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 these web pages, 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).


November 23rd, 2022

W.W.C. blog: The interactions of aspirin with the prostaglandin synthases COX1/2 are now sufficiently well Scottish thistleunderstood that they are standard textbook material (or see here..). The seminal paper on the topic was published by Sir John Vane and describes the experiments supporting his hypothesis that inhibition of prostaglandin synthesis might explain the main pharmacological effects of aspirin and related drugs. He received a knighthood and a share of the Nobel Prize in Physiology or Medicine (1982) for his work. We have reached the 50th anniversary of this important paper, and a new review of the topic has now been published (Patrono, C. Fifty years with aspirin and platelets. Brit. J. Pharm., in press (2022);  DOI). It has taken many years and required the work of innumerable researchers to reach the present state of knowledge, and I enjoyed reading this personal account.

The antioxidant properties of tocopherol (vitamin E) will be well known to most researchers, but the many other non-antioxidant functions that have been reported have been somewhat more controversial, mainly because no receptors or reactions with specific enzymes were known. However, it has now been shown that α-tocopherol interacts with diacylglycerol kinase alpha to ameliorate diabetic nephropathy by binding to membrane-bound 67 kDa laminin receptor (67LR) to mediate activation of DGKα (Hayashi, D. et al. Vitamin E functions by association with a novel binding site on the 67 kDa laminin receptor activating diacylglycerol kinase. J. Nutr. Biochem., 110, 109129 (2022);  DOI).

November 16th, 2022

Guest blog: Bill Christie’s Lipid Matters blog has been very informative and widely appreciated. I’m not sure how he keeps on top across such a wide range of topics, but I’m very impressed both with his insights and with his clarity of expression. Consequently, it’s with a degree of nervousness that I’ve agreed with his request to be an occasional guest editor on his blog.

I’ve long been fascinated by the balance between phenotypic expression and cellular nutrition in the regulation of cell membrane lipid compositions. The ability of different cell types in vivo to maintain distinct membrane compositions in vivo is widely recognized, even within an individual tissue, and this is in spite of a common lipid nutrition. By contrast, virtually all cells in culture, whether primary, cancer or stem cells, have membrane glycerophospholipid compositions dominated by monounsaturated fatty acids, extensively summarized in a recent review (DOI = 10.1016/j.plipres.2019.101017). Polyunsaturated fatty acid availability is typically very limited in cell culture supplements, and as these fatty acids cannot be synthesised de novo by vertebrate cells, cultured cells are in effect at least marginally essential fatty acid deficient.

While essential fatty acid deficiency has been reported in the literature for at least fifty years (for example, www.ncbi.nlm.nih.gov/pubmed/5545273), it is almost universally ignored in the vast number of functional studies of cells in culture. The assumption of these studies, usually implicit, is that as long as morphology and phenotypic protein expression are appropriate for the cell in question, the membrane lipid composition is not important. As polyunsaturated fatty acids are critical for many cellular functions in vivo, this assumption may have significant and wide implications for the interpretation of these studies. In addition, clonal selection in response to reduced lipid nutrition may result in an unrepresentative cell population with longer-term consequences for cell function, for instance for stem cell cultures. I have a concern, which I share with Bill, is that studies relying on automated identification of molecular species derived from detailed mass spectrometry analysis have a tendency to ignore the bulk of historical studies that report fatty acid compositions, but more of that at a later date.

Anthony D. Postle
Faculty of Medicine, University of Southampton, Southampton, U.K.
Email: adp@soton.ac.uk

November 9th, 2022

Continuing my theme of methodology from last week, I am distrustful of papers involving modern mass spectrometry methods in which all the work of lipid identification and quantification seems to be done by computer algorithms. I accept that this is in large part my own fault in that I lack practical experience of the techniques and have not taken the time to study them properly. I prefer to see publications with illustrations of chromatographic separations, where I can evaluate the resolution and have some indication of the signal to noise ratio. Ideally, I like to see sample mass spectra of any novel fatty acids/lipids. One new example that is as close to my ideal as seems possible in terms of the validation protocols and general approach is one describing the analysis of octadecanoid oxylipins (Quaranta, A. et al. Development of a chiral supercritical fluid chromatography-tandem mass spectrometry and reversed-phase liquid chromatography-tandem mass spectrometry platform for the quantitative metabolic profiling of octadecanoid oxylipins. Anal. Chem., 94, 14618-14626 (2022);  DOI), which in contrast to too many ACS publications is open access. In terms of their study, octadecanoids are poor relations of the eicosanoids, but it is a truism that improvements in analytical methodology lead to advances in biochemical knowledge.

