Lipid Matters - Archive of Older Blogs - 2022

This Blog is an occasional series of notes on publications or other items dealing with lipid science that seem to be of particular interest to the editor 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 7^th, 2022

Every month, I come across many review articles that cover various aspects of the function of phosphatidylinositol and the polyphosphoinositides, but especially of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) - I cannot hope to keep up with the primary literature on the subject. Indeed, my web page on this general topic is the one most often updated during the year. It is obvious that this lipid is a highly specific and crucial component of the plasma membrane and is essential to the function of innumerable components of this membrane. The general concept appears to be that PI(4,5)P₂ is a signalling molecule that regulates these functions. However, I have just been reading a new open-access review that presents a very different concept (Wills, R.C. and Hammond, G.R.V. PI(4,5)P₂: signaling the plasma membrane. Biochem. J., 479, 2311-2325 (2022); DOI). It suggests that we may have to rethink this designation and proposes rather that we should think of it as fulfilling a cofactor role. The authors present evidence that “PI(4,5)P2 serves as a necessary cofactor to activate cellular processes selectively at the PM. In other words, it is much more signpost than signal. Under this model, PI(4,5)P₂ is a ‘master regulator’ of all PM functions, i.e., it is a common factor required for each.”

November 30^th, 2022

A new publication poses an interesting question (Annevelink, C.E. et al. Esterified Scottish thistle oxylipins: do they matter? Metabolites, 12, 1007 (2022); DOI ) to which the answer seems to be a resounding yes. The authors point out that oxylipins are measured usually in plasma and other tissues in the free form, although the esterified pool can be much larger even in the circulation as in lipoproteins, establishing the need for a hydrolysis step in all laboratory analytical protocols. The authors suggest that release of oxylipins from esterified forms in tissues may occur more rapidly from phospholipase A2-mediated hydrolysis of oxylipins from membrane phospholipids than from PUFA-driven oxylipin synthesis. They conclude that “the explicit inclusion of esterified oxylipins along with the non-esterified pool has the potential to convey a more complete assessment of the metabolic consequences of oxylipin trafficking.”

November 23^rd, 2022

The interactions of aspirin with the prostaglandin synthases COX1/2 are now sufficiently well understood 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 16^th, 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 9^th, 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 2^nd, 2022

Scottish thistle From 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 19^th, 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 28^th, 2022

Scottish thistle Many 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 14^th, 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 24^th, 2022

Scottish thistle Back 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 10^th, 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 20^th, 2022

Scottish thistle We 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 13^th, 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 6^th, 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 29^th, 2022

Scottish thistle The 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 22^nd, 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 15^th, 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 8^th, 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 1^st, 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 25^th, 2022

Scottish thistle Lipidomics 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 18^th, 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 11^th, 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 acids Wikipedia 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".

April 27^th, 2022

Scottish thistle For much of my early career, we tended to look on oleic acid and its esters as relatively uninteresting molecules that were probably present in tissues simply to provide a balance to physical properties in membranes and to dilute out an excess of potentially toxic polyunsaturated fatty acids. However, when it was discovered that certain amide derivatives of oleate, such as oleamide and oleoylethanolamide, have highly specific biological functions in animal tissues, while 2-oleoylglycerol has a signalling function in the intestines, the view changed entirely. During the same period, it was recognized that although monoenoic fatty acids are abundant in the diet, stearoyl-CoA desaturase (SCD) controls the level of oleic acid production de novo in animals and is an important regulator of body adiposity and lipid partitioning. As one example, insulin-signalling components are upregulated in SCD1 deficiency with effects upon glycogen metabolism in insulin-sensitive tissues. Now, it has been shown that oleic acid per se is an endogenous ligand for the orphan nuclear receptor TLX/NR2E1, which governs neural stem and progenitor cell self-renewal and proliferation; it is essential for the survival of neural stem cells (Kandel, P. et al. Oleic acid is an endogenous ligand of TLX/NR2E1 that triggers hippocampal neurogenesis. Proc. Natl. Acad. Sci. USA, 119, e2023784119 (2022); DOI).

