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).

December 12th 2018

Scottish thistleThe 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".

September 26, 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 (now reaching 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 19, 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 12, 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.).

August 29nd 2018

Scottish thistleA new review (open access) covers the topic of glycosylphosphatidylinositol anchored proteins in plants (Yeats, T.H. et al. Plant glycosylphosphatidylinositol anchored proteins at the plasma membrane-cell wall nexus. J. Integr. Plant Biol., 60, 649-669 (2018);  DOI). As might be expected, these are vital for a host of functions in plant development and signalling especially at the interface of the plasma membrane and cell wall. However, although the synthesis and structure of GPI anchors is believed to be conserved across eukaryotes, this appears to be based on a number of assumptions as far as plants are concerned, as it seems that the O-glycan component of only one species has been determined to date, i.e. that of Pyrus communis (pear), in a publication from 1999. In this instance, the O-glycan was relatively simple with no phosphoethanolamine side chains and sometimes a β-linked galactose side chain on the first mannose. The lipid component was a ceramide, as that in many fungi, rather than a diacylglycerol.

The microbial lipopeptides are fascinating molecules in that they often contain unique fatty acids together with distinctive amino acids, sometimes with the "wrong" stereochemistry. They are usually powerful surfactants, often with anti-bacterial and antifungal properties. Importantly, they are also considered one of the best hopes in the search for novel antibiotics that may replace those to which pathogenic bacteria are becoming resistant. They may be of equal value against plant pathogens. The polymixins are already licensed for topical use against Gram-negative bacterial infections, but they can only be used internally as a last resort because of toxicity problems. A new review discusses the progress that is being made in the synthesis of polymixin analogues that are better tolerated and hopefully will have a greater range of activities (Vaara, M. New polymyxin derivatives that display improved efficacy in animal infection models as compared to polymyxin B and colistin. Med. Res. Rev., 38, 1661-1673 (2018);  DOI). It seems that we are no nearer to finding a magic bullet, although individual compounds are showing promise, especially as they may act in synergy with existing antibiotics. Similarly, there is hope for novel lipopeptides produced by Pseudomonas species as also discussed in another new review (open access) (Geudens, N. and Martins, J.C. Cyclic lipodepsipeptides from Pseudomonas spp. - biological Swiss-army knives. Front. Microbiol., 9, 1867 (2018);  DOI). Some of these have anticancer activities in vitro in cancer cell lines.

August 22nd 2018

It seems a highly ambitious undertaking to use lipidomics to assess how the lipidome has changed during evolution even in mammalian species. From the internet - "According to Mammal Species of the World, 3rd Edition (Wilson and Reeder 2005), the most recent authoritative published checklist of modern mammal species, there are 5,416 different species of mammals". A beginning can be made at least to such a study, and a new publication reports data from six tissues of 32 species of mammals representative of primates, rodents, and bats (Khrameeva, E. et al. Lipidome evolution in mammalian tissues. Mol. Biol. Evolution, 35, 1947-1957 (2018);  DOI). It appears from this selection that the lipidome has not evolved appreciably except in humans, where many of the unique features were found in the brain cortex, suggesting that there has been an accelerated lipidome evolution in the human brain. The paper is open access.

Another pedantic rant: It is now more than 50 years since IUPAC-IUB published their first set of nomenclature recommendations for lipids in which the stereospecific numbering (sn) system was introduced for triacylglycerol positional distributions. My recollection from that time was that this part of the proposal was approved universally, as a sensible and practical way to characterize the chirality of glycerolipids instead of the R/S or D/L nomenclatures, which could cause confusion especially when applied to more complex lipids. It was fondly assumed that the term 'triglyceride' would fall into disuse, although I can understand why it continues to be used in industry and perhaps more surprisingly in medicine (Sigma-Aldrich sell "Serum Triglyceride Determination Kits"). As I may have mentioned before, my pet hate is the hybrid term "triacylglyceride", which still gets passed by referees and editors of reputable journals. Google Scholar tells me that it has been used in more than 2000 publications since 2017. I don't suppose that many read the original IUPAC-IUB publications nowadays (although you can find links here), but all the text books in my library use triacylglycerol. By all means continue to use 'triglycerides' if you wish, but please not 'triacylglycerides'.

My open access bargain of the week is a 30 page review on protein S-acylation (Zaballa, M.E. and van der Goot, F.G. The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics. Crit. Rev. Biochem. Mol. Biol., 53, 420-451 (2018);  DOI).

August 15th 2018

Although the immune system is essential to protect the body from infection, some immune responses can harm tissues. The eye is especially sensitive to immune reactivity, and it has now been determined that cholesterol sulfate is a key protective factor (Sakurai, T. et al. Cholesterol sulfate is a DOCK2 inhibitor that mediates tissue-specific immune evasion in the eye. Science Sign., 11, eaao4874 (2018);  DOI). This is produced by the Harderian gland, which secretes the lipids that form a protective layer in the tear film that covers the eye. Experiments with mice in vitro demonstrated that cholesterol sulfate selectively inhibits the guanine nucleotide exchange factor DOCK2 and by this means suppresses the migration of neutrophils and T cells. When the sulfotransferases responsible for the synthesis of this lipid were inhibited, inflammation occurred that could be cured by administering eye drops containing cholesterol sulfate. As it is produced by most animal cells and circulates in plasma, it seems to me that the next important question is whether cholesterol sulfate might be an endogenous factor that suppresses the immune system in other circumstances, and possibly in a less benign manner in tumours, for example.

