Lipid Matters - A Personal Blog
— by William (Bill) W. Christie

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

March 20th 2019

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

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

March 13, 2019

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

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

March 6th 2019

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

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

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

February 27th 2019

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

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

February 20th 2019

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

34:0 fatty acid

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

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

February 13th 2019

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

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

February 6th 2019

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

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

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

Jan 30th 2019

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

The Journal of Biological Chemistry has just selected a paper that deals with EETs among other oxylipins as their paper of 2018 in their Lipids section (Moon, S.H. et al. Heart failure-induced activation of phospholipase iPLA2γ generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore. J. Biol. Chem., 293, 115-129 (2018);  DOI). In brief, in non-failing human hearts, one isoform of phospholipase A (cPLA2ζ) channels arachidonic acid into protective EETs, whereas in failing hearts, opening of the mitochondrial permeability transition pore increases the activity of a second isoform of phospholipase A (cPLA2γ) that channels arachidonic acid into toxic HETEs. A second lipid biochemistry paper is their 2018 choice for the Immunology section.

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

Jan 23rd 2019

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

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

January 16th 2019

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

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

January 9th 2019

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

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

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

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

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

January 2nd 2019

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

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

December 19th 2018

Scottish thistleThe concept of lipid rafts in membranes is an important one in that it governs many of the functions of sphingolipids in membranes. Although there are some dissenting voices, there appears to be a large area of agreement among experts in the field of their existence and relevance. I can recommend a new and relatively brief review as an introduction to the topic (Goñi, F.M. ‘Rafts'': A nickname for putative transient nanodomains. Chem. Phys. Lipids, 218, 34-39 (2019);  DOI). Among a number of key conclusions, the author deplores the continued use of cold extraction with Triton X-100 as a standard procedure for raft isolation, as it is a source of artefacts. Also, the author obviously does not like the term 'rafts', and I sympathize in that it does appear trivial with little meaning from a scientific standpoint. Instead, he suggests the term '(transient) nanodomain'. While I agree with his idea in principle, his suggestion seems to me to be too general in that it could also apply to other membranes regions such as those enriched in polyunsaturated fatty acids, which may form when sphingolipids segregate. As sphingolipids are the defining constituents of rafts, can I suggest 'sphingoid nanodomains' as an alternative name?

Phytoprostanes and phytofurans are formed in plants via non-enzymatic, free radical-catalysed pathways similar to isoprostane synthesis in animals. They have similar molecular structures to animal oxylipins so may influence animal biology when they are absorbed from plant foods in the diet with potential benefits to human health. A new review summarizes the available evidence (Medina, S. et al. Structural/functional matches and divergences of phytoprostanes and phytofurans with bioactive human oxylipins. Antioxidants, 7, 165 (2018);  DOI - open access).

I wish all my readers a happy Christmas and a prosperous lipidic New Year.

December 12th 2018

The membranes in photosynthetic cells are essential to all life on earth, so the more we understand them and their lipid components the better. The chloroplast inner and outer membranes and the thylakoid membranes within the chloroplast are obviously vital in this process, but the endoplasmic reticulum is also of great importance and mitochondria cannot be neglected. Monogalactosyldiacylglycerols with distinctive fatty acid compositions are key products, and they are essential for the integrity and function of the photosynthetic apparatus. Fatty acid synthesis and desaturation and synthesis of glyceride precursors occur in different parts of the cell so there is need for extensive lipid trafficking between membranes and organelles. A number of lipid transporters have now been identified, and there is evidence for lipid transport at contact sites between organelles. In addition, there is some evidence for vesicular transport. All of these are discussed in a new review on the topic (LaBrant, E. et al. Lipid transport required to make lipids of photosynthetic membranes. Photosynth. Res., 138, 345-360 (2018);  DOI), which happily is open access.