One fatty acid that puzzles me is α-linolenic. It is well established that linoleic acid has many essential functions in tissues as a direct precursor of oxylipins as well as of arachidonic acid. On the other hand, while α-linolenic acid is undoubtedly essential as a source of EPA and DHA in animal tissues, is it required for anything else? As far as I am aware, it does not seem to be a source of any lipid mediators.

April 20^th, 2022

I browse innumerable titles and abstracts of papers dealing with analysis of lipids every year, but I have time to read relatively few, and I have been retired from research for too long to fully appreciate the contents in any case. My lists in the Literature Survey section of this site that deal with analytical methodology are therefore highly subjective and perhaps somewhat arbitrary. However, when Xianlin Han (DOI) writes a commentary on a publication that includes the sentence “The study demonstrates the role of lipidomics in prediction of diseases and translational research, which could herald the beginning of an era of quantitative lipidomics”, I sit up and take notice (even though I only have access to the abstract).

However, the paper in question is open access (Lauber, C. et al. Lipidomic risk scores are independent of polygenic risk scores and can predict incidence of diabetes and cardiovascular disease in a large population cohort. PLoS Biol., 20, e3001561 (2022); DOI). The authors performed lipidomic analyses of more than 4000 plasma samples from a large population-based cohort, and they were able to integrate this with genetics and clinical diagnostics to assess the potential for the development of diabetes and heart disease. They could identify individuals at risk years in advance. As the data were obtained from only one single mass spectrometric measurement “that is cheap and fast”, the potential of the methodology is obviously enormous, and I trust that in addition to saving lives, it will keep lipid analysts gainfully employed for years to come!

April 13^th, 2022

The formation of tetraether lipids has been one of the most intriguing problems in lipid biochemistry. Although it was presumed for many years that it must involve carbon-carbon bond formation between the two methyl termini of isoprenoid chains, which the evidence suggests must be unsaturated, such a reaction is unprecedented in biochemistry, and alternative mechanisms have been suggested. For example, it has been proposed that head-to-head condensation of two C₂₀ isoprenyl molecules, each containing an isopropylidene double bond, could occur prior to attachment to the two glycerol units. However, it now appears that the 'improbable' early suggestion is correct, as a radical S-adenosylmethionine protein tetraether synthase has been isolated from Sulfolobus acidocaldarius from the Thaumarchaeota that when expressed in the methanogen Methanococcus maripaludis, which otherwise does not synthesise GDGTs but produces archaeol, leads to production of GDGT and structurally related lipids (Zeng, Z. et al. Identification of a protein responsible for the synthesis of archaeal membrane-spanning GDGT lipids. Nature Commun., 13, 1545 (2022); DOI).

Biosynthesis of glycerol dialkyl glycerol tetraethers

How this enzyme works has still to be established, but it is suggested that it may have two iron-sulfur clusters that could harbour two distinct active sites with separate catalytic functions. One of these might catalyse the desaturation of a fully saturated diether precursor or mediate double bond migration to generate a terminal olefin, while the second might then generate a carbon-carbon bond between sp² and sp³ carbon centres to trigger the head-to-head condensation of two diether lipids to form one tetraether lipid.

The other distinctive feature of Archaeal lipids is that the isoprenoid alkyl chains that are ether linked to sn‑glycerol-1-phosphate (G1P) and not to G3P. However, bacteria from the Fibrobacteres-Chlorobi-Bacteroidetes superphylum have been shown to have glycerolipids with either or both G1P and G3P stereochemistries. Now a new study involving chiral chromatography of diradyl moieties of phospholipids suggests that this capacity may be more widespread among bacteria (Řezanka, T. et al. Structural characterization of mono- and dimethylphosphatidylethanolamines from various organisms using a complex analytical strategy including chiral chromatography. Symmetry-Basel, 14, 616 (2022); DOI).