More than 100 different components are identified in human plasma in this publication (see the supplementary tables), many of which appear to be new to science. Most of these are derived from linoleate, as might be expected, but a handful appear to be produced from α-linolenate. To my knowledge, this is the first time these have been found in tissues in vivo - please correct me if I am wrong. Linoleate is an essential fatty acid in its own right in animals, partly as a precursor to octadecanoids and partly because of its vital function in skin ceramides. On the other hand, I have had the impression that α‑linolenate is essential only as a precursor to longer-chain omega‑3 polyunsaturated fatty acids. There is work to be done, but it now seems that this assumption may have to be re-evaluated.

November 2nd, 2022

Scottish thistleFrom time to time, I show my age by suggesting that it may be a mistake to abandon some older methodologies, some of which are close to my career and heart (I confess to bias). For example, as I have discussed before, methods for determining the compositions of positions sn-1, 2 and 3 of triacylglycerols seem to be forgotten or ignored (see my web page here..). This seems to me because of an excessive reliance on modern mass spectrometry methods, not because this information is less important biologically.

I also have the feeling that the same is true for methods for determination of the structures of fatty acids. Excessive time seems to be given to adapting instruments costing up to 7 figures to determine fatty acid compositions, when the task can often be accomplished by relatively simple GC-MS systems (electron impact ionization) at a tenth of the cost with much better results. I am not being critical of the fine work being done with the Paternò–Büchi reaction to locate double bonds, for example, but there are times when I simply feel it is overkill.

It is surprising how much information can be gleaned from GC-MS of methyl ester derivatives, especially when this is combined with GC retention data. Double bond positions in polyunsaturated fatty acids, methyl branched points and the positions of cyclic structures and other functional groups can be determined, especially when authentic spectra are available for comparison (more than 500 of methyl esters with 1700 others on this website). Better still, if the fatty acids are converted to certain nitrogen-containing derivatives, pyrrolidides, dimethyloxazolines or 3-pyridylcarbonyl esters, it is relatively easy to obtain definitive structural information (again check this website). In studies of fatty acids from sponges, my colleagues/collaborators and I were often able to identify over 100 different fatty acids in a single sample, many of which were new to science. These thoughts were inspired by a publication describing improved methods for preparing such fatty acid derivatives from methyl esters under much milder conditions than hitherto (Santalova, E.A. and Svetashev, V.I. Preparation of 4,4-dimethyloxazoline and pyrrolidine derivatives from fatty acid methyl esters using sodium borohydride: mild and simple one-pot derivatization procedures for a gas chromatographic-mass spectrometric analysis of fatty acids. Nat. Prod. Res., 17, 1934578X221131408 (2022);  DOI - open access). I would love to try this myself, but those days are gone.

October 19th, 2022

I take a personal interest in any publications that deal with lipids and cognitive decline in the elderly, and it was disappointing that all the practical trials seemed to suggest that omega-3 supplements have no effect. However, that might not remain the case if improved methods of administration can be developed. The opening sentence of a new publication is not a source of cheer - “To date, ~400 trials of experimental Alzheimer’s treatments have failed” (Baloni, P. and many others. Multi-omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer’s disease. Commun. Biol., 5, 1074 (2022);  DOI). However, the rest of the paper offers hope, and suggests “modulators of sphingosine-1-phosphate metabolism as possible candidates for Alzheimer’s disease treatment”. It reports that fingolimod, a drug that has a proven reputation in other fields, “alleviated synaptic plasticity and cognitive impairment in mice”. As there are other fingolimod analogues waiting in the wings, there may be grounds for hope.

Covid is still giving cause for concern, and I did a quick search in the Web of Science this weekend for “lipids and covid” and obtained a list of 1,526 references. Somewhere in this number, there may be something that offers help, but how can anyone begin to search for it (never mind the thousands of papers that do not mention lipids in relation to the disease). I continue to take every sensible precaution (masks, hand sanitizer, mouth wash), and I had my booster of the latest Moderna vaccine (my fifth in total) three weeks ago. Nevertheless, last week, I was flattened by the disease. Believe me, it was not like getting a mild cold as some seem to suggest, but I will survive and so will this blog.

