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. The older entries are archived for at least a year in a separate web page here..


October 11th, 2017

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

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

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

October 4th, 2017

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

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

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

September 27th, 2017

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

Inducer/inhibitors of rosette formation in Choanoflagellates

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

September 20th, 2017

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

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

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

September 13th, 2017

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

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

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

September 6th, 2017

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

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

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

August 30th, 2017

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

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

August 23rd, 2017

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

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

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

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

August 16th, 2017

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

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

August 9th, 2017

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

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

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

August 2nd, 2017

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

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

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

July 26th, 2017

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

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

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

July 19th, 2017

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

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

July 12th, 2017

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

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

Chevreul in laboratory

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

July 5th, 2017

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

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

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

June 28th, 2017

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

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

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

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

June 21st, 2017

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

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

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

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

June 14th, 2017

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

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

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

June 7th, 2017

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

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


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Author: William W. Christie Updated: October 11th, 2017 Credits/disclaimer LipidWeb logo

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