The LipidWeb blank

Lipid Matters - Archive of Older Blogs - 2017

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 2017 are archived, while those for other years can be accessed from the foot of the current blog page.

December 20th, 2017

Scottish thistleAt this time of year, there is only one paper that I wish to highlight because of its appropriateness to the Christmas season, and happily it is open access (Morikawa, T., Matsuda, H. and Yoshikawa, M. A review of anti-inflammatory terpenoids from the incense gum resins frankincense and myrrh. J. Oleo Sci., 66, 805-814 (2017); DOI). It even has three wise men (persons?) as authors. I presume that the word "anti-inflammatory" in the title refers to "Peace on Earth and goodwill to all men".

Merry Christmas and a happy, healthy, prosperous and anti-inflammatory New Year to all my readers!

December 13th, 2017

In recent years, the potential for using natural lipids as pharmaceuticals to treat various disease states has become very evident. Outsiders such as myself are rarely aware of the many pitfalls in taking a new discovery from patent application through to clinical trials and commercial success. A new review discusses this in relation to palmitoylethanolamide and the specialized pro-resolving mediators (Hesselink, J.M.K. Fundamentals of and critical issues in lipid autacoid medicine: a review. Pain Therapy, 6, 153-164 (2017); DOI). For example, palmitoylethanolamide was proven to alleviate neuropathic pain in the 1990s, but the first company to patent and develop this for clinical purposes went out of business because of delays in the Italian licensing system. Now the patents have expired and there is no financial incentive for anyone else to take it on, although there seems little doubt that it is safe and effective. The first patent on the lipoxins was issued in 1984, but only one clinical pilot trial in atopic eczema can be identified so far.

I take some pleasure in reading of natural cholesterol derivatives with important health-giving properties, and one such is dendrogenin A (DDA), a naturally occurring conjugate of cholesterol and histamine. Its synthesis is greatly reduced in cancer cells, and it has now been shown to be a potent tumor suppressor that controls a nuclear receptor to kill cancers (Segala, G. et al. Dendrogenin A drives LXR to trigger lethal autophagy in cancers. Nature Commun., 8, 1903 (2017); DOI - open access).

There is a report in Nature News that Elsevier continues to have a problem with German universities in that negotiations have failed to end a long-term contract dispute. The aim of the universities, which will no doubt be supported by most scientists, is to reduce subscription prices and promote immediate open access. While I accept that commercial publishers must be allowed to make a profit, the last figure I saw for Elsevier was 36% of turnover and this seems grossly excessive. A new business model is surely required. When I read the report, I checked my personal data base of references that are cited in the Literature Survey section of the LipidWeb, and I found that nearly half were to Elsevier journals. This figure is certainly skewed in that I don't have access to many smaller publishers and many of the chemistry journals, not least those from ACS and RSC, but it does demonstrate the influence of Elsevier. If I can't read papers to update my pages here, I rarely cite them, although I do cite those in journals that are sufficiently public spirited to allow open access after 1-2 years.

December 6th, 2017

Most readers today will not need me to explain the importance of lipid mediators in biology, but this was not always so. I recall attending an ICBL Congress in 1968 when a keynote speaker described prostaglandins as "a drug in search of a disease"! (The only virtue of growing older is that you remember such things). The earliest true pharmaceutical to come into general use and probably still that most widely used is aspirin, which is now known to inhibit the synthesis of the prostaglandins and certain other eicosanoids or modify their nature via its action on the cyclooxygenases. A fascinating new review describes how the full potential of aspirin and many other pharmaceuticals could not have been realized without the knowledge gained from lipidomic studies on the eicosanoid patterns in tissues in various clinical conditions (Stephenson, D.J. et al. Lipidomics in translational research and the clinical significance of lipid-based biomarkers. Translat. Res., 189, 13-29 (2017); DOI). For example, by revealing the pattern of eicosanoids during cardiovascular disease or in patients with pre-eclampsia, it became evident that low-doses of aspirin had great therapeutic potential. Many other benefits from lipidomic studies to such disease states as neurodegenerative diseases, cancer, sepsis and wound healing are discussed also in this review.

The tag "et al." has never been more useful than in a new publication in the Journal of Lipid Research, which has 94 authors (I don't guarantee the accuracy of my count) (Bowden, J.A. et al. Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-Metabolites in Frozen Human Plasma. J. Lipid Res., 58, 2275-2288 (2017); DOI). John A. Bowden was fortunate in that his name is first in the alphabetical order of authors so takes pride of place in the list. Joking aside, I suspect that this will come to be regarded as a seminal paper in the science of lipidomics, although it is a pity that it is not open access. However, like me, you may still be able to get hold of a manuscript copy if not the final printed form via the journal.

November 29th, 2017

Scottish thistleIn plants, the external cuticle layer has many of the same functions as the skin in animals in that it acts to prevent water loss while providing a barrier against pathogenic bacteria and fungi as well as insect predators. Lipids play key roles in both although their natures are very different; in skin, ceramides and other sphingolipids are the essential components, but in plants there is a complex polyester that includes polyhydroxy and dibasic fatty acids and this is overlaid by a layer of wax. While some have argued that plant waxes are the most abundant lipids on earth, it is the polyester component of the cuticle that is attracting most interest at the moment because of its structural properties and the potential to modify it to increase crop yields or as a future source of bio-plastics. Incidentally, cutins from decaying plants are also the source of important lipid components of soils. The Journal of Experimental Botany has devoted a special issue to the topic with an introductory article that summarizes many of the key factors and is open access (Domínguez, E. et al. The plant cuticle: old challenges, new perspectives. J. Exp. Bot., 68, 5251-5255 (2017);  DOI).

Among the novel lipids of skin are ceramides containing estolide linked fatty acid constituents. However, it is those with free carboxyl groups or 'FAHFA' (Fatty Acid ester of Hydroxy Fatty Acid) in other tissues that continue to fascinate. A range of (O-acyl)-ω-hydroxy-fatty acids (the hydroxyl group is terminal not centrally located) with up to 52 carbon chain lengths have been found in equine amniotic fluid, together with many other interesting lipid species (Wood, P.L. et al. Lipidomics of equine amniotic fluid: Identification of amphiphilic (O-acyl)-ω-hydroxy-fatty acids. Theriogenology, 105, 120-125 (2018);  DOI). Similar fatty acid estolides have been found in sperm and meibomian glands, but their function is still a matter for speculation.

The journal Seminars in Immunology has devoted a special issue (Volume 33, Pages 1-74, October 2017) to the topic of "Leukotriene B4 mediated inflammation" (edited by Bodduluri Haribabu).

November 22nd, 2017

Of all the health food supplements that are available, it appears that omega-3 fatty acids from fish oil preparations are the most popular. While reputable manufacturers take great pains over the quality of their products, they have no control of how they are stored in supermarkets or whether consumers store them properly or simply let them sit in medicine cabinets. I am sure that oxidation products often develop rapidly, although off-flavours may be disguised by the encapsulation process. A new review summarizes the biological properties of compounds derived from peroxidation of omega-3 polyunsaturated fatty acids, including aldehydes, isoprostanes and more (Wang, W. et al. Chemistry and biology of ω-3 PUFA peroxidation-derived compounds. Prostaglandins Other Lipid Mediators, 132, 84-91 (2017);  DOI). Many potential adverse effects are known, and the authors are concerned that variable amounts of such impurities might explain the mixed results obtained in some nutritional studies. Personally, I prefer fresh fish to fish oil supplements.

S-Palmitoylation is increasingly being seen as an important way of regulating the activities of potential membrane proteins. In humans, 23 palmitoyl transferases are known to exist with a conserved cysteine-rich domain containing a distinctive aspartate-histidine-histidine-cysteine (DHHC) motif, which is required for activity. On the other hand, no conserved amino acid sequence has yet been identified in target proteins. A new open access publication describes interesting mass spectrometry methodology to reveal that there is a random palmitoylation process that depends simply upon the accessible of cysteines in proteins to the palmitoyl transferases (Rodenburg, R.N.P. et al. Stochastic palmitoylation of accessible cysteines in membrane proteins revealed by native mass spectrometry. Nature Commun., 8, 1280 (2017);  DOI).

November 15th, 2017

The hedgehog proteins are among my favourite molecules as they stick up two metaphorical fingers to nutritionists. The first such finger is cholesterol, which is covalently bound to the C-terminus, while the second is palmitic acid covalently bound to the N-terminus. Although they are anathema in some quarters, the vital importance of the two much maligned lipid components is clearly demonstrated since hedgehog proteins have a major role in signalling during the differentiation of cells in the development of all embryos from Drosophila to fish to humans and are required for an extensive range of processes, from the control of left-right asymmetry of the body to the specification of individual cell types within the brain and limb development. They are the subject of a new open access review (Blassberg, R. and Jacob, J. Lipid metabolism fattens up hedgehog signaling. BMC Biology, 15, 95 (2017);  DOI).

Membrane microdomains termed 'rafts' have long been believed to be formed spontaneously in the outer leaflet of the plasma membrane by the physical chemical association of cholesterol, sphingolipids and membrane proteins. They act to compartmentalize and provide a platform for the last and thereby separate different biochemical functions. However, there is a conflicting view of the prevailing raft hypothesis based on studies by high-resolution secondary ion mass spectrometry that suggests that sphingolipids are concentrated in micrometer-scale membrane domains while cholesterol is evenly distributed within the plasma membrane. In this model, sphingolipid distribution in the plasma membrane is dependent on the cytoskeleton, but not on favorable interactions with cholesterol. An open access review, published earlier this year, discusses this alternative theory (Kraft, M.L. Sphingolipid organization in the plasma membrane and the mechanisms that influence it. Front. Cell Dev. Biol., 4, 154 (2017);  DOI).

I was under the impression that I had a good understanding of the nature of bile acids, which are important cholesterol metabolites with essential functions in digestion and signalling. However, I have just come across a paper that describes a small group of bile acids with planar structures of which I had no previous knowledge (Shiffka, S.J. et al. Planar bile acids in health and disease. Biochim. Biophys. Acta, Biomembranes, 1859, 2269-2276 (2017);  DOI). These are found in humans during infancy and in a few disease states, but not otherwise. In evolutionary terms, they may be related to the ancestral bile acids.

November 8th, 2017

Another special journal issue deals with the important topic of specialized pro-resolving mediators, i.e. resolvins, protectins and maresins, (Dalli, J. (Editor) The physiology and pharmacology of specialized pro-resolving mediators. Molecular Aspects of Medicine Volume 58, Pages 1-130 (December 2017)). The editor's own contribution is open access and has the intriguing title of "Does promoting resolution instead of inhibiting inflammation represent the new paradigm in treating infections?" Uncontrolled inflammation as occurs during sepsis is an increasing problem in our hospitals, and the resolvins, protectins and maresins have been shown to "actively reprogram the immune response to promote clearance of invading pathogens, and counter-regulate the production of inflammation-initiating molecules". Clinical trials of these lipids and mimetics against a number of inflammatory conditions, including sepsis, are now in progress and they are discussed in other reviews in this issue.

In contrast, cholesterol 5,6-epoxide formed non-enzymatically was for some time believed to be a causitive agent in cancer, but it has now been established that downstream metabolites are in fact responsible (Voisin, M. et al. Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor. PNAS, 114, E9346-E9355 (2017);  DOI). A cholesterol epoxide hydrolase converts cholesterol 5,6-epoxide into cholestane-3β,5α,6β-triol, which is transformed by 11β-hydroxysteroid-dehydrogenase-type-2 into the oncometabolite 6-oxo-cholestan-3β,5α-diol. By binding to the glucocorticoid receptor, this last metabolite stimulates the growth of breast cancer cells. It is hoped that targeting the enzymes involved in this metabolic process may lead to new treatments for breast and other cancers.