Of course, the plasma membrane of plant cells is just as important as that in animals in that it protects the cell, regulates nutrient exchanges and acts as a platform to receive and send signals. Again, the lipid component are of central importance, but a major shift in our understanding of how the membrane functions has come with the recognition that sphingolipids, i.e. glycosyl inositol phosphoryl ceramides, are major constituents. Until recently, we knew little of them because they are relatively large, polar and complex molecules, which were easily overlooked with the available analytical methodology. The new era of lipidomics has shown that they are one of the most abundant constituents and has enabled comparisons to be drawn with the functions of gangliosides in animal membranes. For example, they are essential for the organization of the plasma membrane and they act as toxin receptors. Again, I am grateful for a new review for bringing me up to speed on the topic (Cassim, A.M. et al. Plant lipids: key players of plasma membrane organization and function. Prog. Lipid Res., 73, in press (2019);  DOI).

December 5th 2018

In my early career at a Dairy Research Institute, we were concerned with the relative lack of essential fatty acids and excess of trans fatty acids in meat and dairy products because of microbial biohydrogenation in the rumen. I am not fully conversant with current research in this area but I guess that it continues. However, there does appear to be great interest in the byproducts of the reaction, i.e. conjugated linoleic and linolenic acids, from a quite different perspective. These have perceived benefits to human health, while the complex mixtures of isomers that are easily obtained from linoleate by chemical isomerization do not always have the same effects when administered in the diet. A number of linoleate isomerases have now been identified from bacteria, some of which occur as multi-enzyme systems. As many of the organisms occur in the human gut, they may affect human metabolism in vivo. A new review discusses the topic (Salsinha, A.S. et al. Microbial production of conjugated linoleic acid and conjugated linolenic acid relies on a multienzymatic system. Microbiol. Mol. Biol. Rev., 82, e00019 (2018);  DOI).

New Scientist has just published a leader article with the provocative title "Time to break academic publishing's stranglehold on research". They comment on how little support there has been from funding agencies internationally for open access proposals. To quote further "The scientists who oppose it have real concerns, but are letting the perfect be the enemy of the good". I am sure that not all publishers are making 40% profits, as the leader suggests, but the big three (Elsevier, Springer, Wiley) are doing pretty well as subscription costs continue to rise. One unintended consequence of this is that academic libraries are no longer a place to browse for general information but have become much more specialized. For as long as I can remember, the libraries with which I have been associated have been faced each year with a necessity to cut the numbers of journal subscriptions as their budgets have been constrained. To compensate, we have greater access online to many journals from the big three publishers, but less to smaller publishers, including those linked to many academic societies (such as ACS, Biochemical Society, and University Presses). For example, my former Institute has just dropped its subscription to the Journal of Biological Chemistry as an economic measure in order to retain journals more in line with its limited remit. Is there also a "stranglehold on research", as the title of the leader suggests? You may be better qualified than I to answer. By the way, I would like to see more open access articles in New Scientist itself.

November 28th 2018

Scottish thistleWhen it comes to any opinions on fats in the diet and nutrition in general, I live in a fog of confusion. I enjoy fish, so I am content to believe that n-3 fatty acids are good for me, and I also enjoy dairy foods with their 'bad' fats so I may die happy at least. According to a recent paper in Science, most nutritional experts are confused also (Ludwig, D.S. et al. Dietary fat: From foe to friend? Science, 362, 764-770 (2018); DOI - open access). A series of questions that require further research are posed, most relating to the amount and type of fat relative to carbohydrate in the diet. There has been a substantial reduction in the proportion of fat in the diet in the U.S.A. and U.K. following well-publicized dietary recommendations in the last century, yet life expectancy is declining. I looked in vain for the words 'alcohol' and 'exercise' in the paper and these surely must be important confounding factors in Western nations. Although I do not suggest that we should give up on research on the topic, it seems to me that there is little chance of defining an optimum diet for populations at large. Perhaps we should simply reduce our expectations for nutritional research and concentrate on life-style factors.

