The LipidWeb blank

Lipid Matters - A Personal Blog

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

January 16th, 2019

Scottish thistleA 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, 1-27 (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 21st, 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 14th, 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 31st, 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 24th, 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 17th, 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 10th, 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. LipidMaps® 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".

September 26th, 2018

Scottish thistleI have to confess that I was entirely unaware of the importance of the nature and function of extracellular vesicles (exosomes and microvesicles) in lipid metabolism until the thematic series on this topic was announced in the Journal of Lipid Research (with the start of formal publication in the August issue). It seems that I was not alone in this regard as the subject is barely mentioned in two recent text books on lipid biochemistry, which I consulted. Although extracellular vesicles were first described as a means of selective elimination of proteins, lipids and RNA from cells, they are now considered to be a new mode of intercellular communication. I have a lot of catching up to do via the continuing JLR series, together with two recent reviews in other journals (DOI-1 and DOI-2).

The mechanism behind the biological effects of tocopherols other than their role as antioxidants has proved elusive, although evidence has been accumulating that the 13'-carboxy metabolites may be of importance. It has now been established that the 13'-carboxy metabolite of α-tocopherol (α-T-13'-COOH) is a potent inhibitor of 5-lipoxygenase, a key enzyme in the biosynthesis of the inflammatory leukotrienes (Pein, H. et al. Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. Nature Commun., 9, 3834 (2018);  DOI - open access). α-T-13'-COOH accumulates in immune cells and inflamed exudates both in vitro and in vivo in mice, and the authors suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on this endogenous metabolite.

This week's lipid oddity is an N-acylhomoserine lactone produced by bacteria in the human gut (Landman, C. et al. Inter-kingdom effect on epithelial cells of the N-acyl homoserine lactone 3-oxo-C12:2, a major quorum-sensing molecule from gut microbiota. PLOS One, 13, e0202587 (2018);  DOI - open access). The full structure of this particular molecule has still to be established, but it has been determined that it has a C12 acyl chain with a 3-oxo group and two double bonds (positions and geometry unknown). Such lipids function normally in a form of intercellular signalling termed 'quorum sensing', which controls gene expression in response to the population density of the species, resulting in coordinated regulation of a range of group-level behaviours, including production of secondary metabolites and virulence factors, bioluminescence and biofilm formation, i.e. when these signal molecules reach a threshold concentration in a particular environment, they bind to their intracellular receptor/activator proteins to induce the expression of relevant genes. The importance of these new molecules is that they also interact with the host intestinal epithelial cells as anti-inflammatory agents with the potential to affect human metabolism including diseases of the gut.

N-acylhomoserine lactone

When we are all dead and gone, it appears that our cholesterol lingers on as in the fossil of a 600 million year old animal (pre-Cambrian) (Bobrovskiy, I. et al. Ancient steroids establish the Ediacaran fossil Dickinsonia as one of the earliest animals. Science, 361, 1246-1249 (2018);  DOI).

September 19th, 2018

A new publication examines a range of N-acylethanolamide derivatives to determine whether they are endocannabinoids as defined by an interaction with CB1 and/or CB2 receptors (Alharthi, N. et al. n-3 polyunsaturated N-acylethanolamines are CB2 cannabinoid receptor-preferring endocannabinoids. Biochim. Biophys. Acta, 1863, 1433-1440 (2018);  DOI). Saturated and monoenoic N-acylethanolamides are not endocannabinoids, but those derived from other members of the n-6 family of polyunsaturated fatty acids (docosatetraenoic and docosapentaenoic acids in addition to arachidonic) activate both CB1 and CB2 receptors, as well as TRPV1 channels, so these should be considered true endocannabinoids (and 'endovanilloids'). Similarly, N-acylethanolamides derived from the n-3 family of polyunsaturated fatty acids (eicosapentaenoic, docosapentaenoic and docosahexaenoic acids) activate CB2 receptors, and of these, the C22 derivatives also activate TRPV1 channels but not the CB1 receptor. The authors suggest that the preferential activation of CB2 receptors by N-acylethanolamides of the n-3 family of polyunsaturated fatty acids contribute in part to the broad anti-inflammatory profile of the latter.

The journal Current Opinion in Cell Biology has a special issue (open access) dealing with the topic of "Membrane Trafficking" (edited by Satyajit Mayor and Anne Spang): Volume 53, Pages A1-A4, 1-110 (August 2018).

A correspondent has drawn to my attention an article in the Guardian Newspaper that is relevant to my comment on open access publication in last week's blog. The author suggests that scientific publication is a rip-off and has no qualms about using the Sci-Hub web site. I have looked at this web site in the past, although my service provider does not now permit access. My own feeling is that while I don't mind bending the copyright law from time to time, I would feel guilty about breaking it in a more comprehensive manner. Also, I would worry about the security of my computer if I were to download material from this source.