It has been less easy to establish definitively the biological effects of other oxysterols as so much cholesterol may be present in experiments in vitro that unwanted metabolites may be introduced inadvertently. However, there is good evidence for the involvement of 27-hydroxycholesterol as an endogenous and selective modulator of estrogen receptors with implications for a number of disease states including neurodegenerative diseases, atherosclerosis, osteoporosis and some cancers (He, S.S. and Nelson, E.R. 27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator. Maturitas, 104, 29-35 (2017);  DOI).

Every year I seem to find a news item highlighting the poor job prospects for new PhD students and I usually predict that nothing will change. This is still true - see Nature News!

November 1st, 2017

While I have been enjoying the sunshine of the Canary Islands, the world of lipids has been turning rapidly. It seems most unfair that after returning from 30°C on a beach in Gran Canaria to 11°C and thermal underwear in Scotland, in addition to scanning many new research papers and other chores, I have now to try to assimilate three special review volumes to update my Lipid Essentials pages, i.e. "Focus on plasmalogens" in FEBS Letters (Volume 591, Issue 20) and open access, "Oxysterols and Phytosterols in Human Health" (edited by Charbel Massaad, Luigi Luliano and Gérard Lizard) in Chemistry and Physics of Lipids (Volume 207, Part B) and "Microbe and host lipids", edited by Jérôme Nigou, Lhousseine Touqui, Michel Record in Biochimie (Volume 141).

Sometimes it is the science oddities rather than major new research findings in terms of lipid metabolism that catch the eye. For example, I was intrigued by a report in the popular scientific press of preen gland lipids being identified in the fossil of a 48-million-year-old bird. It appears that the composition was sufficiently similar to that of the waxes in modern birds to enable an unequivocal identification.

Another fascinating if more relevant observation in relation to human health is carried in a paper that demonstrates that gangliosides are essential for hearing in that their presence in membrane rafts is required to maintain the structural and functional integrity of hair cells in the ear (Inokuchi, J. et al. Gangliosides and hearing. Biochim. Biophys. Acta, General Subjects, 1861, 2485-2493 (2017);  DOI). If you have an interest in these sphingoglycolipids there is a second publication in the same journal issue dealing with gangliosides, rafts and inflammation.

October 18th, 2017

Scottish thistleFor decades, plant biochemists have been looking for a magic bullet that will enable them to alter the lipid composition of membranes in plants to make them less sensitive to cold. Some progress has been made by introducing desaturase genes, and the composition of phosphatidylglycerol appears to be especially important. However, a new review provides a broader context to the problem by comparing the factors that differentiate the model plant Arabidopsis from a close relative that is especially hardy (Barrero-Sicilia, C. et al. Lipid remodelling: Unravelling the response to cold stress in Arabidopsis and its extremophile relative Eutrema salsugineum. Plant Sci., 263, 194-200 (2017);  DOI). It is evident that there are many different factors involved including many compounds other than lipids (sugars, nitrogen compounds and proteins) that are required to conserve membrane integrity during cold acclimatization. Then, we have to understand the role of signalling lipids in controlling how membranes respond to change, where it appears that sphingolipid analogues of sphingosine-1-phosphate are especially important. Despite this complexity, the authors seem to be confident that further lipidomic studies in combination with genome editing in a precise manner "will enable the development of breeding strategies that deliver climate resilient crops."

The nature of the challenges to modifying lipid compositions in plants is illustrated by a further review in the same journal issue, where the authors point out that to introduce new fatty acids of potential industrial interest to crop plants it is rarely possible to introduce a single biosynthetic gene. It is always necessary to add further genes for enzymes that can handle the new fatty acid and complete the transfer to a safe esterified state (Aznar-Moreno, J.A. and Durrett, T.P. Metabolic engineering of unusual lipids in the synthetic biology era. Plant Sci., 263, 126-131 (2017);  DOI).

I suppose it was not really a surprise to learn that Elsevier and the American Chemical Society have filed a lawsuit with the aim of removing copyrighted material from ResearchGate (see Nature News). I have mixed feelings about this, coloured of course by my personal circumstances. My former employer allows me access to a wide range of biological publications from the big three publishers together with a range of journals to which it subscribes, but I can't access chemistry journals or many of those with a medical slant. While I could use interlibrary loan facilities, this bears a significant cost and I cannot justify this when I am only going to use the information I glean for my website and not for research purposes. The prices required by journals for digital access are so unreasonable - far higher than those for interlibrary loan photocopies - that it is no wonder that scientists turn to ResearchGate in the hope of finding copies there. I have to confess that I do this from time to time, and often find preprints rather than the final publications and these are more than adequate for my purposes. Would this be a fair compromise?

As you may guess from the title, I read another review with great interest this week (Bustos, V. and Partridge, L. Good ol' fat: links between lipid signaling and longevity. Trends Biochem. Sci., 42, 812-823 (2017);  DOI). While it is a fascinating account of the use of the nematode worm Caenorhabditis elegans in studies of this kind, it is apparent again that there is no magic bullet alas. However, there is clear evidence that dietary restriction helps, and oleoylethanolamide does extend life in worms at least via its signalling properties. There is also something to be said for higher relative dietary proportions of oleate in general. If it will keep me compos mentis as well for longer, I will volunteer as a guinea pig.

Last month, I highlighted a multiauthor paper describing protocols for the use of NMR spectroscopy for the analysis of lipoprotein classes. Now a new review publication provides a general overview of the techniques involved (Aru, V. et al. Quantification of lipoprotein profiles by nuclear magnetic resonance spectroscopy and multivariate data analysis. Trends Anal. Chem., 94, 210-219 (2017);  DOI).

October 11th, 2017

Developments in mass spectrometric methodology has turned the analysis of lipids into a new science - lipidomics, but I must confess that I tend to pay relatively little attention to the applications of nuclear magnetic resonance spectroscopy to lipid science. The latter lacks the sensitivity of MS methods, but it can make an invaluable contribution to lipid analysis and structure identifications nonetheless, especially when sample size is not limiting. Indeed, NMR spectroscopy may have advantages in settling stereochemical problems. A new review of the subject is therefore timely (Li, J. et al. Applications of nuclear magnetic resonance in lipid analyses: An emerging powerful tool for lipidomics studies. Prog. Lipid Res., 68, 37-56 (2013);  DOI). If the DOI link doesn't work, blame Elsevier.

A new review on the subject of "steryl esters" in BBA reminded me that some years ago when I raised a nomenclatural point with IUPAC-IUB, they rebuked me for using the generic term "cholesteryl esters", which I was told should correctly be termed "cholesterol esters". "Cholesteryl" should be applied only when describing individual lipid species, e.g. cholesteryl palmitate, cholesteryl oleate, etc. Over to you Lipid Maps!

Just has Christmas comes earlier every year in the shops at least, so does the new publishing year roll out earlier. In my literature survey last month, I cited my first 2018 reference! The journal Food Chemistry wins the race every year.

October 4th, 2017

Humans differ from all other animals in that we do not make the sialic acid N-glycolylneuraminic acid (Neu5Gc) for incorporation into gangliosides and glycoproteins. This is believed to have occurred during evolution soon after we diverged from a common ancestor with the great apes and may have had profound implications for the development of the human brain. It could also mean that there might have been a fertility barrier between us and other species of hominids. Proving these conjectures has seemed impossible, but it has now been established that sufficient glycoproteins linked to Neu5Gc are present in intact form in fossil bones to enable determination of its presence. It will be fascinating to see how the story now unfolds. There is a popular account of the research in Science Daily with a link to the original publication for those needing further details.

Just as I was working my way through one special issue, Biochimica Biophysica Acta has brought forward another that deals with "Bacterial Lipids" and edited by Russell E. Bishop; I suspect it will keep me busy updating my web pages here for some time.

A fascinating story has emerged in a new publication that demonstrates how the liver undergoes a metabolic switch to provide fuel for brown fat thermogenesis by producing acylcarnitines. Under cold stimulation, white adipocytes release free fatty acids for acylcarnitine production in the liver to be supplied in the circulation to brown adipose tissue. At the same time, uptake of acylcarnitines into white adipose tissue and liver is blocked (Simcox, J. et al. Global analysis of plasma lipids identifies liver-derived acylcarnitines as a fuel source for brown fat thermogenesis. Cell Metab., 26, 509-522.e6 (2017);  DOI). While the quantitative aspects appear to require further work, the process is certainly an elegant one. I don't have access to the original paper yet, but the journal issue contains a commentary or 'preview' that describes the work and is accessible (if you know where to look via Google).

September 27th, 2017

Scottish thistleWhile my weekly literature searches keep me reasonably up-to-date, the algorithm I use is far from perfect and I have just come across a fascinating lipid story that started in 2012 and continues to the present. First a little background - choanoflagellates are motile microbial eukaryotes that live in aquatic environments and feed on bacteria. They are believed to be the closest living relatives of animals and are normally unicellular. However, it has now been demonstrated that on exposure to novel sulfonolipid analogues of ceramides related to the capnoids and produced by Algoriphagus machipongonensis, a marine bacterium that serves as its prey, the choanoflagellate, Salpingoeca rosetta, forms multicellular 'rosettes' in a manner that may provide insights into how multicellularity evolved in animals. Two such lipids have been isolated and characterized and they have been termed 'Rosette-Inducing Factors' - RIF-1 (illustrated) and RIF-2. Both have capnoid bases attached to 2-hydroxy,iso-methylbranched fatty acids, but RIF-2 differs from RIF-1 in the nature of the capnoid base component. S. rosetta is extraordinarily sensitive to RIF-1 and is induced to form rosettes at femtomolar (10-15M) concentrations. A second lipid class, lysophosphatidylethanolamines, produced also by the symbiotic bacteria elicits no response on its own but acts synergistically with the RIFs to maximize the activity of the latter.

Inducer/inhibitors of rosette formation in Choanoflagellates

A third lipid class now enters the picture as the same bacterial species also produces an inhibitor of rosette formation termed 'Inhibitor of Rosettes (IOR-1)' in the form of a further novel sulfonolipid, which is related structurally to the capnoid bases but with a hydroxyl group replacing the amine group to give the rare syn-diol configuration, i.e. 2S, 3R stereochemistry. It has been determined that there is an absolute requirement for the observed stereochemistry for all of these metabolites to exert their functions. To follow the story in greater detail, see the latest publication from the research group responsible for the work (Woznica, A. et al. Bacterial lipids activate, synergize, and inhibit a developmental switch in choanoflagellates. PNAS, 28, 7894-7899 (2016);  DOI).

September 20th, 2017

Although the evaporative-light scattering detector (ELSD) has its limitations in terms of linearity of response and sensitivity, it was the first truly universal detector for HPLC of lipids at a time when mass spectrometry interfacing was prohibitively expensive for most researchers. It enabled great strides in the development both of mobile and stationary phases for lipid separations and still has value for this purpose today. When charged aerosol detectors (CAD) were introduced, they seemed a step forward but they have never taken off. In part, this seemed to be because impurities in solvents caused problems and ionic species in mobile phases, which are necessary for elution of phospholipids, were especially troublesome. As liquid chromatography-mass spectrometry systems have become more affordable, the perceived need for alternative detectors may have lessened, but I believe the ELSD and CAD will remain useful tools, especially for development of novel elution systems and for semi-preparative applications (with stream splitters). A new publication presents a more positive view of the CAD than I have seen up till now, while also comparing the merits of various ionization techniques employed in mass spectrometry interfacing; atmospheric pressure photoionization (APPI) seems a clear winner (Abreu, S. et al. Optimization of normal phase chromatographic conditions for lipid analysis and comparison of associated detection techniques. J. Chromatogr. A, 1514, 54-71 (2017);  DOI). The paper also describes a rather novel and comprehensive elution scheme for normal-phase separation of lipid classes with silica as the stationary phase and a complex gradient in the mobile phase with ethyl acetate as a major component.