September 28th, 2022

Scottish thistleMany pathogenic species of bacteria, fungi and viruses have evolved to make use of glycosphingolipids in membranes of animal species as receptors to their own advantage through enabling cellular entry and thence toxicity, while conversely animals have had to change the composition of the carbohydrate moieties of their glycolipids through evolutionary mechanisms to avoid the worst effects of infections. For example, lactosylceramide functions as a receptor for many fungal pathogens, including Candida and Cryptococcus sp., and the HIV virus binds to the gangliosides Gb3, GM3 and GD3. Perhaps, the best-known example of a bacterial interaction is that the cholera toxin (Vibrio cholerae) binds specifically to the ganglioside GM1. However, the carbohydrate moiety of a glycolipid can also act as a decoy receptor that binds to the pathogen but prevents it from entering the cell. As an example, the A and B blood group antigens function in this manner by binding to the cholera toxin. A new review surprised me with a fascinating account of how many such glycolipid-pathogen interactions are known (Bereznicka, A. et al. Microbial lectome versus host glycolipidome: How pathogens exploit glycosphingolipids to invade, dupe or kill. Front. Microbiol., 13, 958653 (2012);  DOI).

On a separate topic, I can recommend an accessible review of fatty acid desaturases (Cerone, M. and Smith, T.K. Desaturases: Structural and mechanistic insights into the biosynthesis of unsaturated fatty acids. IUBMB Life, in press (2022);  DOI).

September 14th, 2022

The titles of some papers make you look twice, especially when they appear to offer a candidate for the Guinness book of records (Kusch, S. and Rush, D. Revisiting the precursors of the most abundant natural products on Earth: A look back at 30+ years of bacteriohopanepolyol (BHP) research and ahead to new frontiers. Org. Geochem., 172, 104469 (2022);  DOI). Hopanoids are regarded as sterol surrogates produced by many bacterial species by mechanisms that have parallels with sterol synthesis by eukaryotes but with significant differences. For example, squalene is a precursor but is synthesised by a different route via a hydroxy-intermediate. Then, squalene per se is cyclized (not the epoxide) by a mechanism that is independent of oxygen. The title of the paper refers to the fact that the molecular skeleton of hopanoids is remarkable stable over geological time in rocks and sediments; they have in fact been found in shale deposits in Australia that are 2.7 billion years old.

A surprising new finding is the discovery of a sphingosine-1-phosphate analogue in bacteria (Ranjit, D.K. et al. Characterization of a bacterial kinase that phosphorylates dihydrosphingosine to form dhS1P. Microbiol. Spectrum, 10, 2 (2022);  DOI). The oral anaerobic bacterium Porphyromonas gingivalis, which synthesises a variety of sphingolipids, utilises DhSphK1, a protein that shows high similarity to a eukaryotic sphingosine kinase, to synthesise dihydrosphingosine-1-phosphate, which may have signalling functions in its human host - probably not to our benefit.

Glucosylsphingosine is the LipidMaps 'Lipid of the Month' for September and is interesting for many reasons, not least because it is a major cause of itching. Now, I would like an explanation for how it seems to concentrate in my skin in a small area under my left shoulder blade, the only part that I cannot reach to scratch.

August 24th, 2022

Scottish thistleBack in the days when I was doing real science, I was involved in an EU project headed by Jean-Louis Sébédio of INRA to assess the rate of synthesis of docosahexaenoic acid (DHA) from α-linolenic acid in humans, and like many others, we found that the degree of conversion was remarkedly low. It appeared that humans required pre-formed EPA and DHA in the diet. An interesting article by Burdge suggests that all such studies may have underestimated our capacity to synthesise the long-chain fatty acids, and that evolution must have determined that we produce adequate levels for all essential purposes. For example, there are no reports of problems of health or cognitive development in vegans who do not consume EPA and DHA. However, it is still possible that supplementation of the diet with these fatty acids may confer health benefits (Burdge, G.C. α-linolenic acid interconversion is sufficient as a source of longer chain ω-3 polyunsaturated fatty acids in humans: An opinion. Lipids, in press (2022);  DOI).

