disease because of the anti-thrombotic effect of eicosapentaenoic acid in the diet. The rest as they say is history (Spector, A.A. and Kim, H.-Y. Emergence of omega-3 fatty acids in biomedical research. PLEFA, 140, 47-50 (2019);  DOI). The authors suggest that we should take note of the delay in recognizing the importance of omega-3 fatty acids if we are to avoid similar pitfalls in future.

February 6th, 2019

In my blog of January 16th, I commented briefly on the strange fact that a fatty acid present at rather low levels only in tissues, i.e. myristic or 14:0, had been adopted by natural selection almost exclusively for N-acylation of proteins. I suppose that it is advantageous to have a straight-chain saturated molecule for this purpose, as this may insert more easily into a membrane in comparison to say an unsaturated fatty acid with a kink in the 3-dimensional shape, but why 14:0? Now a new publication provides an explanation for how this occurs if not why (Soupene, E. and Kuypers, F.A. ACBD6 protein controls acyl chain availability and specificity of the N-myristoylation modification of proteins. J. Lipid Res., in press;  DOI). It is demonstrated that a protein designated 'ACBD6' supports the reaction of N-myristoyl-transferase enzymes under unfavorable substrate-limiting conditions, and prevents utilization of potentially competing species such as 12:0 or 16:0.

I have the impression that authors do not put enough thought into the titles of their papers. There is an art to it and titles that avoid abbreviations/acronyms and are brief but to the point are my favourites, such as this recent review (Lone, M.A. et al. 1-Deoxysphingolipids. Biochim. Biophys. Acta, 1864, 512-521 (2019);  DOI). The title of the paper is in fact shorter than the abbreviated name of the journal, but it tells us all we need to know. There are others who would produce a title such as "The chemistry, biochemistry and physical chemistry of 1-deoxysphingolipids with special reference to et cetera, et cetera". Whatever the title, they are fascinating lipids, not least because they have potent anti-cancer activity. You can find an introduction to the topic on this website here..

I was sorry to learn of the death of Professor Rodolfo R. Brenner from Argentina, who died last year just before his 96th birthday. I first met him in the 1960s when he visited Ralph Holman's lab, where I was a post-doc, and this encounter lead to a collaborative project and eventually a joint publication. I remember him as an enthusiastic scientist who gave great encouragement to a young man at the start of his scientific career. There is a brief memorial in PLEFA.

January 30th, 2019

Scottish thistleThere seems to be particular interest in the epoxyeicosatrienoic acids (EETs) at present because of their therapeutic potential, and a new study demonstrates that 11,12-EET enhances the process by which immature precursor cells develop into mature blood cells (hematopoiesis) and their further development (engraftment) in mice and zebrafish in vitro. For the first time, a receptor for EETs has been identified, i.e. GPR132 - a low-affinity EET receptor with physiological relevance in hematopoiesis (Lahvic, J.L. et al. Specific oxylipins enhance vertebrate hematopoiesis via the receptor GPR132. Proc. Natl. Acad. Sci. USA, 115, 9252-9257 (2018);  DOI).

The Journal of Biological Chemistry has just selected a paper that deals with EETs among other oxylipins as their paper of 2018 in their Lipids section (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). In brief, in non-failing human hearts, one isoform of phospholipase A (cPLA2ζ) channels arachidonic acid into protective EETs, whereas in failing hearts, opening of the mitochondrial permeability transition pore increases the activity of a second isoform of phospholipase A (cPLA2γ) that channels arachidonic acid into toxic HETEs. A second lipid biochemistry paper is their 2018 choice for the Immunology section.