Formula of a bacterial proteolipidScientific anniversaries are useful in that they remind us of the work of the pioneers in lipid science, often in areas away from our daily research concerns. For example, a new review reminds us that the most abundant protein in the bacterium E. coli is a triacylated proteolipid, termed 'Braun's lipoprotein' after its primary discoverer of 50 years ago (Asmar, A.T. and Collet, J.F. Lpp, the Braun lipoprotein, turns 50 - major achievements and remaining issues. FEMS Microbiol. Letts, 365, fny199 (2018);  DOI - open access). This has a molecular weight of only 5.8 kDa and folds into a trimeric helical structure. Uniquely, much of it is covalently attached by the ε-amino group of the C-terminal lysine to the carboxyl group of a meso-diaminopimelic acid residue in the peptidoglycan of the cell wall to provide the only covalent connection between the inner and outer membranes. This was the first of innumerable such proteins to be discovered that among a host of biological functions greatly influence the virulence of bacteria.

2-Hydroxyoleic acid has remarkable biological activities in that it suppresses the growth and induces autophagy in certain cancer cells. It therefore has appreciable potential as a non-toxic anticancer drug, and the European Medicines Agency has designated it as an orphan drug for the treatment of glioma. The mechanism for its action is uncertain but a new publication suggests that it may involve effects upon phosphatidylcholine metabolism but not upon activation of sphingomyelin synthesis as originally thought (Lou, B. et al. 2-Hydroxy-oleic acid does not activate sphingomyelin synthase activity. J. Biol. Chem., 293, 18328-18336 (2018); DOI). Intriguingly, it is the 'unnatural' S-enantiomer that produces this effect.

November 21, 2018

Synaptamide, which I discussed in my last blog, takes its name from its occurrence and function in the central nervous system. Now, two new papers describe its occurrence in human breast milk, together with a suite of other bioactive amides, suggesting that it may be required for the development of the newborn infant (DOI-1 and DOI-2). Related endocannabinoids are produced in parasitic worms (helmiths) and a new publication reports that during infection of a host animal the intestines are stimulated to produce their own endocannabinoids that promote the host immune responses and reduce parasite burden while also reducing pain and inflammation. However, there are also benefits to the parasite. The hope is that this knowledge may lead to new treatments for such infections. I won't have access to the original publication for 6 months, but there is a popular report in Science Daily.

Early in my research career, I was involved in the use of pyrrolidides for structural analysis of fatty acids by mass spectrometry, but I could not make full use of this methodology until I obtained my own instrument in the 1980s, by which time 3-pyridylcarbinol ('picolinyl') esters and dimethyloxazoline derivatives had been described. New alternatives are reported from time to time, but there is now such a body of information on these three that they are likely to remain the derivatives of choice for locating double bonds, ring structures, etc for the foreseeable future (see my Mass Spectrometry web pages). Of course, I had access to electron impact ionization only, so I was intrigued to read a new paper in which Orbitrap mass spectrometry was used with 3-pyridylcarbinol esters to determine the structures of fatty acids with cyclopropane rings (Merlier, F. et al. A gas chromatography full scan high resolution Orbitrap mass spectrometry method for separation and characterization of 3-hydroxymethyl pyridine ester of fatty acids at low levels. J. Chromatogr. A, 1575, 72-79 (2018); DOI). The spectra are clear and informative, although they do differ from the analogous electron-impact spectra in significant ways. I will look forward to seeing further publications on this methodology.

GC-MS was also crucial to demonstrate the introduction of a double bond surprisingly and possibly uniquely into the terminal region of trans-vaccenic acid by a methyl-end desaturase in rats (Garcia, C. et al. Conversion of dietary trans-vaccenic acid to trans11,cis13-conjugated linoleic acid in the rat lactating mammary gland by Fatty Acid Desaturase 3-catalyzed methyl-end Δ13-desaturation. Biochem. Biophys. Res. Commun., 505, 385-391 (2018); DOI).

Nearly five years ago, I first mentioned the next item in my blog, but as I have many new readers, this is how to teach lipid science - - with thanks to Michael Eskin!