One of the scourges in modern medicine is septic shock and lack of an appropriate treatment; there are almost 50,000 deaths in the U.K. every year from this cause. Now, a new report suggests that an eicosanoid, 20-hydroxyeicosatetraenoic acid (20-HETE), can inhibit lipopolysaccharide-induced vascular hyporeactivity, hypotension, and tachycardia in rats by activating the recently discovered GPR75/20-HETE receptor. It is suggested that there is a compelling case for initiating clinical trials of 20-HETE or its mimetics to prevent hypotension, multiple organ failure, and death in septic shock (Tuncan, B. et al. Activation of GPR75 signaling pathway contributes to the effect of a 20-HETE mimetic, 5,14-HEDGE, to prevent hypotensive and tachycardic responses to lipopolysaccharide in a rat model of septic shock.). J. Cardiovasc. Pharm., 80, 276-293 (2022);  DOI). There is an open access commentary in the same journal issue for those who lack access to this journal (like me).

I hope the authors will forgive me if I don’t list them all here, but I must commend an attempt to standardize the reporting requirements for publication in lipidomics (McDonald, J.G. and many others. Introducing the lipidomics minimal reporting checklist. Nature Metab., in press (2022);  DOI). The brief abstract is fully explanatory – “the rapid increase in lipidomic data has triggered a community-based movement to develop guidelines and minimum requirements for generating, reporting and publishing lipidomic data. The creation of a dynamic checklist summarizing key details of lipidomic analyses using a common language has the potential to harmonize the field by improving both traceability and reproducibility.”

August 10th, 2022

One of the great challenges in organic chemistry is to be able to insert an oxygen atom onto an unactivated carbon atom. Fungi seem to do it rather easily and can use unspecific peroxygenases to place hydroxyl groups in the alkyl chains of fatty acids with both positional and stereochemical specificity. The enzymes have no cofactor requirements and simply need a source of H2O2; each enzyme molecule can accomplish the reaction over 100,000 times before it declines in activity. The main challenge for biotechnological applications is to be able to express the enzymes, which are produced by complex post-translational mechanisms, in sufficient quantity in more amenable host organisms. A new review discusses how this may be accomplished (Beltran-Nogal, A. et al. Surfing the wave of oxyfunctionalization chemistry by engineering fungal unspecific peroxygenases. Curr. Opinion Structural Biol., 73, 102342 (2022);  DOI).

As an example, a new report shows that fungal peroxygenases can be used to convert arachidonic acid into specific oxylipins, including hydroxy-eicosatetraenes (HETE) and epoxy-eicosatrienes (ETE). It is hoped that this can lead to a more accessible source of these for use as standards and ideally for therapeutic and pharmacological purposes (König, R. et al. Novel unspecific peroxygenase from Truncatella angustata catalyzes the synthesis of bioactive lipid mediators. Microorganisms, 10, 1267 (2022);  DOI).

I regret to inform regular readers of this blog that I will no longer be able to produce it with the same regularity in future. It seems that I am getting older and must pace myself better. Hopefully, LipidMaps will find a guest blogger. For the same reason, I will have to reduce the time I can spend on the monthly literature surveys, though I will continue if even more selectively in what I can cite. This will ensure that I can maintain my regular updates of the Lipid Essentials and Mass spectrometry pages as before. Don't worry, I plan to be around for a while yet.

July 20th, 2022

Scottish thistleWe are accustomed to studies of lipids in tissues at a smaller and smaller scale, nowadays down to the single cell level, but it is surprising how much information can be gathered from lipidomics at the largest scale, and you can’t get much larger than the global ocean (Holm, H.C. et al. Global ocean lipidomes show a universal relationship between temperature and lipid unsaturation. Science, 376, 1487-1491 (2022);  DOI). The authors find that “fatty acid unsaturation is fundamentally constrained by temperature”. A disturbinging prediction from the data is that there will be substantial declines in eicosapentaenoic acid (EPA) in the marine environment over the next century with serious effects upon fisheries.

A further study relating ocean temperatures to lipid composition has quite different objectives but is also concerned with climate change (Rampen, S.W. et al. The Long chain Diol Index: A marine palaeotemperature proxy based on eustigmatophyte lipids that records the warmest seasons. Proc. Natl. Acad. Sci. USA, 119, e2116812119 (2022);  DOI). The authors find that long-chain 1,13- and 1,15-diols (C28 to C32) in the oceans are good predictors of the surface temperatures of the oceans during summer, so the content in sediment may enable estimates of climatic conditions over geological time scales. I had not encountered these lipids before, but it seems that even the most improbable lipids may have scientific value.