Incidentally, for those interested in the history of lipid science, my mentor and colleague Frank Gunstone was the first to identify and characterize a naturally occurring epoxy fatty acid, i.e. vernolic acid or 12,13-epoxy-octadec-cis-9-enoic acid from the seed oil of Vernonia anthelmintica (Gunstone, F.D. Fatty acids. Part II. The nature of the oxygenated acid present in Vernonia anthelmintica (Willd.) seed oil. J. Chem. Soc., 1611-1616 (1954);  DOI). He told me a few years ago that on thinking back, he was now especially pleased with this work because it was accomplished without the aid of chromatography, spectroscopic techniques or computers (any one remember tables of logarithms?). Rather, he had a balance, a burette and his knowledge of chemical reactions - see also his article in the Lipid Library for a general review of Fatty Acid Analysis before Chromatography. Frank recently celebrated his 96th birthday, but is frail and living in a retirement home. Happily, he has an extensive family nearby, including many greatgrandchildren, and he still has a zest for life.

January 23rd, 2019

In recent years, I have read any number of reviews extolling the virtues of the various methodologies available for lipidomics, especially in relation to mass spectrometry, but I have rather enjoyed reading one which deals more with the limitations. In addition to MS (with and without chromatography), nuclear magnetic resonance is discussed, as well as universal detectors for HPLC (evaporative light-scattering and charged-aerosol detectors) (Khoury, S. et al. Quantification of lipids: model, reality, and compromise. Biomolecules, 8, 174 (2018);  DOI - open access). With all of these, quantification is the main issue and the choice of internal standards is critical. While standards are available for most lipid classes, relatively few are available for specific molecular species. The authors point out that for example, 9856 species are listed in the LIPID MAPS® Lipidomics Gateway for glycerophospholipids but only about 80 analytical standards are available commercially. There may be differences in the response to species within a lipid class because of differences in fatty acid composition - hence the need for the 'compromise' of the title. Incidentally, I was pleased to see that there is still interest in universal detectors for HPLC, as I was under the impression that they were in danger of being forgotten.

While we should be aware of the limitations of mass spectrometry, we should also acknowledge its successes, and I have been impressed by a paper describing the separation and quantification of glucosyl- and galactosylceramides, which are virtually identical in structure, by differential ion mobility spectrometry (Xu, H.B. et al. DMS as an orthogonal separation to LC/ESI/MS/MS for quantifying isomeric cerebrosides in plasma and cerebrospinal fluid. J. Lipid Res., 60, 200-211 (2019);  DOI).

January 16th, 2019

A novel lipid to catch my eye this week is 1,28-octacosa-6,9,12,15-tetraenedioate or in other words a C28 dicarboxylic acid with four double bonds, probably produced in tissues by chain elongation of arachidonate, followed by ω-oxidation by various CYP450 enzymes (Wood, P.L. Endogenous anti-inflammatory very-long-chain dicarboxylic acids: potential chemopreventive lipids. Metabolites, 8, 76 (2018);  DOI). Although much about its origin is a matter for conjecture, plasma levels are greatly reduced in certain cancers, so it obviously warrants further investigation. It would also be interesting to know whether similar very-long-chain oxylipins remain to be discovered, as few analysts look that far out in chromatograms.

I am always intrigued by how natural selection has picked certain fatty acids for particular purposes. For example, myristic acid is a rather minor fatty acid in all tissues and it has no functional groups in the chain to modify its three-dimensional shape, yet it is used almost exclusively for N-acylation of proteins. Another fatty acid with perhaps surprising properties is palmitoleic acid (9-16:1), which unusually is O-acylated, as opposed to S- or N-acylated, to a specific serine residue in the Wtn family of proteins and is essential for their vital functions in fetal development (see my web page on proteolipids). Such fatty acylation of Wnt is also required for its recognition by the co-chaperone 'Wntless' and for its binding to the 'Frizzled' receptor family. For background, I had to look this up in Wikipedia and found that "When activated, Frizzled leads to activation of Dishevelled in the cytosol" - some biochemists obviously have a sense of humour, although it sounds like me getting up in the morning. A new review describes the structures of these proteins and how the palmitoleate fits into a specific groove in the receptor to facilitate binding and thence signalling (Nile, A.H. and Hannoush, R.N. Fatty acid recognition in the Frizzled receptor family. J. Biol. Chem., 294, 726-736 (2019);  DOI - Author's choice).