November 14, 2018

Two substantial journal issues dealing with aspects of lipid biochemistry and analysis have now been published, although I have to confess that I have been enjoying the sunshine and beaches of Gran Canaria for the last week so I have not had time to do other than browse through them briefly, i.e. "Dietary fatty acids, lipid mediators, cell function and human health" - edited by Philip Calder (Molecular Aspects of Medicine, 64, Pages 1-182 (December 2018) ) - and "Lipidomics" - edited by James Ntambi and Sarah Spiegel (Biochem. Biophys. Res. Commun., 504, Issue 3, Pages 553-628 (7 October 2018)).

I did, however, note a number of interesting reviews dealing with bioactive amides, both endocannabinoids and others, and one especially dealing with N-docosahexaenoylethanolamine (synaptamide) (Kim, H.Y. and Spector, A.A. N-Docosahexaenoylethanolamine: A neurotrophic and neuroprotective metabolite of docosahexaenoic acid. Mol. Aspects Med., 64, 34-44 (2018);  DOI). This does not interact with the endocannabinoid receptors, but has its own target (GPR110 or ADGRF1), a G-protein coupled receptor that is highly expressed in the central nervous system and promotes neurogenesis in developing neurons at nanomolar concentrations. It invokes a signalling pathway that leads to the expression of neurogenic genes while suppressing the expression of proinflammatory genes. It hardly needs saying that this is yet another indication of the importance of omega-3 fatty acids for our health and well being.

A separate review elsewhere deals with the how various bioactive amides in the gut influence the microbial biome and vice versa, with eventual impacts on the brain (Russo, R. et al. Gut-brain axis: role of lipids in the regulation of inflammation, pain and CNS diseases. Curr. Med. Chem., 25, 3930-3952 (2018);  DOI). I need to spend more time with both of these.

October 31, 2018

Scottish thistle During embryonic development in many mammals, including the rat, the eyelids migrate over the cornea and fuse in order to protect the eyes during birth and early postnatal development. It has now been established that a key factor in this process is the lipid sphingosine-1-phosphate, which promotes the activation of proteins involved in cell migration and stimulates signalling by the epidermal growth factor receptor (EGFR) (Bian, G. et al. Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling. Sci. Signal., 11, eaat147023 (2018);  DOI). In the early part of my career, we looked on sphingolipids as interesting curiosities that simply had ill-defined roles in membranes, so the all-pervasive nature of their signalling properties has come as a surprise - see the latest review (Pulli, I. et al. Sphingolipid-mediated calcium signaling and its pathological effects. Biochim. Biophys. Acta, Mol. Cell Res., 1865, 1668-1677 (2018);  DOI).

I was stimulated myself in writing the above to check the spelling of 'signalling' (ll) or 'signaling' (l); apparently the former is British English and the second American English. "We have really everything in common with America nowadays except, of course, language" - Oscar Wilde (The Canterville Ghost, 1887), not George Bernard Shaw to whom it is often attributed.

A fascinating paper in JBC describes how the acyl-coA synthetase 1 can direct fatty acids to many different functions in different membranes in the liver (Young, P.A. et al. Long-chain acyl-CoA synthetase 1 interacts with key proteins that activate and direct fatty acids into niche hepatic pathways. J. Biol. Chem., 293, 16724-17740 (2018);  DOI). It is reported that the enzyme can interact with a number of different proteins at the outer mitochondrial membrane and the endoplasmic reticulum to determine whether the fatty acids are directed to oxidation or esterification or to other purposes. Incidentally, my former Institute can no longer afford a subscription to JBC, but the journal permits access to early versions of the paper even after formal publication and this is sufficient for my purposes. How I wish others were equally enlightened, especially ACS publications.

October 24, 2018

I have a few open access review bargains for you this week of which my favourite and that most useful in updating my web pages in the Lipid Essentials section of the LipidWeb deals with sphingolipids (Harrison, P.J. et al. Sphingolipid biosynthesis in man and microbes. Nat. Prod. Rep., 35, 921-954 (2018);  DOI). In fact the title is something of a misnomer in that it does not treat sphingolipids as a whole but with the first steps in the biosynthesis of sphingoid bases, i.e. before the involvement of ceramide synthesis, and then with their catabolism via sphingosine-1-phosphate.