The journal Nitric Oxide continues its series of review articles on the chemistry and biochemistry of the potent anti-inflammatory nitro fatty acids in volumes 78 and 79. A separate publication describes the anticancer effects of nitro fatty acids and proposes a mechanism (Kühn, B. et al. Anti-inflammatory nitro-fatty acids suppress tumor growth by triggering mitochondrial dysfunction and activation of the intrinsic apoptotic pathway in colorectal cancer cells. Biochem. Pharm., 155, 48-60 (2018);  DOI). The authors suggest that "these naturally occurring lipid mediators are a new class of well tolerated chemotherapeutic drug candidates for treatment of colorectal cancer or potentially other inflammation-driven cancer types." Good news indeed!

I am always interested in lipid oddities, and it is hard to think of anything more unusual than a triacylglycerol with acetate in position sn-2, as in the seed oils from Polygala species. This was first reported briefly in 1977 but has now been confirmed by mass spectrometry (Smith, M.A. et al. 2-Acetyl-1,3-diacyl-sn-glycerols with unusual acyl composition in seed oils of the genus Polygala. Eur. J. Lipid Sci. Technol., 120, 1800069 (2018);  DOI). Curiosity aside, if any species from the genus can be developed as a commercial crop, the oil may have potential as a low-viscosity biofuel/lubricant or reduced calorie food ingredient.

August 8th, 2018

The uncontrolled inflammatory response that is seen in sepsis is now recognized to be a major cause of death in the UK and I am sure elsewhere. One of the best hopes for novel therapeutic responses lies with the specialized pro-resolving mediators - resolvins, protectins and maresins, but how are such highly stereospecific structures to be produced on a scale that permits clinical testing? A new total synthesis of resolvin D4 (RvD4), which has three chiral hydroxyl groups and three cis- and three trans-double bonds, has just been published that has the potential to be developed on a commercial scale (Winkler, J.W. et al. Structural insights into Resolvin D4 actions and further metabolites via a new total organic synthesis and validation. J. Leukocyte Biol., 103, 995-1010 (2018);  DOI). The product was tested successfully against ischemia models in mice, and in so-doing the importance of the correct stereochemistry was emphasized. An editorial in the same issue of the journal provides a further perspective on the topic.

Resolvin D4

Every Saturday morning, I scan rapidly through the titles of around 500 publications dealing with lipid science to pick out a relative few that are useful to me for my web endeavours, and which are subsequently listed in my Literature survey pages. Inevitably, I miss many that are not picked out by the algorithm I use, or whose significance I do not recognize at first glance. One that I greatly regret missing when it first appeared deals with how lipids are distributed in membranes (Murate, M. and Kobayashi, T. Revisiting transbilayer distribution of lipids in the plasma membrane. Chem. Phys. Lipids, 194, 58-71 (2016);  DOI). I am now using it to update my web pages. When I was a young scientist, the work of van Deenen and colleagues in the Netherlands in which specific lipases were used to determine the sidedness of membranes attracted great interest. However, by today's standards, these methods seem relatively crude and new procedures involving immunoelectron microscopy are providing much greater selectivity and precision. Perhaps surprisingly, the one lipid for which we still lack reliable data is cholesterol, and it seems that new cholesterol-specific probes are required before it will be possible to reliably determine its transbilayer distribution.

August 1st, 2018

I have belatedly come across two fascinating and important papers on the subject of 12,13-dihydroxy-9Z-octadecenoic acid or 12,13-diHOME. This is a further example of a fatty acid with important biological functions that is not an eicosanoid or a docosanoid but an octadecanoid, derived in this instance from linoleic acid via the action of a CYP epoxygenase followed by an epoxide hydrolase. Last year, this was reported to promote fatty acid transport into brown adipose tissue during cold exposure, while the more recent publication suggests that it is a "novel exercise-stimulated circulating factor that may contribute to the metabolic changes that occur with physical exercise" both in humans and laboratory animals (Stanford, K.I. et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metabolism, 27, 1111-1120.e3 (2018);  DOI). While these effects seem beneficial, there are earlier reports of adverse properties, for example that such oxidized linoleate metabolites may be atherogenic through the induction of pro-inflammatory cytokines and by formation of foam cells from macrophages by PPAR activation. Life is complicated!

Excuse a moment of pedantry, but I have often complained about the excessive use of abbreviations in publications, and the reason I missed these articles in my weekly searches was because of the use of the abbreviated name of the lipid in the title; this was not recognized by the search algorithm I use. The authors did use the word "lipokine" in the title and I could add this to my search algorithm, but a quick search in the Web of Science suggests that this term has only been used 14 times in the last five years and then mainly for palmitoleic acid for which it was originally coined. Should it be used more?

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Author: William W. Christie Updated: December 12th, 2018 Credits/disclaimer LipidWeb logo

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