When I saw that a new review had been published on lipids in plant defense, I immediately assumed that this would deal primarily with the oxylipins and then mainly with jasmonates, but it proved much more than that. In fact, it covers a full range of lipids from fatty acids, via complex lipids to wax esters, and provides a fascinating and comprehensive overview of the subject (Lim, G.H. et al. Fatty acid- and lipid-mediated signaling in plant defense. Annu. Rev. Phytopath., 55, 505-536 (2017);  DOI).

The latest online issue of Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids (Volume 1862, Issue 10, Part B, Pages 1129-1284 (October 2017)) covers the topic of "Recent Advances in Lipid Droplet Biology" and is edited by Rosalind A. Coleman and Matthijs K.C. Hesselink.

September 13th, 2017

"A tale of two lipids" may sound Dickensian, but it aptly describes a paper drawn to my attention by the newsletter of the Fats of Life; in truth, it is anything but Dickensian (Houthuijzen, J.M. et al. Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance. FASEB J., 31, 2195-2209 (2017);  DOI). I have encountered hexadeca-4,7,10,13-tetraenoic acid or 16:4(n-3) at trace levels from time to time in marine samples, but never in animal tissues. Yet it is generated when platinum salts are administered as part of an anticancer chemotherapy regime where it induces systemic resistance to a broad range of DNA-damaging effects. The new study demonstrates that this fatty acid acts via a specific receptor to induce the synthesis in macrophages of the second unusual lipid in the tale, i.e. lysophosphatidylcholine containing the fatty acid 24:1, and this is also shown to be a resistance-inducing lipid mediator. Again, I don't recall seeing this particular molecular species when I was analysing animal lipids, though I must admit that it would be easy to overlook.

Nature has an interesting story concerning "predatory journals", which I suppose must be defined as those designed to milk revenue from researchers rather than to inform. While I have heard this epithet applied to the big three commercial publishers from time to time, the authors appear to refer to about ~2000 other journals, which are often published in third world countries and lack proper editorial boards or refereeing panels. It seems that many reputable authors are using them while unaware of the true situation. I can think of a few review articles, which have come from such journals and which I may have cited in this website from time to time because they appeared useful to me in updating my web pages, especially as many are part of the open access trend. In fairness to myself, I usually check whether the authors come from reputable institutions. Unfortunately, no one seems to have any idea what to do about the problem other than to keep researchers informed of the worst examples, and I suspect any solution would have to emerge sector by sector.

The journal Neuropharmacology (Volume 124, Pages 1-170 (15 September 2017)) is a special issue devoted to the topic of "A New Dawn in Cannabinoid Neurobiology", edited by Joseph F. Cheer and Yasmin L. Hurd. Many of the papers deal with the endocannabinoids.

September 6th, 2017

Sulfoquinovosyldiacylglycerols are key lipids in photosynthesis and thence for the survival of all advanced life as I discussed in my blog earlier in the year. A recent paper demonstrates that the positional distributions of fatty acids in this lipid can be determined by mass spectrometry (Granafei, S. et al. Unambiguous regiochemical assignment of sulfoquinovosyl mono- and diacylglycerols in parsley and spinach leaves by liquid chromatography/electrospray ionization sequential mass spectrometry assisted by regioselective enzymatic hydrolysis. Rapid Commun. Mass Spectrom., 31, 1499-1509 (2017);   DOI). One of the tools the authors used to validate their results was to generate the 2-monoacyl-sn-glycerol species by the action of a regiospecific lipase (although the positional data are not tabulated). A few weeks ago I bemoaned the fact that data for positional distributions of fatty acids in complex glycerolipids were only rarely published nowadays, as this is much easier for comparison purposes (and arguably for studies of biological functions) than vast tables of molecular species data. While it is technically possible to accomplish this by MS, I suspect that the precision of the methodology leaves something to be desired. This paper has inspired me to consider whether a useful complementary approach to the analysis of phospholipids especially might be to analyse lipid extracts before and after hydrolysis by enzymes that are specific for either the sn-1 or sn-2 positions, e.g. the sn-1 selective hydrolase used in the above study or an sn-2 specific enzyme such as the phospholipase A2 of snake venom. I would love to see a paper tabulating comparison data for stereospecific distributions of fatty acids in any complex glycerolipid obtained by mass spectrometry with and without enzyme hydrolysis and ideally alongside data obtained by classical methods. It might be a useful student project for someone.

Lysoglycosphingolipids are only rarely discussed in the literature, but they do have considerable biological importance and a new publication describes new sensitive methodology to determine their occurrence in body fluids in relation to screening for sphingolipidoses (Pettazzoni, M. et al. LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: A novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease. PLOS One, 12, e0181700 (2017);   DOI).

If my knowledge of the practicalities of mass spectrometry is somewhat outdated, I have to confess that my understanding of what can be accomplished by NMR spectroscopy has fallen even further behind. However, I do my best to keep up and read with great interest a new open access publication dealing with the use of this technique in the analysis of lipoproteins (Centelles, S.M. et al. Toward reliable lipoprotein particle predictions from NMR spectra of human blood: an interlaboratory ring test. Anal. Chem., 89, 8004-8012;   DOI). I remember well how tedious it was to analyse lipoprotein classes by ultracentrifugation or high-performance liquid chromatography. This new paper describes methodology that has advantages in terms of high reproducibility and speed, and appears to be especially suitable for studies involving large numbers of subjects. The separation techniques will always be needed, but the more information that can be obtained by other means the better especially when standardized protocols are available.

August 30th, 2017

Scottish thistleEvery week there is a report in the literature of a novel lipid being found in some exotic organism. Perhaps more surprising is how often new lipid structures are revealed in human tissues, and there are two good examples this week. While improvements in technology are often behind new discoveries, another explanation is that the authors have simply looked closer at minor components, or perhaps it is a bit of both. Ion mobility mass spectrometry appears to offer new opportunities in terms of separation and analysis of complex glycosphingolipids according to the charge state, the carbohydrate chain length and the degree of sialylation or other substitution with no requirement for a chromatography step, and a new report describes an application to brain lipids in which a large numbers of novel gangliosides modified with acetyl groups were discovered (Sarbu, M. et al. Electrospray ionization ion mobility mass spectrometry provides novel insights into the pattern and activity of fetal hippocampus gangliosides. Biochimie, 139, 81-94 (2017);   DOI). Last year, I commented on a paper from the same laboratory, where novel sialylated gangliosides were found in fetal brain by the same methodology.

The second relevant report is of the discovery of novel cholesterol esters containing estolide bound fatty acids in vernix caseosa, the natural biofilm on the skin of new-born babies (Kalužíková, A. et al. Cholesteryl esters of ω-(O-acyl)-hydroxy fatty acids in vernix caseosa. J. Lipid Res., 58, 1579-1590 (2017);   DOI). By means of reversed-phase liquid chromatography linked to mass spectrometry with atmospheric pressure chemical ionization, approximately 300 molecular species of this new lipid class were identified, with the most abundant containing a 32:1 ω-hydroxy fatty acid linked to those of a more conventional kind. I was aware of vernix caseosa as a source of wax esters containing a complex mixture of branched-chain fatty acids, but they are are very different in nature from these new lipids.

August 23rd, 2017

It is now commonplace to learn of how lipids are involved in various human disease states from the standpoint of errors in metabolism. On the other hand, there is recent evidence that bacteria and their lipids may be involved in what were formerly considered purely metabolic diseases. For example, it has now been reported that significant amounts of rhamnolipids are found in serum from patients with Alzheimer's disease (Andreadou, E. et al. Rhamnolipids, microbial virulence factors, in Alzheimer's disease. J. Alzheimer's Dis., 59, 209-222 (2017);  DOI). These powerful surfactants were first found in Pseudomonas aeruginosa but are now known from other bacterial species. While the connection to the pathology of the disease remains to be proven, it is certainly food for thought. A second study still in press suggests that lipoamino acids/peptides found in commensal Bacteriodetes bacteria of the gut and the oral cavity may contribute to the pathogenesis of TLR2-dependent atherosclerosis through deposition and metabolism in artery walls (Nemati, R, et al. Deposition and hydrolysis of serine dipeptide lipids of bacteroidetes bacteria in human arteries: relationship to atherosclerosis. J. Lipid Res., in press.   DOI).

I have always enjoyed the video articles in JoVE - The Journal of Visualized Experiments. Even when the particular protocol was not of direct interest, I found that I could always learn something from watching how others go about a task in the lab. Regretfully, it seems they have now changed their open access policy, so I won't be able to view a recent article that I would otherwise have hoped to consult (Williamson, K. and Hatzakis, E. NMR spectroscopy as a robust tool for the rapid evaluation of the lipid profile of fish oil supplements. JOVE-J. Vis. Exp., 123, e55547 (2017);   DOI).

Further to my comments in last week's blog on the potential confusion that can arise from using abbreviations - I have been reminded that DHA is the widely used abbreviation both for docosahexaenoic acid (22:6(n-3)) and for the glycerol precursor dihydroxyacetone in the lipid literature.

A special issue of the journal Biochimica et Biophysica Acta (BBA), Molecular Cell Research (Volume 1864, Issue 9, Pages 1435-1524 (September 2017)) deals with a topic relevant to many aspects of lipid biosynthesis, i.e. "Membrane Contact Sites" (edited by Benoît Kornmann and Christian Ungermann).

August 16th, 2017

Phosphatidylcholine and phosphatidylethanolamine can hardly be considered as neglected as they are the most abundant lipids in most cellular membranes in animals. On the other hand, I am not sure that the full range of their biological properties other than as membrane building blocks is always recognized. A new review is certainly helpful and has enabled me to update my pages here (van der Veen, J.N. et al. The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease. Biochim. Biophys. Acta, Biomembranes, 1859, 1558-1572 (2017);   DOI). For example, the role of phosphatidylcholine in lipoprotein metabolism is well known, but I was not aware that phosphatidylethanolamine is present in relatively high concentrations in newly secreted VLDL particles and that this lipid is almost certainly involved in VLDL assembly and/or secretion. On the other hand, it is rapidly and efficiently removed from the VLDL in the circulation but where and how?

One of my pet hates to which I refer here from time to time is the excessive and often unnecessary use of abbreviations and acronyms in scientific papers and especially when they are used in titles. They are a convenience for authors but a nuisance for readers. It seems that every technique, every enzyme, every gene and every metabolite now has its own abbreviation. Of course, I am not arguing that these be shunned entirely, and Lipid Maps, for example, have set out a set of recommended abbreviations for lipid classes that I have used from time to time and find useful especially in figures. In the publication cited above, PC and PE are used throughout in a sensible way. On the other hand, I often find an abbreviation is defined on page 2 of a paper and is then not used again until page 10 when I have to scramble back through to find what it means. A few weeks ago I mentioned that the abbreviation MGDG was used unnecessarily in the title of a publication to replace the one-word lipid class. Of course, it all depends on context; FA means 'fatty acid' in the lipid literature, but it can also mean 'Football Association' and something rather rude. PC can mean 'phosphatidylcholine', 'politically correct', 'police constable' or 'personal computer'. I am not one of the texting generation, who have their own set of abbreviations and may consider my comments are OTT ('over the top') or even ATP ('ATypical Pedantry' - I just made that up - OK). For the moment, I'll let the thought RIP.

August 9th, 2017

In writing this blog, I often allude to those lipids that are most often cited and are therefore actively researched. However, there are a few lipids that appear to be neglected in my opinion. For example, the non-acidic glycosyldiacylglycerols of animal tissues are rarely mentioned in the literature these days. There was a flurry of activity in the 1990s but little since. As they tend to be minor components, they are easily missed, although those in saliva and related secretions may have important functions in these tissues. Another explanation for the neglect may be that they are removed from lipid extracts as part of a procedure for removing glycerolipids to produce pure sphingoglycolipid preparations for analysis. While the acidic glycosyldiacylglycerol seminolipid does feature in many publications in relation to its function in male reproductive tissues, you will struggle to find much on its occurrence and function in brain and nervous tissues. In brain, some of these lipids may be produced adventitiously by the same enzymes that produce comparable sphingolipids, but they may still have distinct functions of their own.

