The LipidWeb blank

Lipid Matters - A Personal Blog



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


December 11th, 2019

Scottish thistleSince the discovery of prostaglandins, thousands of papers have appeared on the chemistry and biochemistry of eicosanoids and docosanoids, but relatively few on the octadecanoids (C18), i.e. the oxylipins derived from linoleic acid. Yet octadecanoids (HODE) are reported to be the most abundant oxylipins in human plasma. Now, a new report suggests that they are also the main components of the oxylipins in the brains of rat pups (Hennebelle, M. et al. Linoleic acid-derived metabolites constitute the majority of oxylipins in the rat pup brain and stimulate axonal growth in primary rat cortical neuron-glia co-cultures in a sex-dependent manner. J. Neurochem., in press (2019);  DOI). 13S-HODE in particular increased axonal outgrowth cortical neurons in male rat pups significantly, but not in female pups where linoleic acid per se displayed this activity. These data contrast with many more negative reports of the biological activities of octadecanoids, which may for example be inflammatory and atherogenic through the induction of pro-inflammatory cytokines.

α-Linolenic acid tends to be of low abundance in animal tissues and I have not been able to find anything in the literature on the occurrence of oxylipins derived from this precursor in animals. I guess the best place to look for them would be in vegans, or better in non-ruminant herbivores such as the horse. My understanding is that linoleic acid is now regarded as an essential fatty acid in its own right, not simply as a precursor of arachidonic acid and eicosanoids, because of its vital functions in skin lipids as well as its conversion to bioactive oxylipins. In contrast, α-linolenic acid may only be essential for conversion to EPA and DHA and their metabolites.

Last week, I discussed briefly the therapeutic properties of bile acids. This week, a new review discusses their potential role as anticancer drugs (Goossens, J.F. and Bailly, C. Ursodeoxycholic acid and cancer: From chemoprevention to chemotherapy. Pharmacol. Therapeut., 203, 107396 (2019);  DOI). Paradoxically, ursodeoxycholic acid inhibits apoptosis in epithelial cells while promoting it in cancer cells.

December 4th, 2019

For much of my research career, I have been hearing about how bad lipids are for health - total fat intake, saturated fats, trans-fatty acids, cholesterol and so forth - are all anathema to nutritionists. This is perhaps why I am always fascinated now to learn of the therapeutic applications of specific lipids. As a non-subscriber, it will be a year before I can read anything other than the abstract, but a new publication from Serhan's group suggests that a resolvin may be of value in the treatment of deep vein thrombosis (Cherpokova, D. et al. Resolvin D4 attenuates the severity of pathological thrombosis in mice. Blood, 134, 1458-1468 (2019);  DOI). It is reported that this specialized pro-resolving mediator not only has a direct effect by significantly reducing the thrombus burden, but it also promotes "the biosynthesis of other D-series resolvins involved in facilitating resolution of inflammation".

For 160 years after the discovery of cholic acid in 1838, bile acids were considered to be simply a form of detergent that functioned to solubilize dietary lipids to facilitate their absorption. That has changed, and there have been a number of useful reviews on their other biological properties in recent years. However, I was attracted by the opening sentence of the abstract of new review, which happily is open access, and to quote - "Of all the novel glucoregulatory molecules discovered in the past 20 years, bile acids are notable for the fact that they were hiding in plain sight" (Ahmad, T.R. and Haeusler, R.A. Bile acids in glucose metabolism and insulin signalling - mechanisms and research needs. Nature Rev. Endocrin., 15, 701-712 (2019);  DOI). Now they are known to act through the nuclear receptor FXR and many others, and to have appreciable therapeutic potential. In fact, the hydrophilic secondary bile acid ursodeoxycholic acid (3α,7β-dihydroxy-5β-cholan-24-oic acid) and its taurine conjugate are already used clinically for cholesterol gallstone dissolution and in the treatment of primary biliary cirrhosis. This particular review concentrates on the manner in which bile acids regulate glucose homeostasis. Incidentally, I was intrigued to read in the review that bile acids are important for the biosynthesis of anandamide and other bioactive amides.