April 6^th, 2022

I take a special interest in those lipids that have potential health benefits for this blog, possibly because for much of my research career I was assailed by reports of the nasties such as cholesterol and saturated fatty acids, and it was hard to find good news. Of all the lipids, that I have read about in recent years, the single class which I would have imagined that we would need to really avoid is the lipopolysaccharide of the external leaflet of the outer membrane of Gram-negative bacteria. This is recognized by the host immune system and is a basic event for detection of pathogenic invaders, including Yersinia sp. (the 'Black Death' of the Middle Ages). The lipid A components of lipopolysaccharides are endotoxins that can cause severe illness, sometimes leading to septic shock and ultimately death. However, minor changes in the composition of lipid A, including the number and nature of the fatty acid components, can dramatically alter the outcome of infections. A new review suggests that by altering the chemistry of lipid A, we may be able to use them to antagonize the natural molecules to build up immunity so giving us a new therapeutic approach (Garcia-Vello, P. et al. Lipopolysaccharide lipid A: A promising molecule for new immunity-based therapies and antibiotics. Pharmacol. Therapeut., 230, 107970 (2022); DOI).

Lipid chemists are preparing to go to Mars. I exaggerate, but Mars may be coming to lipid chemists in the form of mineral samples brought back by ESA's ExoMars rover in the hope that hydrocarbons of biological origin will be present. If so, they will be analysed by chiral chromatography to determine whether they display chiral branching indicative of enzymic activity (Leseigneur, G. et al. Absolute configuration of aliphatic hydrocarbon enantiomers identified by gas chromatography: theorized application for isoprenoid alkanes and the search of molecular biosignatures on Mars. Symmetry-Basel, 14, 326 (2022); DOI). If they find phytane, does it mean there may really be little green men there?

March 30^th, 2022

Scottish thistle It is well established that aberrant ganglioside metabolism can be a factor in cancer and neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, and much pharmacological research is underway to find cures or at least alleviate the symptoms. Cancer has been the main target, and clinical trials with modified antibodies to GD2 have been carried out successfully against the rare childhood cancer neuroblastoma, and a phase I clinical trial with an antibody to GD3 has shown promising results in patients with malignant melanoma. However, there has been less success with diseases of the central nervous system, largely because it is near impossible to overcome the blood-brain barrier. The approach in this instance has been mainly stem cell transplantation and gene therapy, although other solutions are being attempted.

In the 1970s to early 1990s, an Italian company marketed drugs based on gangliosides from calf brain and then with purified ganglioside GM1 preparations to tackle peripheral neuropathies and subsequently for neurodegenerative diseases and cerebral and spinal injuries. In the 1990s, these were withdrawn from sale, and I have never understood why until a new review (Fazzari, M. et al. Gangliosides and the treatment of neurodegenerative diseases: a long Italian tradition. Biomedicines, 10, 363 (2022); DOI). The explanation is that claims emerged that anti-ganglioside antibodies occurred in the blood after administration of gangliosides and that these might be responsible for the onset of some cases of Guillain-Barré syndrome (GBS), an acute inflammatory disorder, which affects the peripheral nervous system and can result in paralysis. On the other hand, the authors of this review state that “the use of gangliosides for over twenty years has never produced autoimmune diseases, GBS, or other neuropathies.” If this is so, twenty years for potential research has been needlessly neglected.

March 23^rd, 2022

The term ‘lipidome’ first appeared in print in 2001, followed a year later by ‘lipidomics’. That this is now recognized as an important lipid discipline is a tribute to too many scientists for me to mention here other than the authors of a new review, who have been prominent for much of this time (Han, X.L. and Gross, R.W. The foundations and development of lipidomics. J. Lipid Res., 63, 100164 (2022); DOI). It may seem a little premature to write a history of the subject, but such has been the pace of developments in terms of instrumental improvements, chromatographic separations, and derivatization strategies that this may indeed be a time to look back and take stock. As a spectator rather than a participant, I am equally interested in what the future holds, and the authors have opinions on the subject that include even greater sensitivity to enable improved analyses of the lipids in single cells and integration with other ‘omics’.

This review dates the development of lipidomics from the late 1980s and the development of soft ionization techniques for mass spectrometry (although they do cite earlier papers), but I would argue that it really started in the early 1960s with the development of silver ion chromatography for separations of molecular species by degree of unsaturation, together with enzymatic methods for determining the distribution of fatty acids on the glycerol backbone of triacylglycerols and glycerophospholipids. Lipidomics has moved over time from labour intensive methodologies to those that are instrument intensive. These older separation techniques should not be forgotten, as they may still be required for the isolation of individual molecular species for study. Again, a new review may be a reminder of this (Momchilova, S. and Nikolova-Damyanova, B. Regio- and stereospecific analysis of triacylglycerols - a brief overview of the challenges and the achievements. Symmetry-Basel, 14, 247 (2022); DOI). Determination of the fatty acid compositions of each of positions sn-1, 2, and 3 in triacylglycerols, i.e., stereospecific analysis, is a subject close to my heart (hence my web page on the subject here..), and it is a task that cannot be accomplished by mass spectrometry.