July 13th, 2022

Some lipids and lipid metabolites are analysed routinely in clinical laboratories as aids to the diagnosis of disease, and cholesterol and lipoproteins come to mind immediately. I am not sure how widely it is available, but I have seen many reports of the use of rapid screening of acyl carnitines in plasma and dried blood spots as an aid to diagnosis of metabolic diseases and especially for genetic defects in new-born infants, and I can recommend a substantial new review that covers all the important aspects of carnitine and acylcarnitine metabolism (Dambrova, M. and 14 others. Acylcarnitines: nomenclature, biomarkers, therapeutic potential, drug targets, and clinical trials. Pharm. Rev., 74, 506-551 (2022);  DOI). In addition to this, I see new reports every week during my literature reviews of advances in methodology of the use of lipid analyses in clinical diagnostics. For example, this week alone, I noted a paper on the analysis of lysophosphatidic acid, which is well known as a diagnostic marker for ovarian cancer, one on lipoproteins in Covid19 infections, another on lipopolysaccharides and atherosclerosis, and one on aldehydes in exhaled breath for lung cancer detection (these will be listed in my next monthly survey). I would love to believe that some of these would soon make the leap from the research environment to routine clinical practice, but this may be wishful thinking. First, there needs to be some standardization of each method (but by whom?), and then I suspect that only large regional clinical laboratories could provide the required equipment not to mention the skilled analysts (hopefully a few more lipid scientists gainfully employed).

If you would like something to read during your next lunch break that is lipid related but not too taxing, I recommend - Dennis, E.A. Outtakes from my journey through the world of LIPID MAPS. Molecules, 27, 3885 (2022);  DOI.

July 6th, 2022

One topic that has always puzzled me is how the activity of some prostaglandins can change, for example from pro- to anti-inflammatory, apparently depending on the tissue. It seems that I have simply not been sufficiently up to date on the properties of the prostaglandin receptors, and a new review has put me right with a clear explanation (Fujino, H. The biased activities of prostanoids and their receptors: review and beyond. Biol. Pharm. Bull., 45, 684-690 (2022);  DOI – open access). It is apparent that the different receptors characterized from diverse cell types tend to have high, but not absolute, specificity for each prostanoid with characteristic functions in each cell. The concept of a receptor-ligand as a lock and key is no longer tenable, and interactions of receptors with other G-proteins alter their mode of action. For example, the EP4 receptor can couple with the Gαs-protein to activate adenylyl cyclase to form cAMP when stimulated by PGE2, or it can couple with the Gαi-protein to activate kinases that include phosphatidylinositol 3-kinase. This can mean the difference between pro- and anti-inflammatory or pro- and anti-cancer effects.

It is a while since I have written a diatribe against the publishing industry, and this is because I am grateful for the greater availability of open access publications. Elsevier/Wiley/Springer are more generous than formerly, and the growth of open access publishers has been helpful; they are attracting reputable scientists, especially for review articles, so quality is less of an issue. One trend that is emerging and that I like is to do away with volume numbers and just list the year of publication. But! The chemistry literature is still much less open than that for the biological sciences. With some journals, there is too long a time between early access and formal publication, often over a year. Some publishers give downloaded pdf files names that are meaningless to the downloader, and it is a nuisance that some journals capitalize titles of papers while others do not.

June 29th, 2022

Scottish thistleThe literature on Covid in relation to lipids is very substantial, and a quick search on the Web of Science listed 378 for this year so far. Only the true specialist in this area can hope to keep up to date, so where should the rest of us start. I suggest a current multi-author publication (Saud, Z. and 25 others. The SARS-CoV2 envelope differs from host cells, exposes procoagulant lipids, and is disrupted in vivo by oral rinses. J. Lipid Res., 63, 100208 (2022);  DOI). An important finding of the lipidomics study is that the lipid component of the virus envelope is appreciably different from that of the host with mainly phospholipids and little cholesterol or sphingolipids (the cholesterol:phospholipid ratio is like that of lysosomes). In addition and of special importance, it is shown that in contrast to most membranes phosphatidylethanolamine and phosphatidylserine are exposed on the surface of the virus envelope at concentrations greater than in activated platelets where they have a pro-coagulant function; there are also appreciable amounts of lysophospholipids, which have inflammatory properties. This composition would be expected to adversely influence the pathogenicity of many inflammatory disease states, especially thrombosis, and this new knowledge does at least open up possibilities for the design of new antiviral treatments. Incidentally, I now know which dental rinse I will be using in future.