An even more substantial review deals with glycolipids from marine organisms (Cheng-Sanchez, I. and Sarabia, F. Chemistry and biology of bioactive glycolipids of marine origin. Marine Drugs, 16, 294 (2018);  DOI). This is perhaps one for the specialist, but it encompasses an astonishing array of glycosphingolipids, together with glycosyldiacylglycerols and others that seem to defy simple classifications. Marine organisms can produce polyunsaturated fatty acids in many different ways, and for example marine bacteria can synthesise such fatty acids both by aerobic and anaerobic mechanisms. In particular, marine invertebrates contain many diverse enzymes involved in the introduction of double bonds into fatty acids including both "front-end" and "omega" desaturases, and they are even able to produce what for most other animals are essential fatty acids. This is the subject of my third review of the week (Monroig, O. and Kabeya, N. Desaturases and elongases involved in polyunsaturated fatty acid biosynthesis in aquatic invertebrates: a comprehensive review. Fisheries Sci., 84, 911-928 (2018);  DOI). This is not simply an esoteric exercise as such enzymes may have appreciable biotechnological potential.

A month ago, I discussed the discovery of a cholesterol metabolite in a 600 million year old fossil, confirming that it was of an animal. Now the molecular fossil record for animals has been pushed back another 35 million years with the discovery in pre-Cambrian rocks of sterane structures that are made exclusively by demosponges (see the report in Science Daily).

October 17, 2018

The journal Biochimie has a special issue devoted to "Current trends in oxysterols and related sterols", edited by Gérard Lizard, Giulio Muccioli and Luigi Iuliano (Volume 153, Pages 1-238 (October 2018)). So far I have only had time for a brief overview, but I was especially interested in a multi-author inter-laboratory comparison of methods of oxysterol analysis (Lutjohann, D. et al. International descriptive and interventional survey for oxycholesterol determination by gas- and liquid-chromatographic methods. Biochimie, 153, 26-32 (2018);  DOI). Some surprising discrepancies among the various laboratories were noted, highlighting a need for standardized methods, and especially for the use of appropriate deuterated standards. Also, as I suggested some weeks ago to deafening silence, it would also be useful to have ready access to standard mass spectra of sterol derivatives for those new to the subject or with limited access to mass spectral libraries, ideally in a dedicated website - the next task for this multi-author panel? Those working with plant oxysterols have the same or perhaps greater problems because of the wide range of different sterols and triterpenoid alcohols in plant species. Similar aims to standardize methodologies are discussed in a multi-author study of plasma lipidomics (Burla, B. et al. MS‑based lipidomics of human blood plasma: a community-initiated position paper to develop accepted guidelines. J. Lipid Res., 59, 2001-2017 (2018);  DOI).

Oxidized lipids were the theme of a number of papers in this week's literature search, headed by a rather substantial review in an ACS journal for those of you who have access (I don't) (Parvez, S. et al. Redox signaling by reactive electrophiles and oxidants. Chem. Rev., 118, 8798-8888 (2018);  DOI). On the other hand, I have been able to read and can recommend an open access review on the signalling properties of oxidized phospholipids as opposed to the unesterified oxylipins (Tyurina, Y.Y. et al. "Only a life lived for others is worth living": redox signaling by oxygenated phospholipids in cell fate decisions. Antiox. Redox Signal., 29, 1333-1358 (2018);  DOI). Both enzymic and non-enzymic routes to such species are known, and oxidized cardiolipin is crucial to apoptosis and phagocytosis of mitochondria. This has been recognized for some time, but the role of oxygenated phosphatidylethanolamines as pro-ferroptotic signals has emerged relatively recently.