Together these two reviews list 400 references, as is appropriate, but when I started this web site, I decided that there would never be more than 25 cited in any of my web documents, and then they would be mainly review articles not primary literature. This is obviously unfair to countless researchers, to whom I apologize sincerely, but it does make it easy to update my pages rapidly and replace older reference to a topic with newer.

March 16^th, 2022

In recent weeks, I have commented on octogenarians and nonagenarians, and now it is the turn of centenarians, who it appears may owe their longevity and reduced susceptibility to ageing-associated illnesses to their lipids and the gut microbiome. Bile acids secreted into the intestines to aid digestion are eventually deconjugated and absorbed in the process of enterohepatic circulation. However, a proportion can be further metabolized by microorganisms in the intestines in reactions that include hydroxylation, oxidation of hydroxyl groups in positions 3, 7 or 12 to oxo groups, and epimerization to generate secondary bile acids (more than 50 identified so far), which are absorbed into the colon via passive diffusion. Intriguingly, centenarians have a distinct gut microbiome that is enriched in microorganisms that can generate unique secondary bile acids, including various isoforms of lithocholic acid (LCA), i.e., iso-, 3-oxo-, allo-, 3-oxoallo- and isoallo-lithocholic acid (Sato, Y. and many others. Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians. Nature, 599, 458-464 (2021); DOI).

These have anti-microbial properties, and isoalloLCA especially is highly potent against Gram-positive microorganisms, including multidrug-resistant pathogens, and it may aid the human hosts to resist harmful infections and live longer and more healthily. This finding is obviously relevant to the vital search for new antibiotics and treatment for sepsis. Now, if I can arrange a suitable microbiome transplant, I may be able to continue this blog for another 20 years, although whether this will reduce the incidence of what my wife call my 'senior moments' is another matter.

My nomination for the most interesting new lipid of 2022 to date is lysyl-glucosyl-diacylglycerol, which is synthesised in high abundance by the bacterium Streptococcus agalactiae and is involved in the pathogenesis of neonatal meningitis. Unfortunately, this new lipid contributes to infection by enabling traversal of the endothelial blood-brain barrier (Joyce, L.R. et al. Identification of a novel cationic glycolipid in Streptococcus agalactiae that contributes to brain entry and meningitis. PLOS Biol., 20, e3001555 (2022); DOI).

Formula of lysyl-glucosyl-diacylglycerol

March 9^th, 2022

I have followed the story of the dioxygenation products of eicosanoids and docosanoids, i.e., resolvins, protectins, and maresins and collectively termed specialized pro-resolving lipid mediators (SPMs), from the first publication on the subject as exciting evidence for the importance of lipids in general and omega-3 fatty acids especially in controlling so many aspects of human health. Now, a new review by a multiauthor and multinational group appears to have pulled down a large part of the edifice (Schebb, N.H. and 18 others. Formation, signaling and occurrence of specialized pro-resolving lipid mediators - what is the evidence so far? Front. Pharmacol., 13, 838782 (2022); DOI). As individually and collectively, this group is much more competent to examine the published work on this topic in depth than I am, I must take their account seriously.

I can only summarize the arguments briefly here, but the authors challenge the analytical methodology when applied to leukocytes and other cells, suggesting that the concentrations in vivo are too low and the SPMs are too unstable to be assayed with any confidence, i.e., the measured values are comparable to noise levels, and they are indistinguishable from autoxidation products. In addition, the concentrations that are determined are too low to have the biological effects claimed. These levels do not increase with supplements of the omega-3 precursors. Aspects of the proposed biosynthetic mechanisms are cast into doubt, while the identity of the proposed G-protein-coupled SPM receptors and the signalling functions have not been supported by studies in knock-out mice. I suppose the most damning criticism is that they are not even formed during the resolution phase of inflammation, i.e., the term SPM is a misnomer.