I have mixed feelings when there are so many authors to a publication, as it is difficult to truly apportion credit, and there are many notable names in the list; my antique reference software cannot handle so many. On the other hand, it is very helpful to a general reader that so much data and the conclusions therefrom are in one place. At least, it is an improvement on some CERN and NASA papers, where the number of authors can top a hundred.

June 22nd, 2022

Does everyone believe that palmitic acid, as a saturated fatty acid, in the diet is always bad for you? The soybean industry in the USA has been lobbying against palm oil for years, and nutritionists appear to have taken it on board. In the UK, some supermarket chains boast that they have eliminated it from their food products. On the other hand, palmitic acid is essential for sphingolipid biosynthesis, and it is required for certain protein modifications (proteolipids). Palmitoylethanolamine in brain has important functions (as I outlined in a recent blog). I could go on. A new review discusses the importance of palmitic acid in nutrition (Murru, E. et al. Impact of dietary palmitic acid on lipid metabolism. Front. Nutr., 9, 861664 (2022);  DOI). In particular, the authors point out that it is vital for the developing brain in humans, hence so much is synthesised there de novo. They contend (I am paraphrasing) that under normal physiological conditions, there is tight homeostatic control of palmitic acid concentrations, and that excess synthesis occurs only under pathophysiological conditions such as insulin resistance. The greater the intake of palmitic acid, the less room for polyunsaturates to suppress lipogenic gene expression. I am sure there is more to the story than this, but it is certainly food for thought.

Incidentally, I am not arguing that the vast expansion of palm plantations in Asia is good for the planet, although palm oil is an important source of calories in poorer parts of the world.

June 15th, 2022

Two weeks ago in my blog, I discussed how minor changes in the fatty acid attached to lipids could profoundly outer their biological properties, and I selected the relatively simple molecules, acylethanolamides, as examples of this phenomenon. However, this can also be observed with highly complex molecules such as the lipid A component of lipopolysaccharides produced by Gram negative bacteria and located on their exterior surface as part of their defences against stress factors. However, lipid A is an endotoxin and an important modulator of innate immune responses in animal hosts of the organisms. For example, it has long been known that the pathogenicity of Yersinia pestis, the causative agent of bubonic plague, depends on the number of fatty acids attached to the molecule.

However, relatively minor changes can have a dramatic outcome. After an outbreak of Enterobacter cloacae infections in critically ill infants, a mass spectrometric study of the lipid A molecules demonstrated that they were very heterogeneous, comprising fifteen different molecular species. The virulence and fatalities were found to be linked to the presence of one fatty acid, 2-hydroxymyristic acid, as a secondary substituent in lipid A (Augusto L.A. et al. Presence of 2-hydroxymyristate on endotoxins is associated with death in neonates with Enterobacter cloacae complex septic shock. iScience, 24, 102916 (2021);  DOI). It will not be any consolation to the parents, but hopefully this fatty acid marker will serve as a detection tool in future for high-risk patients and help to reduce their mortality.

I have new candidates for novel lipid structures of the year to date - ceramide phosphoglycerate and diphosphoglycerate from genetically modified, Gram-negative bacteria, deficient in lipid A (Zik, J.J. et al. Caulobacter lipid A is conditionally dispensable in the absence of fur and in the presence of anionic sphingolipids. Cell Rep., 39, 110888 (2022);  DOI).

ceramide phosphoglycerate

June 8th, 2022

Some yeast species and especially the non-pathogenic Starmerella bombicola secrete extracellular glycolipids known as sophorolipids, as they contain the sugar sophorose (β-D-Glc-(1→2)-D-Glc), linked glycosidically to the hydroxyl group of a long-chain hydroxy fatty acid. One to three sugar units may be linked, they can be acetylated, and they can exist as acidic or neutral (lactone) forms. As highly active, green surfactants, they have appreciable biotechnological potential because of their low toxicity and biodegradability. However, costs of production are as yet too high for most purposes in comparison to synthetic chemical and other biobased alternatives. Genetic engineering tools are slowly improving this picture (Qazi, M.A. et al. Sophorolipids bioproduction in the yeast Starmerella bombicola: Current trends and perspectives. Biores. Techn., 346, 126593 (2022);  DOI).