Cytidine diphosphate diacylglycerol (CDP-DAG) is a key intermediate in the biosynthesis of phospholipids so features in innumerable biochemical studies, but what about its natural occurrence and composition in tissues. Just try to find data! Is the explanation is that its natural occurrence is too low and modern mass spectrometric methods are not sufficiently sensitive, or that it is too unstable, or that analysts are simply not looking for it?

Two important journal issues have just come to my attention - Biochimica et Biophysica Acta (BBA), Biomembranes (Volume 1859, Issue 9, Part B, Pages 1493-1748, September 2017) dealing with the topic of "Membrane Lipid Therapy: Drugs Targeting Biomembranes" and edited by Pablo V. Escribá - and Free Radical Biology and Medicine (Volume 111, Pages 1-344, October 2017) on the theme of "4-Hydroxynonenal and Related Lipid Peroxidation Products" and edited by Giuseppe Poli and Neven Zarkovic.

August 2nd, 2017

The opening sentence of a new open-access publication is thought provoking - "The major light-harvesting complex (LHCII) found in the chloroplasts of green plants contains more than half of the chlorophylls (Chl) and is the most abundant membrane protein on earth" (Seiwert, D. et al. The non-bilayer lipid MGDG stabilizes the major light-harvesting complex (LHCII) against unfolding. Sci. Rep., 7, 5158 (2017);  DOI). It must also be the most important protein for advanced life on earth as all the oxygen in the atmosphere is produced as a byproduct of the photosynthesis reaction. Monogalactosyldiacylglycerols for those of you unfamiliar with the abbreviation in the title have a conical structure and do not form bilayers, but their shape appears to match that of the trimeric LHCII complex and stabilize it while modulating the folding, conformation and function of the protein components.

The importance of the physical properties of lipids to the functions of animal organs is also illustrated by two publications in a recent issue of the Journal of Biological Chemistry. Over the years, I have read innumerable suggestions as to why docosahexaenoic acid (DHA) is important in tissues, but especially in relation to visual acuity. It now appears that its role in phospholipids is primarily to maintain the disc shape in photoreceptor cells (Shindou, H. et al. Docosahexaenoic acid preserves visual function by maintaining correct disc morphology in retinal photoreceptor cells. J. Biol. Chem., 292, 12054-12064 (2017);  DOI). Cellular membrane containing DHA in the phospholipids are more flexible than those containing arachidonic acid and other fatty acids, and they may also increase the stability and function of rhodopsin. Similarly, during spermatogenesis, DHA-containing phospholipids provide membranes in spermatids with the physicochemical properties needed for normal cellular processes (Iizuka-Hishikawa, Y. et al. Lysophosphatidic acid acyltransferase 3 tunes the membrane status of germ cells by incorporating docosahexaenoic acid during spermatogenesis. J. Biol. Chem., 292, 12065-12076 (2017);  DOI). The second of these papers is the authors' choice and therefore open access.

The latest issue of the journal Molecular Aspects of Medicine (Volume 56, Pages 1-110 (August, 2017)) deals with the theme of "Bile acids, roles in integrative physiology and pathophysiology" (edited by David H. Volle).

July 26th, 2017

Scottish thistleFollowing on from last week's blog, a paper on protein S-palmitoylation has caught my attention. New methodology involving a site-specific acyl-biotin-exchange reaction for the complete palmitoylated-proteome of a tissue has enabled the identification of what appears to me at least to be an extraordinary number of palmitoylation sites in brain tissue (Collins, M.O. et al. Global, site-specific analysis of neuronal protein S-acylation. Sci. Rep., 7, 4683 (2017);  DOI). 490 Palmitoylation sites have been identified on 342 synaptic proteins, 44% of which are integral membrane proteins. It is now apparent that protein palmitoylation is essential for intracellular signalling and for the folding, trafficking and function of such disparate proteins as Src-family kinases, Ras family GTPases, G-proteins and G-protein coupled receptors. Many of the palmitoylation sites co-located with phosphorylation sites, and it seems to me that the biochemical world must now regard protein palmitoylation-depalmitoylation in the same light as phosphorylation-dephosphorylation in the regulation of enzyme activity.

My enthusiasm for the potential of bacterial lipopeptides as a source of new antibiotics (see last week also) has taken something of a blow with a new publication describing the practical difficulties in recovering them from natural sources (Coutte, F. et al. Microbial lipopeptide production and purification bioprocesses, current progress and future challenges. Biotechn. J., 12, 1600566 (2017);  DOI). There are three major challenges: bacteria produce quorum-sensing molecules that sense cell density and thence limit their growth - the more important of these are in fact lipids, i.e. N-acylhomoserine lactones. Secondly there are problems of foam production because of the amphiphilic nature of the products that cause handling difficulties, and finally the complex mixtures formed are not easily resolved into single components. It may take time but I suspect these problems will eventually be overcome.

Both publications cited this week are open access. Incidentally, I maintain a rough log of my updates to my Lipid essentials pages here. Last year sphingosine 1-phosphate and phosphoinositides received most attention, this year so far it is proteolipids and isoprostanes.

July 19th, 2017

In the search for new antibiotics, lipopeptides appear to offer great potential if problems of toxicity can be overcome. Paenibacillus sp. have proved to be of special interest, and a new report describes a fresh isolate that produces novel cyclic and linear lipopeptides, both of which have antibiotic activity against Gram-negative and Gram-positive bacteria (Huang, E. et al. New Paenibacillus strain produces a family of linear and cyclic antimicrobial lipopeptides: cyclization is not essential for their antimicrobial activity. FEMS Microbiol. Letts, 364, fnx049 (2017);  DOI). Much of the emphasis of recent work has been on cyclic lipopeptides, but chemical synthesis of linear lipopeptides is much easier technically than of cyclic equivalents so this should open up opportunities for the design and testing of new families of related molecules for their therapeutic value.

When I was revising my web page on protein acylation (proteolipids) recently, I became aware that I had written much less on N-myristoylation than on S-palmitoylation, and this was reflected in the reading list at the end. On thinking it over, I believe this is because the latter is a more dynamic modification, the regulation of which can be seen to be relevant to a host of metabolic processes. Indeed, one element of the regulation of the activity of N-myristoylated proteins is additional S-palmitoylation/deacylation reactions. I was able to redress the balance a little after reading a new open access publication (Udenwobele, D.I. et al. Myristoylation: an important protein modification in the immune response. Front. Immunol., 8, 751 (2017);  DOI). Incidentally, a second open access review in this general area was published this week (Chen, J.J. and Boehning, D. Protein lipidation as a regulator of apoptotic calcium release: relevance to cancer. Front. Oncol., 7, 138 (2017);   DOI).

July 12th, 2017

It is astonishing how the view of lipids held by biochemists has changed in the last 50 years. I have to confess that I did not always recognize each milestone in lipid science as it was achieved but I can look back now in admiration of the work of so many of my contemporaries. One such is William Dowhan who has just described his career and research philosophy in an open access publication (Dowhan, W. Understanding phospholipid function: Why are there so many lipids? J. Biol. Chem., 292, 10755-10766 (2017);  DOI). While signalling was a major focus for research in the lipid field over the period, Dowhan was instead pioneering the study of how lipids interact with proteins to modify their functions using E. coli as his model organism to reveal "direct lipid-protein interactions that govern dynamic structural and functional properties of membrane proteins". I can recommend this as a good read both for the science and as a personal record of a distinguished career. Incidentally, he published a review with a very similar title back in 1997, and it is fascinating to learn what has been accomplished since then.

I was not around when cholesterol was discovered and a new open access review marks the 200th anniversary of the recognition by the great French chemist Michel Chevreul that it was a non-saponifiable lipid present in gall stones (Chaudhuri, A. and Anand, D. Cholesterol: Revisiting its fluorescent journey on 200th anniversary of Chevruel's "cholesterine". Biomed. Spectr. Imaging, 6, 1-24 (2017);  DOI). Aside from the fascinating historical introduction (in which the subject's name is unfortunately misspelt), this open access publication describes the use of fluorescent probes in studying cholesterol function in cells. My former mentor Frank Gunstone kept a picture in his office of Chevreul at work in his laboratory in his 100th year, and I reproduce it below. Now there is an ambition!

Chevreul in laboratory

If I am to achieve this, it seems that I have to keep up my fish and presumably fish oil consumption (Zeng, L.F. et al. An exploration of the role of a fish-oriented diet in cognitive decline: a systematic review of the literature. Oncotarget, 8, 39877-39895 (2017);  DOI).

July 5th, 2017

Eric Murphy makes a cogent plea for respect for copyright in an editorial in the latest issue of Lipids (Murphy, E.J. An ethical dilemma: to share or not to share your paper published in Lipids using an on-line outlet. Lipids, 52, 573-574 (2017);  DOI). Posting papers to sites such as ResearchGate is a breach of copyright if the paper is not already open access and is undoubtedly illegal. He suggests that rather than doing this authors should use open access journals if they feel strongly about freedom of use. While I am sympathetic to much of what he says, I do not believe that the problem can be discussed entirely in such black and white terms. If I email an author and ask for a pdf file of a paper in the same way as years ago I might have requested a reprint, this probably comes into the category of fair use, but if we extend this to consider a correspondent who sends me a pdf file of a paper not his own to which I do not have immediate access, should I have to search my conscience? Who am I cheating; there is no way that as a private retiree I could consider spending up to £40 as demanded by publishers for a pdf file that may or may not be of use to me (though if it were £2 I might). If I accept an 'illegal' copy, I will not distribute it elsewhere and I will cite it in this website so the authors and the journal get some publicity at least.

Ethics aside, it is hard to feel sorry for scientific publishers, some of whom are apparently making huge profits on turnover according to an article in the Guardian newspaper. For example in 2010, Elsevier made a 36% profit on turnover. When you consider that they do not have to pay anything to authors or referees this seems grossly excessive. On the other hand, I have no sympathy for sites such as Sci-Hub, who according to Nature News have just been ordered by a US court to pay US$15 million in damages to Elsevier for copyright infringement, although the latter are unlikely to see any of this money as the site is run out of the jurisdiction of the court in Russia. As I understand it, this site is still operating and largely offering preprints of papers without charge, although they are aggressive in seeking donations (assuming that anyone is willing to send bank/credit card details to Russia). Incidentally, the problem is not new in that I recently read a biography of Charles Dickens, who was greatly aggrieved because US publishers reprinted his books as soon as they could get their hands on them without paying him royalties.

What is the answer? Apart from having more open access journals and papers, I would be content if more publishers allowed access to back content after 1-2 years as is already the case with many non-commercial journals especially those with a biological remit. It seems wrong that I am not able to have digital copies of my own papers in journals published by the Royal Society of Chemistry in the 1960s without paying a hefty fee.

June 28th, 2017

Scottish thistleThe journal Biochim. Biophys. Acta - Molecular and Cell Biology of Lipids has a special Issue for August just online entitled "BBALIP_Lipidomics Opinion Articles" and edited by Sepp Kohlwein. At first glance, there seems to be a wide and diverse range of topics going beyond the technical aspects into the biology. While I am fascinated and a little envious of the new methodology, I am more interested in the results. So far, I have only had time to look at one of the reviews, which is highly relevant to my Lipid Essentials pages here in relation to presentation of data (Liebisch, G. et al. Reporting of lipidomics data should be standardized. Biochim. Biophys. Acta, 1862, 747-751 (2017);   DOI). Many of the points made seem sensible, including the suggestion that data should be reported in terms of absolute amounts although I am not clear whether they mean by weight or in terms of molar amounts. They also suggest that data should be available in spreadsheets rather than Word documents or pdf files to make inter-laboratory comparisons easier.