What is not in dispute is probably as important as these criticisms. My impression is that the detailed analytical and synthetic work to locate and determine the chirality of the hydroxyl groups and to locate the double bonds and determine their configuration in products formed in vitro from EPA and DHA are not questioned, and this is unlikely to happen. Also, I see no reason to doubt the increasing body of work that demonstrates that ‘SPMs’ have beneficial effects when applied in sufficient concentration in various disease states. I sincerely hope that their therapeutic potential remains.

I must commend the authors of this review for their public spiritedness and courage in writing this review. It cannot have been easy to do. As I have a 6000-word document with 12 figures on SPMs in the LipidWeb, I must decide how and when to modify it in the light of this publication.

March 2^nd, 2022

I have seen many illustrations that show lipid droplets form in cells, and indeed I am rather envious of the graphics abilities of authors and wish that I could do something similar in my web pages. At a basic level, it is clear that biosynthesis of the triacylglycerol core lipid begins in the endoplasmic reticulum, and that this grows into a lens-shaped protuberance between two layers of phospholipid membrane and eventually reaches a size such that the droplet buds off, probably aided by an asymmetric accumulation of phospholipids that decrease surface tension towards the cytosol. It is also well known that a non-enzymatic protein seipin stabilizes the nascent droplets with minimal disruption to the membrane and enables them to mature, but until now, how this happens has been a matter for speculation.

A new study based on cryogenic-electron microscopy and structural modelling data shows that in S. cerevisiae, seipin monomers assemble into a decameric cage-like structure and sit in the ER to provide a space that permits triacylglycerol molecules to interact with each other, rather than with phospholipid acyl chains. The process is probably aided by trans-membrane protein segments. This enables phase separation of the triacylglycerols, lens formation, and growth to a point where the seipin oligomer opens toward the cytoplasm so the lens can form a budding lipid droplet. In essence, it appears that that the main elements of the seipin structure are evolutionarily conserved in yeast, fly and human proteins (Arlt, H. et al. Seipin forms a flexible cage at lipid droplet formation sites. Nature Struct. Mol. Biol., in press (2022); DOI).

The Lands cycle, named for its discoverer W.E.M. (Bill) Lands (see my blog of 2/2/22), explains how glycerolipid fatty acid and molecular species compositions, and positional distributions on the glycerol moiety are determined post synthesis by extensive re-modelling. This involves orchestrated reactions of hydrolysis (phospholipase A₂ mainly) to lysophospholipids, acyl-CoA synthesis and re-acylation by lysophospholipid acyltransferases or transacylases. I was delighted to see a new review on the topic by Valerie O’Donnell, who recalls the seminal papers from the 1960s in addition to a discussion of new developments (New appreciation for an old pathway: the Lands Cycle moves into new arenas in health and disease. Biochem. Soc.Trans., in press (2022); DOI).

February 23^rd, 2022

Scottish thistle Despite all the storms we have faced recently, we have had a relatively mild Winter in Dundee, and the first Spring flowers, snowdrops and crocuses, are putting on a fine display in my garden. It seems that we can thank lipids for early flowering. A mobile protein, known as florigen, moves through the phloem over long distances to reach the shoot apical meristem, where it induces flowering by regulating nuclear transcription. In cold weather, this protein is sequestered by phosphatidylglycerol, so flowering is delayed; warming has the opposite effect by reducing the bonding and allowing the protein to move (Susila, H. et al. Florigen sequestration in cellular membranes modulates temperature-responsive flowering. Science, 373, 1137-1142 (2021); DOI).

It seems to be firmly established that N-myristoylation of terminal glycine residues in proteolipids is not reversible, unlike S‑palmitoylation. However, it is now known that at least two proteins modified by N-myristoylation of lysine residues can be deacylated by the enzyme histone deacetylase 11 (HDAC11). For example, demyristoylation at two sites of gravin-α in adipocytes by HDAC11 prevents β‑adrenergic (G protein-coupled) receptors from translocating to the membrane microdomains that are required for downstream protective signalling. This is in effect a control mechanism with relevance to obesity (Bagchi, R.A. et al. Reversible lysine fatty acylation of an anchoring protein mediates adipocyte adrenergic signaling. PNAS, 119, e2119678119 (2022); DOI).