October 10, 2018

I was intrigued by the title of a recent paper (Zaidi, A. et al. Forgotten fatty acids - Surface properties supply conclusive evidence for including carotenoic acids. Chem. Phys. Lipids, 216, 48-53 (2018);  DOI), and I read through it rapidly to see whether I should add anything on these lipids to my Lipid Essential pages on the LipidWeb. I decided against, but was prompted to consider more deeply by a correspondent. I did not change my mind. Yes they are fatty and yes they are acids, but they do not occur naturally with the exception of retinoic acid, which I discuss appropriately in my web page on retinoids. LIPID MAPS® appear to agree with me as they list it in their isoprenoid group. Similarly, the acidic (carboxy) derivatives of tocopherols, which I mentioned in my blog of two weeks ago (September 26th), are technically fatty acids but to my mind are best discussed with the tocopherols. What about triterpenoids such as oleanolic and betulinic acids? They are fatty and acidic, but do we really need to call them fatty acids? I suppose another question raised by the publication might be whether surface active properties are of sufficient value in determining whether a lipid should be classified as a fatty acid. Retinoic acid, for example, is bound in tissues to specific transporter-carrier proteins, so I doubt whether it ever reaches an effective concentration in vivo where its surface active properties are relevant. If it does, my guess is that this would be a signal for oxidation, glucuronidation and elimination. Should any isoprenoids be classified primarily as fatty acids? In my personal view, phytanic acid should be because of its occurrence in esterified form in main-stream lipids in animals. Of course, all classification systems are simply academic exercises and they all boil down to personal opinions, so the authors of the paper are just as entitled to their view as I am to mine.

The journal Cancer and Metastasis Reviews has published a special issue (Volume 37, Issue 2-3, pp. 199-572 September 2018) that deals with the topic of "Bioactive Lipids" (Issue Editors: Dipak Panigrahy and Allison Gartung).

October 3rd 2018

Two reviews dealing with mass spectrometry of lipids have caught my eye this week, both by eminent practitioners of the subject. The first by Robert Murphy deals with mass spectrometry of neutral lipids, especially triacylglycerols and cholesterol esters, both by shotgun techniques and as part of chromatographic separations (Murphy, R.C. Challenges in mass spectrometry-based lipidomics of neutral lipids. Trends Anal. Chem., 107, 91-98 (2018);  DOI). The large number of molecular species present in triacylglycerols of natural origin, even those with relatively simple compositions, will always cause problems, especially when positional distributions are taken into account, and the author stresses the need for careful calibrations in quantitative analyses with internal standards labelled with stable isotopes. The second review by Fong-Fu Hsu deals with shotgun lipidomics (Hsu, F.F. Mass spectrometry-based shotgun lipidomics - a critical review from the technical point of view. Anal. Bioanal. Chem., 410, 6387-6409 (2018);  DOI). As an armchair scientist these days, I often get the impression that life is so much easier for the current generation with such powerful instrumentation at their disposal. This and the previous review clearly demonstrate that there is just as much need for care and attention to detail in experimentation as there ever was. As an example of what can be achieved by such methodologies, a new multi-author paper describes the lipidomics and proteomics of every cell type in the human lung (Kyle, J.E. et al. Cell type-resolved human lung lipidome reveals cellular cooperation in lung function. Sci. Rep., 8, 13455 (2018);  DOI - open access). The authors claim that this is the first such lipidome map of any organ.

While strongly supporting the open access movement for science publication, I have expressed concern in past contributions to this blog that some of the new journals may not operate to the same standards as the older pay-for-view journals. A correspondent has drawn to my attention a report in about the open access journal Nutrients. The Editor-in-Chief and all of his senior editors have resigned "alleging that the publisher, the Multidisciplinary Digital Publishing Institute (MDPI), pressured them to accept manuscripts of mediocre quality and importance." The presumed intention of the publisher is to increase the profitability of the journal, but the editors believe that this will harm the journal's impact factor and lead to a drop in submissions in the long term. I have been assured by my correspondent that this journal has had a good reputation until now.

The journal Biological Chemistry (Volume 399, Issue 10, October 2018) is devoted to the topic of "Sphingolipids in Infectious Biology and Immunology".

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