In my articles here, I do not quote any analytical data made by modern mass spectrometric methods - all come from papers published in the 70s and 80s when the methodology was more time consuming but capable of high precision. The problem is that data obtained now in terms of molecular species compositions are in a format that does not lend itself to simple presentation. A phospholipid with 10 fatty acids can exist in the form of 90 molecular species, including positional isomers on the glycerol moiety, while a similar triacylglycerol can have 500 species not including enantiomers. When I came into lipid science, we were more concerned with positional distributions of fatty acids as determined following hydrolytic cleavage with specific lipases; analysis of molecular species was often secondary. It was a simple task to tabulate data for the fatty acid composition of each position in a phospholipid as two columns of fatty acids normalized to 100 mol% with roughly 10 numbers in each. Comparison of data from other laboratories was straight forward, and if you need examples look at almost any of the tables in my web page here on triacylglycerol compositions where data from several sources are presented in a single table.

Such positional data are relevant to biosynthetic processes, hydrolysis by enzymes and lipid remodelling. To give just two examples, arachidonic acid from position sn-2 of phospholipids is used for eicosanoid production while that from position sn-1 is used for anandamide biosynthesis. Of course, molecular species data are important also but this may not be as immediately obvious.

Although mass spectrometric methodology produces data in the form of amounts of the various molecular species, is it necessarily to present it in this form only? Lipidomics methodology is available to determine positional distributions of fatty acids on the glycerol moiety in each species, and while I am not up to date on the mechanics of this there are certainly plenty of papers on the topic. I suspect that the older methods may be capable of greater precision, but mass spectrometry may be good enough for comparative purposes. If so, would it not be possible to add simple mathematical formulae to the spreadsheets to generate tables of positional data for the fatty acids in each lipid class from the molecular species data? Data in both formats are important, but a simple comparison of positional data for each lipid as a first step in interpretation might point to the areas of the molecular species information that require a closer examination. It would certainly simplify interlaboratory comparisons.

June 21st, 2017

In this blog, I have often discussed the therapeutic potential of particular lipids against human diseases. It may be worth a reminder that lipids can have similar beneficial functions in plants. For example, plants in the Solanacea and other families have glandular trichomes, i.e. secretory organs on the external surfaces that secrete mixtures of sugar esters onto the plant aerial surfaces that act as protective agents against both insect herbivores and pathogenic fungi Luu, V.T. et al. O-Acyl sugars protect a wild tobacco from both native fungal pathogens and a specialist herbivore. Plant Physiol., 174, 370-386 (2017);  DOI). In the tomato, for example, these metabolites consist of a carbohydrate backbone, usually glucose or sucrose, to which two to five fatty acids are esterified. The aliphatic acyl chains vary in length from C2 to C12 and are straight chain or have iso- or anteiso-methyl-branches.

My open access publication of the week is perhaps more mainstream and deals with the role of sphingolipids in brain development (Olsen, A.S.B. and Færgeman, N.J. Sphingolipids: membrane microdomains in brain development, function and neurological diseases. Open Biol., 7, 170069 (2017);  DOI).

In the discussion of the new biologically active lipids 'FAHFA' (Fatty Acid Hydroxy Fatty Acid), I do not recall the term "estolide" mentioned although this has been in use since at least the 1950s (according to Google scholar). The definition from the review cited here is "they are intermolecular esters comprised of at least two fatty acid molecules". In animals, the best known example is skin ceramides, but they are also present in bacteria (ornithine lipids and lipid A), many seed oils and yeast. However, the FAHFA are distinctive and differ from the rest in that they have a free carboxyl group. As an example, it may seem something of a misnomer, but hexaacyl triacylglycerols were reported from ergot oil, i.e. with three moles of ricinoleate attached to glycerol each of which is esterified with a long chain fatty acid (Morris, L.J. and Hall, S.W. Structure of glycerides of ergot oils. Lipids, 1, 188-196 (1966);  DOI). In fact, estolides are important industrial products with applications in lubricants (Zerkowski, J.A. Estolides: From structure and function to structured and functionalized. Lipid Technology, 20, 253-256 (2008);  DOI). Incidentally, this review suggests that the first description of an estolide may have been "a 1915 report in Die Naturwissenschaften mentioning their isolation from conifer needles".

I was not around in 1915, but I do remember Lindsay Morris - the author of the 1966 paper. He was a few years ahead of me first as a PhD student with Frank Gunstone and then as a post doc with Ralph Holman, so I knew him first simply as a legendary figure for his activities both within and out of the lab. He will be best remembered as one of the inventors of silver ion chromatography. When we did eventually meet, I found him an engaging person with boundless energy and enthusiasm. I understand that he moved back to Scotland when he retired from Unilever Research, and sadly he died a few years ago.

June 14th, 2017

In my essays here, I have used a rather strict definition of what constitutes an endocannabinoid, i.e. that they must interact with the cannabinoid receptors CB1 and CB2. Thus of the amides, anandamide is obviously an endocannabinoid as is oleamide, but oleoylethanolamide is not. For many purposes this is a useful practical distinction, but there are grey areas and I wonder if I have been too pedantic especially as the 'true' endocannabinoids interact with a number of other receptors. Perhaps we need a new collective term that embraces all the fatty acid amides and simple lipaminoacids - 'amidolipins'? For example, of the other amides palmitoylethanolamide does not interact with the CB1 and CB2 receptors to a significant extent, but it has does have synergistic or "entourage" effects with the 'true' endocannabinoids. This interesting lipid exerts many biological effects in its own right, apparently by a multiplicity of mechanisms and receptors that impinge upon the activities of the other acyl amides. It is undergoing clinical trials for the relief of chronic pain and is the subject of a new review (Petrosino, S. and Di Marzo, V. The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. Brit. J. Pharmacol., 174, 1349-1365 (2017);   DOI).

The N-acylserotonins are another class of fatty amides that also fall into a grey classification area, simply because we do not yet appear to know with which receptors they interact. In particular, it is now clear that N-docosahexaenoylserotonin is present in human intestinal tissue and is a potent anti-inflammatory mediator that may be relevant to intestinal inflammatory conditions such as Crohn's disease and ulcerative colitis. It is a fascinating addition to the list of lipids containing polyunsaturated fatty acids of the (n-3) family with beneficial properties (Wang, Y. et al. Docosahexaenoyl serotonin emerges as most potent inhibitor of IL-17 and CCL-20 released by blood mononuclear cells from a series of N-acyl serotonins identified in human intestinal tissue. Biochim. Biophys. Acta, 1862, 823-831 (2017);   DOI).

In relation to the 'true' endocannabinoids, a new review suggests that some of their biological properties may be mediated through the production of nitric oxide, which functions as a versatile signalling intermediate and is ubiquitous in tissues (Lipina, C. and Hundal, H.S. The endocannabinoid system: ‘NO’ longer anonymous in the control of nitrergic signalling? J. Mol. Cell Biol. 9, 91-103 (2017);   DOI).

June 7th, 2017

The presence of α-galactosylceramide as opposed to the β-form in human tissues and its astonishing biological activity as an anti-tumor immunotherapeutic agent has been one of the pleasant surprises of this year (and has featured earlier this year in this blog). Indeed, I understand that it is undergoing clinical trials as an anti-tumor agent. One major difficulty in studying its metabolism and function is the low levels at which it occurs naturally in tissues (0.02% of the total galactosylceramides in RBL-CD1d cells, for example). A new LC-MS2 separation of the stereoisomers has now been described that appears to solve the problem (von Gerichten, J. et al. Diastereomer-specific quantification of bioactive hexosylceramides from bacteria and mammals. J. Lipid Res., 58, 1247-1258 (2017); DOI). As this lipid is produced by intestinal bacteria, it is a useful reminder after my previous two blogs that bacteria have many virtues and they are not always harmful. It is a truism that advances in methodology often lead to advances in the science, so watch this space. If I want to be picky, I would raise my old chestnut that the term "hydrophilic interaction chromatography" applied to the separation is meaningless unless we know more about the nature of the stationary phase. In fairness to authors, the manufacturers are often silent on this point.

The Journal of Steroid Biochemistry and Molecular Biology has published a special issue on the topic of "Oxysterols: Players in Different Metabolic Leagues" (Volume 169, Pages 1-234 (May 2017)) and edited by Luigi Iuliano, Dieter Lütjohann, Gérard Lizard and Ingemar Bjorkhem.

May 31st, 2017

Scottish thistleWe can never fully free ourselves of the national and occupational stereotypes that are part of our cultural heritage, and I am sure my readers will have an idea at the back of their mind of a "typical" Scotsman. Our view of Russians and scientists is of a very serious and possibly humorless people, so it was a rather pleasant surprise to find an item in Nature NewsDOI ) regarding a 'Monument to an Anonymous Peer Reviewer' outside the Higher School of Economics in Moscow. Immortalized in concrete, "the sculpture takes the form of a die displaying on its five visible sides the possible results of review - 'Accept', 'Minor Changes', 'Major Changes', 'Revise and Resubmit' and 'Reject'." One more stereotype bites the dust.

Phosphatidylserine is known to have an important role in the regulation of apoptosis or programmed cell death, the natural process by which aged or damaged cells are removed from tissues before they can exert harmful effects. A new review (open access) gives a clear explanation of the process in relation to erythrocytes, where phosphatidylserine is located in the inner leaflet of the membrane bilayer under low Ca2+ conditions when a phospholipid scramblase is suppressed by membrane cholesterol, but it is exposed to the outer leaflet under elevated Ca2+ concentrations which activate the scramblase (Arashiki, N. and Takakuwa, Y. Maintenance and regulation of asymmetric phospholipid distribution in human erythrocyte membranes: implications for erythrocyte functions. Curr. Opinion Hemat., 24, 167-172 (2017); DOI). The phosphatidylserine on the outer leaflet of the cell is then recognized by a receptor on the surface of macrophages and related scavenger cells, and these proceed to remove the apoptotic cells in a non-inflammatory manner.

Last week, I discussed two reviews that dealt with the sneaky ways pathogens made use of the lipids of their hosts for their own nefarious purposes. A new review that has the virtue of being open access discusses this in relation to cholesterol specifically (Samanta, D. et al. Manipulation of host cholesterol by obligate intracellular bacteria. Front. Cell. Inf. Microbiol., 7, 165 (2017); DOI). To gain entry into cells, pathogens utilize the cholesterol-rich microdomains in membranes known as rafts. Then, it is apparent that they can manipulate host cholesterol metabolism, including uptake, efflux, and storage, to access nutrient-rich vesicles or acquire membrane components. They also hijack the host cell signaling pathways involving cholesterol that are favorable for their intracellular survival.

The Journal of Experimental Botany has a special issue devoted to the "The Flowering of Jasmonate Research" (1 March, 2017).

May 24th, 2017

A week in the Canary Islands has taken my mind off lipid science for a time, but now I have twice as many papers as usual to read. A catchy title to a review often heralds a more entertaining discussion to follow as in this instance (Pathak, D. and Mallik, R. Lipid - motor interactions: soap opera or symphony? Curr. Opinion Cell Biol., 44, 79-85 (2017); DOI). Motor proteins are here defined as "ATPases that convert chemical energy into mechanical energy to drive many cellular functions including intracellular transport of vesicles". These enzymes require interactions with specific lipids, especially the phosphoinositides and cholesterol, to direct them to specific membranes. As to "soap opera etc", read the first paragraph for an elegant explanation of the analogy. The protein can have highly specific binding sites for particular lipids or it can indirectly react to membrane curvature induced by characteristic lipid head groups. Here much of the discussion focuses on the endosome/phagosome compartment partly because of the importance to normal cellular metabolism, and partly because pathogens in phagosomes use the lipid interactions to survive in host cells. Incidentally, there is a rather substantial new (if relatively inaccessible) book chapter that relates to the latter process (Fozo, E.M. and Rucks, E.A. The making and taking of lipids: the role of bacterial lipid synthesis and the harnessing of host lipids in bacterial pathogenesis. Adv. Microb. Physiol., 69, 51-155 (2016); DOI).