Incidentally, I suspect that I am fighting a losing battle, but I prefer the term ‘proteolipids’ for all proteins containing covalently bound lipid moieties such as fatty acids, reserving ‘lipoprotein’ for the non-covalently linked lipid-protein complexes of the type found in plasma.

February 16^th, 2022

Glycerol-3-phosphate acyltransferases and lysophospholipid acyltransferases are key enzymes that are conserved across the kingdoms of life and determine the compositions of the two positions in all glycerophospholipids, ultimately controlling their physical properties and biological functions. For an external viewer such as myself, it is easy to get lost in a plethora of acronyms, GPAT, LPLAT, AGPAT and MBOAT, each with several numbers potentially affixed to complicate the position further. Multiple names can refer to the same enzyme, or one name can be applied to different enzymes. Now a new review of the mammalian enzymes has used genetic studies to bring sense to the confusion, and proposes a more systematic nomenclature (Valentine, W.J. et al. Update and nomenclature proposal for mammalian lysophospholipid acyltransferases, which create membrane phospholipid diversity. J. Biol. Chem., 298, 101470 (2022); DOI). It will give me some extra work when I update many of my web pages here, but I can live with that.

Although there is nothing new in the concept, it never ceases to surprise how small changes in stereochemistry can lead huge differences in function in all fields of biochemistry never mind lipids. For example, the monoglycosylceramides β‑galactosylceramide and β‑glucosylceramide differ simply in the stereochemistry of carbon 4, but the corresponding synthases are so different in amino acid sequence that they must have evolved separately (in contrast to acyltransferases!). To take just two examples for illustrative purposes, galactosylceramide is a major component of myelin and cannot be replaced by glucosylceramide, while the latter is essential for the functions of animal skin. Each of these lipids has highly specific distributions and functions and a new review is a valuable summary of their properties (Reza, S et al. Glucosylceramide and galactosylceramide, small glycosphingolipids with significant impact on health and disease. Glycobiology, 31, 1416-1434 (2022); DOI). While on the subject, it should not be forgotten that another stereoisomer α‑galactosylceramide has very different biological activity from the normal β‑form with considerable therapeutic potential.

The only aspect of the concept of evolution that really bothers me is how self-replicating entities could have emerged from a primordial chemical soup. I can accept that all the building blocks of life might be available, including lipids, which might spontaneously form bilayers and putative cell walls, but what then? Now a new publication demonstrates highly specific interactions between lipids and RNA that “introduces a mechanism for riboregulation in cellular, synthetic, and prebiotic systems” (Czerniak, T. and Saenz, J.P. Lipid membranes modulate the activity of RNA through sequence-dependent interactions. Proc. Natl. Acad. Sci. USA, 119, e2119235119 (2022); DOI). It doesn't answer all the questions but is a step on the way.

February 9^th, 2022

My plan for my web section Lipid Essentials was to base it on documents dealing with individual lipid classes, as this appeared to be the only simple way to deal with lipid structures, composition, physical properties, biosynthesis and functions in a manageable way that permitted me to build the site over the years (more than 20 so far). By and large this has worked for me, although there are anomalies. For example, in my document on arsenolipids, I deal with lipids that vary in structure from hydrocarbons to glycolipids that have an arsenic atom in common. However, one group where this approach may have failed is with Mycobacterial lipids, many of which are so unique to these organisms that I fear I may not have done justice to their distinctive nature, especially as many of these are responsible for their pathogenicity. More than a million people world-wide die from tuberculosis every year.