January 9th, 2019

Gangliosides are fascinating lipids, not least because they demolish any definition of lipids based on their solubility in organic solvents. In the Folch extraction procedure, gangliosides partition into the aqueous phase. There is no doubt that the bargain of the week is a comprehensive review (more than 300 references) of the chemistry and metabolism of gangliosides (Sandhoff, R. and Sandhoff, K. Emerging concepts of ganglioside metabolism. FEBS Letts, 592, 3835-3864 (2018);  DOI - open access). The article is dedicated to Professor Wilhelm Stoffel on the occasion of his 90th birthday. I have some work to do now to update my web page on this lipid class, especially as there is a further review article on glycosphingolipid-enriched lipid rafts in immune systems in the same journal issue (also open access).

ananatoside AThe first new lipid that I have encountered in the new year is an unusual glycolipid surfactant of bacterial origin (Gauthier, C. et al. Structural determination of ananatoside A: An unprecedented 15-membered macrodilactone-containing glycolipid from Pantoea ananatis. Carbohydrate Res., 471, 13-18 (2019);  DOI). It consists of glucose esterified to two 3-hydroxy fatty acids to form a novel cyclic structure.

For those fortunate enough to have access (not me), a new book is available - "Sphingolipids in Cancer" edited by Charles E. Chalfant and Paul B. Fisher (Advances in Cancer Research, Volume 140, Pages 1-388 (2018)), while a substantial review on lipid rafts has been published (Cebecauer, M. et al. Membrane lipid nanodomains. Chem. Rev., 118, 11259-11297 (2018);  DOI).

Why do PDF files from journals vary so much in size? A 9-page pdf that I downloaded from one journal this week was 16Mb, while a 30-page pdf in another was only 2 Mb; the number and quality of the illustrations did not seem to be a factor. I have a fast broadband connection and more disk space than I am every likely to need, so it hardly matters to me, but what about our scientific colleagues around the world without such generous provision?

I am not sure if the word 'fatberg' has found its way into any modern dictionary, but their existence is certainly proving a concern to towns in the UK (see the BBC News website). This is one problem in lipid science/technology that I am happy to leave to others to solve.

January 2nd, 2019

At this time of year, I have usually looked back through the reference lists in my literature survey pages to see which lipid classes have been trending in relation to my Lipid Essentials pages. This approach is not ideal in that a single review issue of a journal can distort the picture, but every year until now, sphingosine-1-phosphate and phosphoinositides have topped the list. Instead, this year I have used the log that I keep of the regular updates to my web pages in this section to determine where I have had to make most improvements. These can range from simply a new reference and/or a line of text to more substantial revisions (and hopefully on rare occasions only to correction of errors). The clear winner under my new approach was my web page on hydroxyeicosatetraenoic acids (HETE) closely followed by that on specialized pro-resolving mediators (SPMs). If the web page on leukotrienes is also taken into account, it is evident that oxylipin research is where I appear to be noticing appreciable progress. Among the glycerolipids, triacylglycerols (surprisingly?) and phosphoinositides tied for first place (although the latter wins when the web page on glycosylphosphatidylinositol anchors for proteins is taken into account), with the web page on phosphatidic acid (and lysoPA) a close third. Endocannabinoids were also well represented in my updates. Other than sphingosine-1-phosphate, my sphingolipid web pages tended to be updated relatively less frequently, as were those on fatty acids other than oxylipins. The poor relations were the web pages on cyanolipids (zero updates), and ceramide-1-phosphate and hopanoids (1 each).

The first special review issue of a journal of the new year is on the topic of "Brown and Beige Fat: From Molecules to Physiology" edited by Paul Cohen (Biochim. Biophys Acta, 1864, Issue 1, Pages 1-112 (January 2019)).

Blogs for the previous year (2018) can be located here..

Author: William W. Christie Updated: May 6th, 2020 Credits/disclaimer LipidWeb logo