Cost is much less a factor when pharmaceutical applications are considered, and sophorolipids are known to possess anti-cancer activity against a wide range of cancer cell lines such as those derived from breast, cervical, colon, liver, brain, and the pancreas. They function by inhibiting proliferation, inducing apoptosis, and by disrupting membranes. Here also, genetic engineering tools are proving invaluable to determine which molecular structures are most effective against cancer cells, and to design new molecules with greater efficacy for specific pharmaceutical interventions (Miceli, T.R. et al. Sophorolipids: Anti-cancer activities and mechanisms. Bioorg. Med. Chem., 65, 116787 (2022);  DOI).

June 1st, 2022

The fatty N-acylethanolamides are an interesting lipid class that illustrates well how differences in fatty acyl components can result in very different biological effects. It is certainly an active area of research, as references to at least four different members of this lipid class are cited in my latest literature survey. The best known of these is anandamide or N-arachidonoylethanolamine, which is an endocannabinoid in that it interacts with the same signalling receptors as the phytocannabinoids and has similar biological effects. Docosahexaenoylethanolamine or 'synaptamide' is present in brain tissue in amounts comparable to anandamide and binds to one of the same receptors, if less strongly, so it is also generally listed with the endocannabinoids.

Other N-acylethanolamines may not bind to the cannabinoid receptors but can bind to other G-protein coupled receptors to exert biological effects, so the line between them and endocannabinoids has become increasingly blurred. Palmitoylethanolamine, for example, has been known for its biological activity for more than 50 years and has anti-inflammatory, analgesic, and neuroprotective actions; it functions through at least three known receptors but not via those of the the cannabinoids. Oleoylethanolamine is an endogenous regulator of food intake, and it may have some potential as an anti-obesity drug. However, the isomer cis-vaccenoylethanolamine is relatively abundant in plasma, but as far as I am aware, its biological function has not been determined, and there may be confusion with the oleoyl isomer. Linoleoylethanolamine is also relatively abundant in plasma, but I have only seen one publication regarding its biological activity, which seems similar to that of oleoylethanolamine. Stearoylethanolamine is an immunomodulator and induces apoptosis of glioma cells.

In an ideal world, I would like to drop the word ‘endocannabinoid’ and call them all biologically active amides, but then where would we classify 2‑arachidonoylglycerol? Oleamide adds to the classification confusion as it interacts with the cannabinoid receptors, and of course there are many other simple amides other than the ethanolamides. I had better not start on those in plants.

The correct nomenclature for these compounds (amide/amine) has me confused. After discussion with Matt Conroy, I think it is palmitoylethanolamine or palmitylethanolamide, for example. As a class, they are N-acylethanolamides. Comments?

May 25th, 2022

Scottish thistleLipidomics methodology acquires data in the form of molecular species of each lipid class, but I suspect that relatively little thought has been given as to whether there are specific biological functions for individual species (realistically, this would not in general be possible). One exception is with phosphatidylserine (PS), where there are two main molecular forms, i.e., 1-stearoyl-2-oleoyl and 1-stearoyl-2-docosahexaenoyl, each with important roles in tissues. For example, in neurons, membrane domains containing PS enriched in DHA facilitate the translocation and activation of several kinases and activate signalling pathways that promote neuronal development and survival (Kim, H.Y. et al. Molecular and signaling mechanisms for docosahexaenoic acid-derived neurodevelopment and neuroprotection. Int. J. Mol. Sci., 23, 4635 (2022); DOI).

Molecular species in general and of PS especially are the subject of a recent review (Skotland, T. and Sandvig, K. Need for more focus on lipid species in studies of biological and model membranes. Prog. Lipid Res., 86, 101160 (2022); DOI). It is well known that externalization of this lipid in the plasma membrane is important for blood coagulation and for apoptosis, but I was surprised to learn that there is apparently no information on which molecular species are involved. Incidentally, the function of PS in blood coagulation is shared with oxidized phospholipids with important medical implications, as discussed in another review (Protty, M.B.B. et al. The role of procoagulant phospholipids on the surface of circulating blood cells in thrombosis and haemostasis. Open Biol., 12, 2103181 (2022); DOI).