I am a spectator only to modern mass spectrometric techniques, but I have the impression that advances in software and data management are as important as those in instrumentation in driving what can now be achieved. For example, LipidFinder optimizes analysis based on users' own data, and a new open access publication describes its use to identify three 12-hydroxyeicosatetraenoic acid phosphoinositides in thrombin-activated platelets (O'Connor, A. et al. LipidFinder: A computational workflow for discovery of lipids identifies eicosanoid-phosphoinositides in platelets. JCI Insight, 2, e91634 (2017); DOI). Another research group describes the use of the software IE-Omics to automate data acquisition by MS/MS in sequential injections to improve the coverage of the lipidome especially with regard to trace species (Koelmel, J.P. et al. Expanding lipidome coverage using LC-MS/MS data-dependent acquisition with automated exclusion list generation. J. Am. Soc. Mass Spectrom., 28, 908-917 (2017); DOI).

The therapeutic potential of docosanoids such as the resolvins is increasingly becoming evident, and an application of 17(R)-hydroxy-docosahexaenoic acid to the relief of pain in osteoarthritis, if not yet the underlying cause, in animal models is described in a new publication hopefully as a prelude to clinical studies (Huang, J.T. et al. Targeting the D series resolvin receptor system for the treatment of osteoarthritis pain. Arthritis Rheumatol., 69, 996-1008 (2017); DOI).

May 10th, 2017

There is a short series of reviews on the theme of 'Lipid Methodology' (edited by Howard Goldfine and Ziqiang Guan) in a recent issue of Analytical Biochemistry (Volume 524, Pages 1-76 (1 May 2017)). One of these dealing with cholesterolomics is open access, but the one that caught my eye especially deals with the various modes of high-performance liquid chromatography that can be applied for the separation of regio- and stereoisomers of triacylglycerols (Rezanka et al. Regioisomeric and enantiomeric analysis of triacylglycerols. Anal. Biochem., 524, 3-12 (2017); DOI). Modern mass spectrometric methods dominate the recent analytical literature, but they cannot accomplish stereospecific analysis of triacyl-sn-glycerols, so I am always encouraged to see that alternative methods are still being pursued.

Some months ago, my attention was drawn to the fact that some subjects were being reviewed to exhaustion, with more than 20 reviews a year devoted to each of the topics of phosphoinositides and sphingosine-1-phosphate in particular. Of course, the reason these topics receive so much attention is because they are so dynamic and there is much important new research to discuss. Therefore, I make no apology for drawing your attention to a new review dealing with sphingosine-1-phosphate, which among its many virtues is open access (Pyne, N.J. and Pyne, S. Sphingosine 1-phosphate receptor 1 signaling in mammalian cells. Molecules, 22, 344 (2017); (2017); DOI).

May 3rd, 2017

One of the more surprising lipid discoveries in recent years has been fatty acids with a centrally located hydroxyl group to which a further fatty acid is linked as an estolide or 'FAHFA' (Fatty Acid Hydroxy Fatty Acid), such as the palmitoyl ester of 9-hydroxy-stearic acid (note that both component fatty acids are fully saturated), which was first found in the adipose tissue of mice. These have anti-diabetic and anti-inflammatory effects, even when administered orally, and they protect against colitis by regulating gut innate and adaptive immune responses. Although details of the biosynthesis have still to be established, there seems little doubt that they are formed endogenously as a new study has established that the hydroxyl group has defined stereochemistry, i.e. it is of the R-configuration (Nelson, A.T. et al. Stereochemistry of endogenous palmitic acid ester of 9-hydroxystearic acid and relevance of absolute configuration to regulation. J. Am. Chem. Soc., 139, 4943-4947 (2017);   DOI). Unfortunately, I am dependent on the abstract for this information as access is closed to non-subscribers.

I try to keep up with with the plethora of new eicosanoids and docosanoids that continue to be discovered, but I did not realize that more than 70 oxygenated metabolites of docosahexaenoic acid (DHA) had been discovered to date as summarized in a new review (Kuda, O. Bioactive metabolites of docosahexaenoic acid. Biochimie, 136, 12-20 (2017);  DOI). Included among these are FAHFA derived from essential fatty acids, i.e. with 14-hydroxydocosahexaenoic acid (14-OH-DHA) esterified to 9- and 13-hydroxyoctadecadienoic acids, for example; these have profound anti-inflammatory effects.

A few weeks ago, I pointed out here that the Journal of Lipid Research had taken a retrograde step in closing access to papers that had been accepted but were still in manuscript form. Either this was a technical error or they have seen the error of their ways and this policy has now been reversed.

April 26th, 2017

Scottish thistleUrine samples are usually regarded as the easiest non-invasive method of obtaining samples for analysis, but then any metabolites have passed through the kidney and may have been substantially altered. I had not considered human tears for this purpose, but it seems that tear fluid can serve as a means to identify and monitor novel biomarkers in ocular and systemic disease, and in particular the specialized pro-resolving mediators (SPMs). For example, resolvin D1, protectin D1, lipoxin A4, and resolvin E1 are accessible in this way in quantities that are known to be active biologically (English, J.T. et al. Identification and profiling of specialized pro-resolving mediators in human tears by lipid mediator metabolomics. PLEFA, 117, 17-27 (2017);   DOI). When I first saw the title, it brought to mind the old Julie London song "Cry me a River", but it seems that only 100μl of tears obtained "through an induction of an emotional response" were required for the identification and quantification of 21 different metabolites. This seems an astonishing example of the sensitivity of modern mass spectrometric methodology. The results are also surprising in that while SPMs were detected in male donors, they were essentially absent in females. Incidentally, if any of my younger readers don't know the above song (or the Barbra Streisand version), a treat awaits you.

Another record appears to have been broken in that trace levels of highly unsaturated fatty acids of the (n-3) family suggested to be 38:7(n-3) to 44:12(n-3) have been reported from brains of patients with genetic impairments of peroxisome function. The last must be the most highly unsaturated fatty acid of conventional origin known (Takashima, S. et al. Detection of unusual very-long-chain fatty acid and ether lipid derivatives in the fibroblasts and plasma of patients with peroxisomal diseases using liquid chromatography-mass spectrometry. Mol. Gen. Metab., 120, 255-268 (2017);  DOI).

April 19th, 2017

Some years ago, I took issue with the LipidMaps consortium over some aspects of their lipid classification system. In particular, I though they were wrong to create a distinct class for glycerophospholipids while lumping glycosyldiacylglycerols in with triacylglycerols. As glycosyldiacylglycerols can substitute for phospholipids under conditions of phosphate deprivation in plants and both function exclusively in membranes, I believed that both groups should have the same ranking. Apparently, I did not persuade them as the ranking did not change. One lipid that is particularly anomalous in this classification is the highly polar plant sulfolipid sulfoquinovosyldiacylglycerol, which cannot be compared with storage lipids in any respect; it is the subject of a new review (Goddard-Borger, E.D. and Williams, S.J. Sulfoquinovose in the biosphere: occurrence, metabolism and functions. Biochem. J., 474, 827-849 (2017);   DOI). As access is closed to non-subscribers, I am grateful to a friend for giving me a sight of it. While I was familiar with much of what the authors had to say about the biochemistry and function, I was not aware that it was such an important component of the sulfur cycle in the biosphere. The total annual synthesis of sulfolipid is thought to be of the order of 1013 kg per annum!

The March issue of Biochimie (Volume 134, Pages 1-138 (March 2017)) contains a number of articles with the theme of brown fat metabolism (Edited by Frédéric Bouillaud, Louis Casteilla, Susanne Klaus and Bruno Miroux). The May issue of this journal (Volume 136, pages 1-104) is devoted to "Pleiotropic physiological roles of PPARs and fatty acids: A tribute to Paul Grimaldi" (edited by Nada A. Abumrad, Ez-Zoubir Amri, Serge Luquet and Claude Forest).

Fatty acid binding proteins (FABPs) are a family of small cytoplasmic proteins that are highly conserved and as the name suggests bind long-chain fatty acids; they facilitate the transfer of fatty acids between extra- and intracellular membranes and receptors. Of these, FABP7 is located in astrocytes of the brain and binds DHA with the highest affinity. It is now reported to be required for normal sleep in humans and other animals. There is a brief popular report in Sci News with a link to the original article.

I have come across the Latin expression "in silico" in the titles of several recent publications, and I now understand that this means "in silicon" strictly speaking but is used to mean "performed on computers or via computer simulation". Those ancient Romans were cleverer than I would have believed if they knew of silicon and anticipated the use of computers.

April 12th, 2017

An item in Nature News drew my attention to Unpaywall - a free web-browser extension that hunts for papers in more than 5,300 repositories worldwide, including preprint servers and institutional databases, to find freely accessible (and legal) copies of research articles. It is an add-on to Firefox or Google Chrome that is quick and easy to install and use. In a brief trial, it found me one paper quickly that I needed to update these pages, and just as importantly found that two of interest were not available yet as open access so saving time in fruitless searching. The article in Nature suggests that more such tools are on the way.

The titles of some publication simply shout for attention (e.g. Li, X.B. et al. The slim, the fat, and the obese: guess who lives the longest? Current Genetics, 63, 43-49 (2017);   DOI). It appears that there is a phenomenon called the "obesity paradox" in that the overweight population enjoys the lowest rate of mortality from all causes in contradiction to everything that scientists and clinicians think they know. The authors believe that the answer may lie in a new cytoprotective function of triacylglycerols. As a relatively lean 140 pounder, should I be worried? Certainly, I wont feel guilty next time I am offered a big sugary doughnut with my morning coffee.

Fascinating new lipids are discovered all the time, but occasionally nature springs a nasty surprise. The latest in this category are alkyl cyanides produced by bacterial species. These can be either unbranched saturated or unsaturated with an omega-7 double bond, such as (Z)-11-octadecenenitrile, or methyl-branched unsaturated cyanides with the double bond located at C-3, such as (Z)-13-methyltetradec-3-enenitrile. Fatty acids are the biosynthetic precursors, and these are first converted into their amides and then dehydrated. While their functions are not yet known, some of these nitriles showed bactericidal activity; any possible homicidal properties were not investigated (Vidal, D.M. et al. Long-chain alkyl cyanides: unprecedented volatile compounds released by Pseudomonas and Micromonospora bacteria. Angew. Chem.-Int. Ed., 56, 4342-4346 (2017);   DOI). Some plant species contain cyanolipids but of a very different kind.

Formula for an alkyl cyanide

April 5th, 2017

I have commented on the uniqueness of cardiolipin in this blog on many occasions in the past, usually in relation to its special functions in membranes. Perhaps the most distinctive feature is that it possesses a dimeric structure in essence with four acyl groups arranged in a very limited range of molecular species. In heart muscle, for example, linoleate makes up 80% of the total fatty acids, so a high proportion of the lipid exists as the tetralinoleoyl species. This composition is attained after its initial synthesis by a remodelling process, catalysed by the enzyme tafazzin, which transfers fatty acids from other phospholipids by a mechanism that does not require a coenzyme A ester as an intermediate, and it is reversible. The question has arisen as to whether the fatty acid specificity is inherent in tafazzin per se or is dependent on thermodynamic considerations. It now appears that the question has been answered definitively by two papers from the laboratory of Professor Michael Schlame (Schlame, M. and Greenberg, M.L. Biosynthesis, remodeling and turnover of mitochondrial cardiolipin. Biochim. Biophys. Acta, 1862, 3-7 (2017);   DOI; Schlame, M. et al. The basis for acyl specificity in the tafazzin reaction. J. Biol. Chem., 292, 5499-5506 (2017);   DOI). It seems now to be established that sufficient energy differences arise from the packing properties of the entire lipid assembly in the membrane to enable tafazzin to catalyse the remodeling of cardiolipin by combinations of forward and reverse transacylations, essentially creating an equilibrium distribution of acyl groups. The shape of tetralinoleoyl-cardiolipin is such that it fits the geometry of negatively curved monolayers particularly well so this structure is favoured.