November 27th, 2019

Scottish thistleThe journal Free Radical Biology & Medicine has devoted a special issue to the topic of "Redox lipidomics and adductomics - Advanced analytical strategies to study oxidized lipids and lipid-protein adducts" with more than 300 pages of articles. The editors have contributed a useful commentary, which is open access, with this title (Cruciani, G. et al. Free Rad. Biol. Med., 144, 1-5 (2019);  DOI). I have only had time to read of few of these, but my eye was drawn to a short series of papers on the sub-topic of "Advances in analysis of nitrated lipids". Nitro fatty acids are produced while in esterified form in lipids, but it is the unesterified acids that have attracted most of the attention, as they are believed to be important mediators in physiopathological processes such as inflammation. Research seems to be an early stage and mainly with model systems in vitro, but it would be not at all surprising if, after nitration, intact lipids were found to have significant biological activities as is now recognized for oxidized phospholipids. "Adductomics" is a new word for my omics collection.

Text books tend to discuss autoxidation as a product of two reactions, the Haber-Weiss and Fenton reactions. However, it appears that in terms of living systems at least, the Haber-Weiss reaction can be discounted as negligible, and I have to confess that I was in error in over emphasizing its importance in my web page on isoprostanes (see - Filipovic, M.R. and Koppenol, W.H. The Haber-Weiss reaction - The latest revival. Free Rad. Biol. Med., 145, 221-222 (2019);  DOI). Although I have now made an appropriate correction, I should have been aware of this earlier.

November 20th, 2019

Lipid A is the glycolipid component that serves as the anchor for the lipopolysaccharides that make up a large part of the external cell walls of Gram-negative bacteria, including a great number of human pathogens. Unfortunately for us, once inside a human host, lipid A is recognized as a pathogen-associated molecule by many different receptors on immune cells and stimulates a robust inflammatory response, which can cause tissue damage and in the worst scenario septic shock and death of the host. However, some bacteria produce lipid A forms that act as antagonists to the toxic molecules, and it is apparent that the gut microbiome may be a good source of these (Di Lorenzo, F. et al. Lipopolysaccharide structures of Gram-negative populations in the gut microbiota and effects on host interactions. FEMS Microbiol. Rev., 43, 257-272 (2019);  DOI). The immune system must be able "to distinguish the beneficial microbes from the pathogens, even if the commensal bacteria have molecular patterns resembling those of the pathogenic counterparts." Hopefully, a better understanding of the molecular mechanisms involved in these interactions will lead to a new approach to the treatment of bacterial infections.

The gut microbiome is now known to be the source of a further health-promoting lipid, i.e. α-galactosylceramide (normally present in tissues with a β-anomeric linkage), which activates invariant natural killer T cells with benefits against viral as well as bacterial infections (see a research publication and commentary in the November issue of the Journal of Lipid Research, for example). Perhaps I am naive, but I hope that such findings for these lipid classes could be utilized to produce nutraceuticals containing appropriate bacteria that are analogous to those containing Lactobacillus casei and are already available commercially. Anything that reduces the demand for antibiotics must be good.

November 13th, 2019

It is almost an axiom among nutritionists that dietary palmitic acid is bad for you, and I can even remember a newspaper headline 30 years ago to the effect that palmitic acid was "a poison produced by cows". Palm oil is widely derided in Western countries for its high content of palmitate and for the destruction of so many tropical habitats for palm plantations. Why then should plant biochemists strive to increase the content of palmitic acid in position sn-2 of triacylglycerols in seed oils as described in a new paper (van Erp, H. et al. Engineering the stereoisomeric structure of seed oil to mimic human milk fat. PNAS, 116, 20947-20952 (2019);  DOI). The title of the paper gives the game away, as human milk fat (and that of many other species) has a high content of palmitic acid in position 2. It appears that during digestion in the human infant, 2-palmitoylglycerols are produced that are absorbed in the intestines with relative ease. Infant formulae are now produced by technological means to have this distinctive structure, so the intention is to avoid chemicals in producing milk fat substitutes. On the other hand, I can imagine there will be howls of indignation in some quarters about the use of genetically modified crops for this purpose and the phrase "Frankenstein foods" will be used.

While palmitic acid has many essential functions in animal tissues, not least for the synthesis of sphingoid bases, there seems to be little doubt that dietary palmitic acid in excess is undesirable. In particular, it has inflammatory properties as discussed in a new review (Korbecki, J. and Bajdak-Rusinek, K. The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms. Inflam. Res., 68, 915-932 (2019);  DOI).