One of the more interesting classes of lipids to have emerged in recent years is the fatty acid esters of hydroxy FAs (FAHFAs), which are lipokines with many physiological functions, including effects upon insulin sensitivity and glucose homeostasis. However, it now appears that many reports of their occurrence in plasma may be erroneous, because of artefactual formation of fatty acid dimers during mass spectrometry that have similar spectra to FAHFA (Nelson, A.B. et al. Artifactual FA dimers mimic FAHFA signals in untargeted metabolomics pipelines. J. Lipid Res., 63, 100201 (2022); DOI). Too many isomers at too high concentrations have been reported. Presumably, authors will undertake some reassessment of their published data, or am I too optimistic?

May 18th, 2022

Many of us have used deuteration reactions as a means of studying fragmentation mechanisms in mass spectrometry, and I have a protocol for deuterating double bonds for this purpose on this website here. However, several publications have appeared in recent years that describe selective deuterations and do not involve double bonds but rather the divinyl carbons of polyunsaturated fatty acids, often using D2O as the source of deuterium and a Ruthenium catalyst. I have just been catching up on this type of methodology via a new publication that describes a method for selective deuteration of carbons 2 and 3 in fatty acids (without affecting double bonds). The reaction is used in a study of how linoleic is oxidized to hydroxyoctadecadienoic acid (HODE) and then incorporated into specific positions of phosphatidylcholine via the action of acyltransferases and lysophosphatidylcholine (Watanabe, A. et al. Controlled tetradeuteration of straight-chain fatty acids: synthesis, application, and insight into the metabolism of oxidized linoleic acid. Angew. Chem.-Int. Ed., e202202779 in press (2022); DOI).

Selective deuteration at bis-allylic positions can greatly reduce the rate of oxidation of arachidonic acid via the isotope effect when hydrogen abstraction is the initiating event. A new publication describes the use of arachidonic acid deuterated in this way to ameliorate the effects of lipopolysaccharides on lung damage in mice (Molchanova, A.Y. et al. Deuterated arachidonic acid ameliorates lipopolysaccharide-induced lung damage in mice. Antioxidants, 11, 681 (2022); DOI). The authors suggest that this kind of methodology has the potential to be a safe and effective way of alleviating the effects of inflammation in other diseases.

Over the last two years, I have applied more alcohol externally than internally, but a new study of a lipid metabolite in plasma confirms that I am unlikely to become tipsy as a result (Reisfield, G.M. et al. Blood phosphatidylethanol (PEth) concentrations following intensive use of an alcohol-based hand sanitizer. J. Anal. Toxicol., in press (2022); DOI).

May 11th, 2022

In my last blog, I highlighted a publication that described a very specific function for oleic acid, a fatty acid that was long considered to be simply a makeweight in tissues. Now, hot on its heels, another very specific role for this fatty acid in its unesterified form has been described, i.e., it can block an ion channel in membranes with the potential for a beneficial impact on the cardiovascular system (Leon-Aparicio, D. et al. Oleic acid blocks the calcium-activated chloride channel TMEM16A/ANO1. Biochim. Biophys. Acta, Lipids, 1867, 159134 (2022); DOI). I suppose that one question that should be asked is what then controls the availability of oleic acid to these sites? As this is a major component of all lipids in membranes, its release for such specific functions must be tightly regulated.

Formulae of ladderane fatty acidsWikipedia is often criticized for its inaccuracies and simplistic or biased accounts of topics. I would not recommend its main page on 'lipids' to anyone, for example, although this does have links to better pages. That said, it is usually the first website that I turn to for information on countries or geography, or on authors or musicians, hoping that the references will lead me in useful directions, even if I don’t trust it entirely. However, it does have some superb illustrations that I have reproduced in this website under creative commons licences, including of a membrane bilayer, membrane rafts, and the cell wall of Gram-negative bacteria. Also, I recently looked up ‘ladderane’ in Wikipedia to see whether it had any useful background information on the organisms that produce ladderane fatty acids with concatenated cyclobutane rings of use to a non-microbiologist such as myself. I found a fascinating article that it did indeed add a little to what I knew of the natural fatty acids, although the main content was a fascinating account of the stereochemistry and chemical synthesis of cyclobutane rings. Incidentally, I learned that first synthesis of a ladderane fatty acid was from the laboratory of E.J. Corey in 2004 (Wikipedia have the wrong date), who was a recipient of the Nobel Prize in Chemistry in 1990 "for his development of the theory and methodology of organic synthesis".


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Updated: November 23rd, 2022 © Data compiled by Bill Christie LipidWeb icon
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