It seems that we now have a good understanding of the nature of the complex phytoglycosphingolipids from higher plants, although much remains to be learned of their biochemistry and especially their function. However, following the recent discovery of inositol phosphorylceramide glucuronosyltransferase 1, i.e. the first enzyme in the GIPC glycosylation pathway, it has now been shown that these highly polar membrane lipids are essential for normal growth and function in Arabidopsis (Tartaglio, V. et al. Glycosylation of inositol phosphorylceramide sphingolipids is required for normal growth and reproduction in Arabidopsis. Plant J., 89, 278-290 (2017);   DOI).

March 29th, 2017

Scottish thistleProfessor Roscoe O. Brady (1923-2016) will long be revered as one of the pioneers of research into the sphingolipidoses and especially Gaucher's disease. In large part through his efforts, an effective enzyme replacement therapy has been developed for one form of this disease. As part of a Festschrift in his honour in the journal Molecular Genetics and Metabolism, his many colleagues have published their personal reminiscences and insights into his accomplishments (Desnick, R.J. et al. Roscoe Owen Brady, MD: Remembrances of co-investigators and colleagues. Mol. Gen. Metab., 120, 1-7 (2017);  DOI). This tribute is accompanied by a number of further papers relevant to this topic.

According to Nature News ([Link]), the Gates Foundation has announced a new open-access publishing venture modeled on that of the Wellcome Trust. The open-access movement in general seems to be gaining momentum, a boon to someone like myself who has more limited access to journals than those with university positions. In the biological sciences, we tend to be more fortunate than those whose primary interest is chemistry, but there are occasional backward steps. For example, the Biochemical Journal used to allow full access after one year - now 2013 is the last year to which this applies. The Journal of Lipid Research has just stopped access to papers in manuscript form ahead of publication, although I assume that they will still be available one year after publication. I don't recall seeing any formal announcements of these changes.

March 22nd, 2017

Proteolipids are protein lipid conjugates in which the lipid portion is necessary to direct the protein to a membrane where it is required for a specific function. Many of these are signalling proteins (e.g. receptors, G-proteins, protein tyrosine kinases) with implications for the relevant signalling events at the cell surface, and many influence human disease states and are potential pharmacological targets. For example, deregulation of S-palmitoylation has been associated with heart disease, cancer, mental retardation and schizophrenia. A correspondent has brought to my attention a new website that is both informative and elegantly designed that covers the topic of S-palmitoylation, i.e.

HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) is a very different type of protein-lipid complex. The protein component is α-lactalbumin, which is the most abundant protein in human breast milk and normally exists in a tightly packed globular conformation stabilized by four disulfide bridges and a divalent calcium ion. The lipid is oleic acid, and this is not linked covalently but by nonspecific hydrophobic interactions in the loosely organized hydrophobic core of the protein when it is in a molten globular state, as is produced during casein precipitation at low pH. The HAMLET complex can be internalized into cancer cells where it initiates a series of metabolic changes that can result in cell death. In human clinical studies, HAMLET has been shown to be efficacious against skin papillomas and bladder cancers, as well as against many other cancers in animal models. A new review summarises progress with this fascinating molecular complex (Ho, J.C.S. et al. HAMLET - A protein-lipid complex with broad tumoricidal activity. Biochem. Biophys. Res. Commun., 482, 454-458 (2017);  DOI).

A title such as "Masochistic Enzymology: Dennis Vance's Work on Phosphatidylcholine" should catch the eye of most readers. To find what it means, follow this Link to a brief open access commentary in the Journal of Biological Chemistry.

March 15th, 2017

Oxidized phospholipids are important biological mediators, and it is increasingly being recognized that oxylipins of various kinds are esterified to glycerophospholipids, which may serve in part as reservoirs from which they can be released rapidly upon stimulation by various means or the oxidized glycerophospholipids may have biological activities of their own. This is perhaps more surprising when oxylipins formed by non-enzymatic means are concerned, but there appears to be ample evidence that isoprostanes can act in this way. For example, an oxidized species derived from sn-2-arachidonoyl phosphatidylcholine has been shown to modulate the expression of a large number of genes in human aortic endothelial cells, and it is also a potent activator of the peroxisome-proliferator-activated receptor (PPARα).

Similarly, phospholipids that have been oxidatively cleaved to produce "core-aldehydes" have biological activities that resemble those of platelet-activating factor, while other related phospholipids interact with receptors that are normally associated with the recognition of microbial pathogens, as discussed in separate web pages.

Phosphatidylcholine is the most common phospholipid in animal cells, and it is not recognized by any pattern-recognition receptors in native low-density lipoproteins (LDL) or on the surface of cells. However, once oxidized it becomes a key ligand that, for example, mediates the binding of oxidized LDL to receptors, which are normally believed to have very different binding characteristics in relation to microbial pathogens. A concept has been developed of the formation of damage-associated molecular patterns (DAMPs) that arise from the oxidative damage of lipids and lipoproteins. These share common structural motifs with microbial pathogen-associated molecules, and so they activate the same pattern-recognition receptors that are present on the surface of macrophages and of immune and vascular cells. This enables them to initiate many different inflammatory signalling processes. A new review deals with this topic (Miller, Y.I. and Shyy, J.Y.J. Context-dependent role of oxidized lipids and lipoproteins in inflammation. Trends Endocrinol. Metab., 28, 143-152 (2017);  DOI).

Most work on this problem has been concerned with phosphatidylcholine, but a new analytical study has examined the nature of the oxidized phosphatidylinositol in LDL. Of course, there is much less of this phospholipid but it is highly unsaturated so it may make a sigificant contribution to oxidative stress (Hasanally, D. et al. Identification of oxidized phosphatidylinositols present in OxLDL and human atherosclerotic plaque. Lipids, 52, 11-26 (2017);   DOI). Now, the knowledge of what is there should be a stimulous to biological studies

March 8th, 2017

The latest Fats of Life Newsletter was a welcome arrival in my email inbox this week. In addition to the usual section on highlights from the recent literature, it contains two original articles of which I can certainly recommend that entitled "F3-isoprostanes and F4-neuroprostanes: non-enzymatic cyclic oxygenated metabolites of omega-3 polyunsaturated fatty acids: biomarkers and bioactive lipids" (by Galano, G.M. and 7 others), as it will be helpful in updating my web pages here.

When I do my weekly search for new lipid analysis publications, I try to list only those that demonstrate something that is truly new either in terms of the methodology or the sample under analysis. Nowadays, the result is a list of papers dealing mainly with mass spectrometry of lipids, which generally show only minor improvements on what has gone before. Please do not think that I am being disparaging here, as this is how science usually works. Only rarely do I find a publication that marks a step forward simply in chromatography terms these days, but a new paper describing the separation of regio-isomers of triacylglycerols by reversed-phase HPLC seems to fall into this category (Sompila, A.W.G.T. et al. Fast non-aqueous reversed-phase liquid chromatography separation of triacylglycerol regioisomers with isocratic mobile phase. Application to different oils and fats. J. Chromatogr. B, 1041, 151-157 (2017);  DOI). Although such separations have been demonstrated before with model mixtures, the methodology now seems to have reached a stage where it is applicable to natural samples.

I tend to take a cursory note only of new publications that deal with most clinical aspects of lipid science and leave these for others elsewhere to comment, as this topic lies outside my area of expertise. However, I can't resist a mention of a new paper (open access) dealing with sphingosine-1-phosphate (Soltau, I. et al. Serum-sphingosine-1-phosphate concentrations are inversely associated with atherosclerotic diseases in humans. PLOS One, 11, e0168302 (2016);  DOI). The authors demonstrate that decreased serum concentrations of this lipid are better markers of peripheral artery disease and carotid stenosis than is HDL cholesterol. Regretfully, I suspect that it will be some time before HPLC linked to tandem mass spectrometry becomes a routine screening tool for this purpose.

March 1st, 2017

Arachidonic acid is not present in higher plants, other than two species of Gymnosperms; I discount other alleged occurrences as not adequately characterized. However, it is present in lower plants such as algae, mosses and ferns. In a new systematic search for arachidonic acid in the plant kingdom (open access), the earlier findings were confirmed together with an inverse correlation between the concentration of this acid and that of the plant hormone jasmonic acid (Gachet, M.S. et al. Targeted metabolomics shows plasticity in the evolution of signaling lipids and uncovers old and new endocannabinoids in the plant kingdom. Sci. Rep., 7, 41177 (2017);  DOI). A further interesting discovery was the presence of two novel "endocannabinoid-like" molecules derived from 5,11,14,17-eicosatetraenoic or juniperonic acid, an omega-3 structural isomer of arachidonate, namely juniperoyl ethanolamide and 2-juniperoyl glycerol in gymnosperms. I don't like the use of the term "endocannabinoid" in the title as this implies the existence of a specific receptor, but I can accept "endocannabinoid-like" from the abstract. Semantics aside, this seems to be an interesting report that may be relevant to the evolution of signalling pathways in plants.

A correspondent has brought a paper to my attention that demonstrates the occurrence of the systemic oxidative stress marker 8-isoprostane in sewage, with the suggestion that it may be a marker for general health in different populations; the authors report a 5-fold change from three sewage collection points supplied by different communities located in the Detroit metropolitan area (Santos, J.M. et al. Could sewage epidemiology be a strategy to assess lifestyle and wellness of a large scale population? Medical Hypotheses, 85, 4080411 (2015);  DOI). Whatever the answer to the question posed by the authors, it is a novel application of lipid analytical methodology and a tribute to its sensitivity.

February 22nd, 2017

Scottish thistle Gangliosides are essential constituents of the central nervous system and of some non-neural tissues. They are arguably the least lipid-like of all animal lipids, by some definitions at least, in that they are as soluble in water as in many of the organic solvents used for extracting lipids from tissues. The hydrophobicity is due to a complex oligosaccharide component to which highly polar sialic acid units are attached, i.e. N-acetylneuraminic acid and its metabolite N-glycolylneuraminic acid, which differ only by the presence of one oxygen atom in the acyl moiety. Both sialic acids are present in nearly all animal species including other primates such as the great apes. Humans are the sole exception in that they lack gangliosides containing N-glycolylneuraminic acid. We have the genes that are required to produce this, but they have been irreversibly silenced. As far as I am aware, this is the only important biochemical distinction between humans and apes, and it is regarded as a major biochemical branch-point in human evolution. It may even be a factor in the superior performance of the human brain. We cannot test evolutionary hypotheses, but the relevance of gangliosides containing N-glycolylneuraminic acid to brain function can be tested in experimental animals at least as in a new publication (Naito-Matsui, Y., et al. Physiological exploration of the long term evolutionary selection against expression of N-glycolylneuraminic acid in the brain. J. Biol. Chem., 292, 2557-2570 (2017);  DOI). The results show that in transgenic mice in which expression of N-glycolylneuraminic acid was enhanced in the brain, the consequence was "abnormal locomotor activity, impaired object recognition memory, and abnormal axon myelination"; the transgenic mice were also lethally sensitive to a specific bacterial toxin. Whatever caused this evolutionary change appears to have done us a favour. The paper is an editor's choice and is open access.

There is a new paper entitled "Localized aliphatic organic material on the surface of Ceres" (De Sanctis, M.C. et al. Science, 355, 719-722 (2017);  DOI). Or see the more accessible report in Sci-News. Are there fatty acids in space?