When I started this project, I was not aware of these complex lipids other than the fact that the mycolic acids of the bacteria were very different from anything else in nature, with up to 90 carbons in total, a large unsubstituted alkyl branch in position 2 and a hydroxyl group in position 3, together with on occasion cis or trans double bonds, cyclopropane rings, and methoxyl, epoxy and keto groups (depending on species). I incorporated a description of these into my document on branched-fatty acids, as this seemed the most appropriate at the time. As my project continued, I found more and more unusual lipids, which one by one were incorporated into other web documents according to their differing structures. These include phosphatidylinositol mannosides, lipomannans, phenolphthiocerol and phthiocerol dimycocerosates, trehalose esters, which include di- to penta-acyltrehaloses and sulfatides, glucose monomycolates, mannosyl-phosphomycoketide (illustrated), gentiobiosyl-diacylglycerols, and (glyco)-peptidolipids. To add to the complexity, many of these are esterified to mycolic (and other multibranched) fatty acids, which also exist in the free state. You can find links to these from the mycolic acid page. Even, the more conventional lipids, such as triacylglycerols and phosphatidylethanolamine, are distinctive in that they contain a rather uncommon fatty acid – 10-methylstearic (tuberculostearic) acid. If I were to start again (unlikely), I might try to incorporate all of these into one web document.

Structure of beta-D-mannosyl phosphomycoketide

Now, I would like to know why it was necessary for Mycobacteria to synthesise so many novel lipids. What were the evolutionary pressures that drove this? Why could they not simply adapt more common bacterial lipids to their purpose? No doubt microbiologists have ideas on the subject. I was drawn to the topic by two recent reviews, the main purposes of which are to discuss chemical syntheses, but which include a great deal of fascinating biological information along the way (Holzheimer, M. et al. Chemical synthesis of cell wall constituents of Mycobacterium tuberculosis. Chem. Rev., 121, 9554?9643 (2021); DOI:: Burchill, L. and Williams, S.J. From the banal to the bizarre: unravelling immune recognition and response to microbial lipids. Chemical Commun., in press (2022); DOI).

February 2^nd, 2022

I was pleased to receive an e-mail last week from Bill Lands, who many of you will know from the eponymous Lands' cycle, whereby glycerolipids are remodelled by concerted action of lipases and acyltransferases until the optimum compositions are reached for their functions in specific tissues or membranes. Of course, this has been just one of his research interests over a long career. The email is headed “A nonagenarian's list of things to do” and points me to his “last review” (Lands, B. Lipid nutrition: “In silico” studies and undeveloped experiments. Prog. Lipid Res., 85, 101142 (2022); DOI). I first encountered Bill in 1965 when I was a post-doc in Ralph Holman’s lab at work on the chemical synthesis of unsaturated fatty acids (linoleate isomers). He saw biochemical opportunities in these that were relevant to his own work on acyltransferases, and a collaboration resulted in two papers in JBC. If the techniques had been available then for isolation of specific acyltransferases to which we now have access, it would have been possible to do much more to relate double bond positions to protein binding with consequences on acyltransferase and cell replication events. This is just one of a number of topics that Bill suggests requires further exploration, and I can recommend this review to any young scientist who feels a need for further inspiration.

Incidentally, I was pleased to see Bill's tribute in this review to my former mentor Frank Gunstone, who is also memorialized in the February issue of INFORM (AOCS).

I had thought my publishing career was at an end until recently, when I contributed some mass spectrometry advice to a paper, and then co-authored a review article. One unforeseen and unwanted drawback of this is that I have been inundated with spam emails asking me to attend and often chair conferences, submit papers to journals and even to join editorial boards. The journals vary in scope from engineering to medicine, and it seems to me that any journal that wants a retired octogenarian to serve on their board must be rather desperate. I assume that those of you who publish more often will be used to this, but apart from putting a block on further correspondence for each message there does not seem to be an answer to the nuisance.

January 26^th, 2022

Scottish thistle Scientists are often accused of using jargon to describe their work, by which our critics mean polysyllabic words with no meaning to non-scientists. This criticism is unfair as there is often no simple or common equivalent to a technical term, and of course students of the arts have their own specialized vocabularies. That said, we do have an occasional tendency to prefer a 5 to 7 syllable word when one with 1 or 2 is available. Therefore, I find it refreshing when a simple term becomes established in the literature. One that comes to immediate mind is to use the phrase ‘eat‑me’ to describe the signal sent to phagocytes when a cell has reached the end of its life. Of course, we could use ‘pro-apoptosis’ (5 syllables) and given time, I could probably think of something longer. ‘Eat-me’ is concise and descriptive (and to use a guid Scots word - couthy).