September 12th, 2018

Another new fatty acid caught my eye this week that is novel in terms of both structure and function, i.e. one containing a tetrahydrofuran ring, i.e. (+)-(2S, 3S, 5R)-tetrahydro-3-hydroxy-5-[(1R)-1-hydroxyhexyl]-2-furanoctanoic acid, which is shown to be a secreted pheromone that controls the migratory behaviour of a fish species, the sea lamprey. This is secreted by the fish larvae and draws the mature fish towards the spawning grounds. (Li, K. et al. Fatty-acid derivative acts as a sea lamprey migratory pheromone. Proc. Natl. Acad. Sci. USA, 115, 8603-8608 (2018);  DOI - open access). The compound is potentially useful for both control and conservation of sea lamprey populations. As far as I am aware, this is the first natural fatty acid to have been found with a tetrahydrofuran ring, i.e. produced by enzyme systems, although isofurans with a ring structure of this kind are formed adventitiously together with other isoprostanes by autoxidative processes in animal tissues. Fatty acids with a furan ring are common minor components of fish oils, although they are presumed to come from algae and phytoplankton in the diet.

Tetrahydrofuranoid fatty acid from sea lampreys

A news item in Nature reports that a number of funding organizations are moving towards a policy of free access to all publications for work that they have supported. I am happy to see an increase in the number of open access publications, but I have the one caveat as to how is it to be decided which open access publications are reputable in the light of innumerable reports that there are a host of frankly fraudulent publications on line. Incidentally, the Nature article has some interesting statistics on the growth of open access publishing. Between 2012 and 2016, the proportion of publications in subscription-only journals fell from 49.2 to 37.7%, though those in fully open access publications only rose by 3%, and there was virtually no change in the number of papers published in journals that permit open access after a fixed period.

It barely touches upon lipids, but who could resist this title (Cao-Pham, A.H. et al. Nudge-nudge, WNK-WNK (kinases), say no more? New Phytologist, 220, 35-48 (2018);  DOI).

September 5th, 2018

It is rare to see an announcement of the discovery of novel fatty acids in the popular science news websites, but both Sci-News and Science-Daily have picked up on nebraskanic (illustrated) and wuhanic acids (as the previous but with an additional double bond in position 22) from a seed oil from a Chinese plant. Both reports carry an interview with Prof. Edgar Cahoon, who describes the scientific interest in that biosynthesis involves a break in the cycle of two-carbon additions involved in the assembly of the acyl chain in a manner usually seen only in the synthesis of bacterial fatty acids. Also, the fatty acids seem to form estolide linkages to each other as well as being esterified to glycerol. From a practical standpoint, the oil may have value as a lubricant of natural origin. The names are of course derived from the institutions of the lead authors. This is a long and honorable tradition, as I recall from my days as a post-doc at the Hormel Institute in the 1960s that Helmut Mangold gave the name 'hormelic acid' to a new cyclopentenyl fatty acid. The 60s and 70s were a golden age in the discovery of novel fatty acids, when the Northern Regional Laboratory of the USDA in Peoria, especially, had a major research programme the aim of which was to discover new seed oils of potential industrial value.

Formula of nebraskanic acid

Coincidentally, a tweet to LIPID MAPS® alerted me to a report of the presence in plant tissues of other estolide-linked fatty acids, i.e. fatty acid esters of hydroxy fatty acids, which are proving to have some surprising biological properties in animal tissues (Zhu, Q.-F. et al. Comprehensive screening and identification of fatty acid esters of hydroxy fatty acids in plant tissues by chemical isotope labeling-assisted liquid chromatography–mass spectrometry. Anal. Chem., 90, 10056-10063 (2018);  DOI).

If I had to pick the most neglected of all lipid classes, I would suggest the non-acidic glycosyldiacylglycerols of animal tissues for which I have to depend on a review from 1987 in my account of the topic in the LipidWeb. I suspect that one reason is that they may suffer degradation in some methods for the isolation of the oligoglycoceramides with which they have similar physical and chromatographic properties. Even the acidic seminolipid or sulfogalactosyldiacylglycerol does not rate a mention in many lipid text books, although it is essential for male reproduction. Hopefully, a new review will rekindle interest in the the latter lipid at least (Tanphaichitr, N. et al. Properties, metabolism and roles of sulfogalactosylglycerolipid in male reproduction. Prog. Lipid Res., 72, 18-41 (2018);  DOI.).

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Author: William W. Christie Updated: January 16th, 2019 Credits/disclaimer LipidWeb logo