February 15th, 2017

The isoprostanes are fascinating lipid mediators produced by non-enzymatic mechanisms that closely resemble the prostaglandins in structure. Indeed, so close is the similarity that it has been suggested that during evolution, the first primitive animals found these molecules so useful for signalling purposes that they developed enzymatic methods to produce analogues on demand in response to specific stimuli. Because of their formation by simple chemical reactions, one major difference is that the isoprostanes are produced as many different structural and stereo-isomers, while prostaglandin synthesis is highly stereospecific. Another important difference is that isoprostanes are produced while esterified to complex lipids in membranes, while prostaglandins are synthesised as the free acids. The latter fact is attracting special interest now as it has become apparent that lipid-bound isoprostanes are involved in many biological reactions, in part simply by causing disruption to membranes but also by highly specific interactions with receptors and proteins in general. A new review suggests that phosphatidylcholines containing isoprostanes with an cyclopentenone structural motif are potent pro-resolution mediators like the protectins, resolvins and maresins. In this instance, the cyclopentenone unit, an electrophilic α,β-unsaturated carbonyl moiety, can form covalent adducts with cysteine residues by Michael addition. Then, activation of the antioxidant response factor Nrf2 in this way might be one of a number of reasons for the anti-inflammatory effects (Friedli, O. and Freigang, S. Cyclopentenone-containing oxidized phospholipids and their isoprostanes as pro-resolving mediators of inflammation. Biochim. Biophys. Acta, 1862, 382-392 (2017);  DOI).

This review is part of a special issue of Biochim. Biophys. Acta - Molecular and Cell Biology of Lipids (Volume 1862, Issue 4, Pages 369-440 (April 2017)) dealing with the topic of "Lipid modification and lipid peroxidation products in innate immunity and inflammation" (edited by Christoph J. Binder).

February 8th, 2017

I have mentioned JOVE-Journal of Visualized Experiments before in this blog. It contains laboratory protocols for many types of analytical method, and is unique in that it supplements the written procedures with online videos showing in detail how to go about each analysis. Happily, it is also largely open access. Nowadays, I am an armchair scientist, but I enjoy viewing these videos, if only to see how others go about procedures with which I have some familiarity. Often they use different types of glassware, or equipment for handling samples with which I am not acquainted. I sometimes bring them to the attention of my former colleagues, not so that they should change how they go about things but simply to give them a fresh viewpoint. Two recent publications from this journal are relevant to my past research interests (Ginies, C. et al. Identification of fatty acids in Bacillus cereus. J. Vis. Exp., 118, e54960 (2016);  DOI; and Quideau, S.A. et al. Extraction and analysis of microbial phospholipid fatty acids in soils. J. Vis. Exp., 114, e54360 (2016);  DOI). Although both topics may appear rather specialized at first glance, many aspects of the methodology have more general applications. For example, the first illustrates the preparation of dimethyloxazoline (DMOX) and 3-pyridylcarbinol esters of fatty acids for mass spectrometry, while the second shows how to prepare a phospholipid fraction by solid-phase extraction methodology. There are some parts of both publications that I might prefer to do differently, but they are very useful guides for the novice while the expert can always learn something new.

February 1st, 2017

Studies of the occurrence and biochemistry of nitro adducts of unsaturated fatty acids only started in a systematic way in 1999 with the discovery that were present in the membrane phospholipids of human tissues in vitro and in vivo, and at concentrations that had the potential to exert biological effects. Now, their biology is a highly dynamic subject, not least because it has been demonstrated that they afford protection from inflammatory injury in several experimental models and so have therapeutic potential. In addition, they are electrophiles with a propensity to undergo reversible Michael addition reactions with cellular nucleophiles such as cysteine and histidine-containing peptides and proteins with further effects upon metabolism. While many different fatty acids can act as precursors, it has become evident that conjugated linoleate (CLA) isomers are by far the most active. A new important paper on the topic is a mechanistic and kinetic study of the reaction of CLA with thiols in the Journal of Biological Chemistry; it is the editor's choice and is therefore open access (Turell, L. et al. The chemical basis of thiol addition to nitro-conjugated linoleic acid, a protective cell-signaling lipid. J. Biol. Chem., 292, 1145-1159 (2017); DOI). Amongst many interesting findings, CLA reacts rapidly with thiols occur form adducts both β and δ to the nitro group, especially the latter. Indeed, the cysteine-δ-adducts have been detected in human urine.

Another paper from the same group (also open access) describes how nitro-fatty acids are catabolized and eliminated from the body in the urine. The main metabolite is 4-nitro-octanedioic acid (NO2-8:0-diCOOH) (Salvatore, S.R. et al. Evaluation of 10-nitro oleic acid bio-elimination in rats and humans. Sci. Rep., 7, 39900 (2017);   DOI). Stop Press: the February issue of the Journal of Lipid Research will contain a paper on the metabolism of nitro fatty acids in adipose tissue.

January 25th, 2017

Scottish thistleA special issue of the journal Neuropharmacology (Volume 113, Part B, Pages 595-672, 2017) is devoted to the topic of "Lipid Sensing G Protein-Coupled Receptors in the CNS" (edited by Kumlesh K. Dev and Andrew J. Irving). One review that interested me especially deals with sphingosine-1-phosphate metabolism in relation to health. (O'Sullivan, S. and Dev, K.K. Sphingosine-1-phosphate receptor therapies: Advances in clinical trials for CNS-related diseases. Neuropharmacology, 113, 597-607 (2017)). The realization that this lipid is involved in many different metabolic diseases has lead to the development of a number of new drugs with great therapeutic potential. In particular, a molecule derived synthetically from considerations of the structures of sphingoid bases and termed 'fingolimod (or FTY720)' has been approved by the Food and Drug Administration (USA) as an oral treatment for relapsing and remitting multiple sclerosis, a condition caused by an autoimmune attack on the myelin sheaths of nerves. Within affected tissues, fingolimod is phosphorylated by sphingosine kinase 2 and the resulting fingolimod-phosphate is released from cells as an agonist for sphingosine-1-phosphate receptors to cause immunosuppression. In addition, I learned that this drug has reached the phase II stage in clinical trials for amyotrophic lateral sclerosis, acute stroke and schizophrenia, and the phase I stage for Rett syndrome and glioblastoma, while pre-clinical studies suggest that it may be of value for a number of other diseases including Alzheimer's, Parkinson's and Huntington's diseases.


I have few regrets about retirement from my research post, though I sometimes wish I had had access to some of the newer instrumental methodologies. For example, mass spectrometry with electrospray ionization would have been a great boon. Similarly, I would love to have been able to use the modern counter-current chromatography equipment, which fits onto a bench top. When I was a post-doc at the Hormel Institute in the 1960s, they had a massive all-glass instrument that filled a room to do the same job and required vast quantities of solvent. The modern equivalent would have been ideal for studies of lipid mediators in plants, for example. I can recommend a new paper from Vetter's lab that shows what can be achieved with some lipids (Hammann, S. et al. More than 170 polyunsaturated tocopherol-related compounds in a vitamin E capsule: Countercurrent chromatographic enrichment, gas chromatography/mass spectrometry analysis and preliminary identification of the potential artefacts. J. Chromatogr. A, 1476, 77-87 (2016); DOI).

January 18th, 2017

The Nature Publishing Group has brought a large number of new scientific journals in many disciplines onto the market in recent years, many internet only. I had thought that with the stresses on library budgets, the market was saturated with journals, but apparently not. Regretfully I have very limited access to any of these. One exception is Scientific Reports, which is open access and where I have found a number of interesting publications in recent months. For example, one such is a paper in which mass spectrometric imaging has been used to look at the changes in lipid content during cerebral ischaemia. The authors were able to watch how a number of bioactive lipid mediators, normally present at very low levels, accumulated in specific cells types from the initial phase of inflammation and tissue injury through to the later phase of resolution and repair (Nielsen, M.M.B. et al. Mass spectrometry imaging of biomarker lipids for phagocytosis and signalling during focal cerebral ischaemia. Sci. Rep., 6, 39571 (2016); DOI). It appears to me to be a good example of how good analytical work can reveal how lipids function and point the way forward to biochemists.

A special issue of the Journal of Molecular Biology (Volume 428, Issue 24, Part A, Pages 4737-4866 (2016)) deals with the topic of "Molecular Biology of Membrane Lipids" edited by Kai Simons and Ünal Coskun. For my purposes, several papers dealing with sphingolipids are of particular interest

January 11th, 2017

I recently came across a blog dealing with microbiology (Small Things Considered), in which one article started with the words "The Lipids That Last Forever - The world of lipids does not always gets its due. Their oleaginous charm is not always appreciated". An earlier article from this blog started with the sentence "In the beginning, there were fats, and in the end, only fats will remain". It is not surprising that both caught my immediate attention. The lipids in question are hopanoids, and I came across the blog when I was updating my article here on the subject. If you are unfamiliar with these compounds, they are pentacyclic structures produced mainly by bacteria that are similar to sterols and indeed have been called 'sterol surrogates', as they perform similar roles to sterols in membranes. The reason they live for ever is that the ring structures are highly stable to chemical degradation, so geochemists tend to look upon them as molecular fossils ('geohopanoids') that serve as biological markers for particular organisms in geological formations from recent sediments to petroleum deposits and rocks. For example, they have been found in 2.7 billion year old shales in Australia. In one estimate, their mass in sedimentary rocks and oil reservoirs is said to be ~1012 tons, an amount comparable to the total mass of carbon in all living organisms! They may therefore be the most abundant lipids on earth.

What is the most abundant lipid class in living organisms on earth? Two suggestions come to mind from the world of plants - first the layer of wax that covers the surfaces of all leaves, and secondly the galactosyldiacylglycerols that are major constituents of the photosynthetic membranes in all plants. Then, I have read somewhere that the total living microbial biomass, including that in the oceans, soils and sediments, is greater than that of plants and animals, so perhaps a microbial lipid - possibly phosphatidylethanolamine - is more abundant. I will leave others to do the calculations.

January 4th, 2017

A fascinating new publication describes a method by which the complex lipids in the outer leaflet of the plasma membrane can be replaced in intact cells in culture. Methyl-α-cyclodextrin loaded with lipids effects a rapid exchange with the membrane lipids without removing any of the cholesterol that might otherwise cause membrane disruption (Li, G.T. et al. Efficient replacement of plasma membrane outer leaflet phospholipids and sphingolipids in cells with exogenous lipids. Proc. Natl. Acad. Sci. USA, 113, 14025-14030 (2016); DOI). The initial results were broadly as expected and confirmed that 70-80% of cell sphingomyelin resides in the plasma membrane outer leaflet and that the phosphatidylcholine in this membrane contains less unsaturated fatty acids than that in the remainder of the cell. However, the main promise of this new technique is that it opens opportunities for studying the metabolism of living cells in which the membrane composition has been modified with exogenous lipids, including the use of non-natural synthetic lipids.

I spend much of my early research career at the Hannah Research institute in Ayr, which was then concerned with animal science in general and dairy animals in particular. We lived with the concern that animal rights activists might decend opon us at some time with the potential to do untold damage to our research and career development. When I moved to a plant research institute, I thought those troubles were behind me only to discover that I was now in danger from those fanatics who perceived that genetically modified crops would prove the end of mankind. Fortunately, they never troubled us in Dundee, and now the furore seems to have died down. Great strides have been made in recent years towards producing new oil-seed crops containing enhanced value both for industrial purposes and for the health of consumers. To this end, it has not been simply (!) a matter of introducing new desaturases, for example, but it has been necessary to modify many aspects of the biosynthetic machinery. An open access publication provides an excellent account of this new technology (Haslam, R.P. et al. Synthetic redesign of plant lipid metabolism. Plant J., 87, 76-86 (2016); DOI).

Blogs for the previous year (2016) can be located here..

Author: William W. Christie Updated: May 2nd, 2018 Credits/disclaimer LipidWeb logo