The term is usually applied to phosphatidylserine, which in aged or damaged cells is oxidized and moved from the inner leaflet of the plasma membrane to the outer leaflet by the action of scramblases. There, it is recognized by a cohort of receptors on the surface of macrophages and related scavenger cells that undertake controlled degradation. A new paper suggest that this is not the only lipid to function in this way but that externalized phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P) does the same (Kim, O-H. et al. Externalized phosphatidylinositides on apoptotic cells are eat-me signals recognized by CD14. Cell Death Differentiation, in press (2022); DOI). Is there anything that phosphoinositides don’t do?

When on the inner leaflet of the plasma membrane, PI(3,4,5)P has very different and indeed opposing properties. By recruiting proteins with pleckstrin homology (PH) domains to the plasma membrane, it has been implicated in a variety of cellular functions that include growth, cell survival and proliferation, and it is an important participant a signalling pathway in the cell nucleus.

January 12^th, 2022

I was pleased to see that the open access journal Molecules is publishing a special virtual issue to honour a stalwart of LipidMaps - "Lipids–Lipolytic Enzymes–Lipid Analysis: A Themed Issue Dedicated to Prof. Edward A. Dennis for His 80th Birthday" edited by Prof. Dr. George Kokotos and Prof. Dr. Jesús Balsinde. At the time of writing this blog, there are three research papers and three review articles listed, but more will undoubtedly follow as the closing date for submissions is still some way off. It always seems a little unfair to select one of these for special mention, but I have been following the theme of nitro fatty acids from their discovery in 1999 when they were simply an intriguing curiosity, and they have been a topic for this blog on many occasions. Now we know that they are important biological mediators with generally beneficial properties, and that they have reached the milestone of phase II clinical trials for several disease states (Koutoulogenis, G. and Kokotos, G. Nitro fatty acids (NO₂-FAs): an emerging class of bioactive fatty acids. Molecules, 26, 7536 (2021); DOI).

In an otherwise excellent review of lipid biochemistry last month, I found the sentence "Lipids are a structurally diverse group of molecules and can be best defined as substances that are soluble in non-polar organic solvents (e.g. chloroform) but not in water". My apology for raising this topic again, and I know this is a hobby horse of mine, but you can find three much better definitions of "lipid" on this website here.. that are based on biosynthetic mechanisms or structural features.

January 5^th, 2022

Scientists love to prevaricate in their writings, presumably because opinions so often change as new information becomes available. For example, we use words and phrases such as ‘presumably’, ‘it appears/seems that’, ‘possibly’, ‘apparently’, ‘probably’, ‘it is reported/believed that’, etc. Therefore, I was pleased to see that there is no equivocation in the title of a new review article (Reyes-Soffer, G. et al. Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American Heart Association. Arterioscler. Thromb. Vasc. Biol., 42, E48-E60 (2022); DOI). For those unfamiliar with this area of research, lipoprotein(a) (Lp(a)) is structurally and metabolically distinct from the other lipoproteins, and it consists of an LDL-like particle containing a specific highly polymorphic glycoprotein named apolipoprotein(a) (apo(a)), which is covalently bound via a disulfide bond to apo B100. The title of another recent review on the topic may appear less definitive, but only superficially so (Ruscica, M. et al. Lipoprotein(a): Knowns, unknowns and uncertainties. Pharm. Res., 173, 105812 (2021); DOI). We need the uncertainties otherwise we would be out of a job.

At this time of year, I like to look back at the log of updates to my web pages, to get an idea of what has been trending throughout the year. The usual suspects in past years have been the phosphoinositides and sphingosine-1-phosphate together with most of the oxylipins, and this is true again this year. However, my triacylglycerol pages have kept me especially busy, because of so much interest in intracellular lipid droplets. My single most worked on topic is ferroptosis, i.e., the iron and peroxide dependent form of apoptosis, while the most recent addition to my top ten of frequently cited lipid classes is the fatty acid esters of hydroxy fatty acids (FAHFA).

Blogs for the previous year (2021) can be located here..

Bill Christie with Guest Contributors
Updated: May 10^th, 2023	Contact/credits/disclaimer