November 6th, 2019

From time to time, I enjoy reading a review that challenges accepted dogma, and one such discusses the biosynthesis of polyunsaturated fatty acids of the omega-3 family (Metherel, A.H. and Bazine, R.P. Updates to the n-3 polyunsaturated fatty acid biosynthesis pathway: DHA synthesis rates, tetracosahexaenoic acid and (minimal) retroconversion. Prog. Lipid Res., 76, 101008 (2019);  DOI). The measured rates of DHA biosynthesis in animals are very low, but the authors argue that this cannot be true. Among the authors' explanations are that DHA is used as quickly as it is produced for purposes other than for incorporation into membranes. They also have questions regarding the role of EPA in DHA synthesis and the proposed retroconversion mechanisms, and they point out that DHA is both a product and a precursor to tetracosahexaenoic acid (24:6(n-3)).

The same journal provided further food for thought with an intriguing article on the role of dietary C18 trans fatty acids in heart disease (Valenzuela, C.A. et al. Eighteen-carbon trans fatty acids and inflammation in the context of atherosclerosis. Prog. Lipid Res., 76, 101009 (2019);  DOI). I have always been sceptical of the suggestion that trans fatty acids of industrial origin are harmful, although those in dairy products are not - could it be fear of offending the massive dairy farming lobby? However, the authors accept that differences do indeed exist, which may be related to differences in the composition of the different isomers (and I bow to their superior knowledge). Dairy products have relatively high concentrations of trans-11-18:1 (vaccenic acid) in comparison to products of industrial hydrogenation, and importantly of conjugated linoleic acid (cis-9, trans-11-18:2 or CLA). The latter can also be produced in animal tissues by desaturation of ingested vaccenic acid, as can trans-11,cis-13-18:2. While the authors consider that CLA may be a cause of the perceived differences, one possible mechanism that they do not mention is that CLA is the preferred substrate for the formation of nitro fatty acids, which have pronounced anti-inflammatory effects.

October 30th, 2019

Scottish thistleA recent publication caused me to look up what I had written on lipoxygenase metabolites of eicosapentaenoic acid (EPA or 20:3(n-3)) in my web page here - to find not a word - and I soon found that I was not alone in this regard, as they are not mentioned in several major reviews on the topic, other than that 18-HEPE is a precursor for the E-series resolvins. A quick and relatively superficial survey found several brief mentions in the literature but only a little substantive information. It will be a year before I have access, but the paper that provoked my interest is by Leiria, L.O. et al. (12-Lipoxygenase regulates cold adaptation and glucose metabolism by producing the omega-3 lipid 12-HEPE from brown fat. Cell Metab., 30, 768-783.e7 (2019);  DOI). To quote from the abstract "The cold-induced 12-LOX product 12-HEPE was found to be a batokine that improves glucose metabolism by promoting glucose uptake into adipocytes and skeletal muscle through activation of an insulin-like intracellular signaling pathway".

I have now partially rectified my omissions, but I need to do more work on the topic. For example, it appears that 18-HEPE per se has cardioprotective properties and inhibits metastasis in a cancer model, while 5-HEPE enhances the induction of regulatory T cells (Tregs) that modulate the immune system and prevent autoimmune diseases. Fortuitously, the September issue of the journal International Immunology contains some relevant reviews in an open-access series on the theme of "Lipids in Inflammation". Perhaps surprisingly, I found more in my brief survey on the functions of lipoxygenase metabolites of EPA as plant oxylipins, as they are produced by marine algae as defense compounds against bacteria and other predators.

October 23rd, 2019

It is not at all easy to find data on the composition of cytidine diphosphate diacylglycerol (CDP-DAG) in animal tissues although it is a key intermediate in the biosynthesis of many complex glycerolipids, and I have to list data from a 1976 paper in my contribution on the topic here. I guess that it turns over so quickly that the levels in tissues remain too low to be easily detected by lipidomics methodology. It is relatively uncommon to even find this lipid as the major topic of a research publication. Mitochondria have their own unique CDP-diacylglycerol synthase (translocator assembly and maintenance protein 41 or Tam41), first characterized in yeast, and this is of course a key enzyme in the biosynthesis of cardiolipin with its myriad of essential functions. Although I will have to wait a year to read the paper, the structure of this enzyme has now been published and should help us understand how the enzyme functions (Jiao, H.Z. et al. Structures of the mitochondrial CDP-DAG synthase Tam41 suggest a potential lipid substrate pathway from membrane to the active site. Structure, 27, 1258-1269e4 (2019);  DOI). It appears that a binding pocket for the precursor/product has been identified in the structure, where phosphatidic acid may enter and CDP-DAG may exit, while the C-terminal region is crucial for membrane association.

In considering the metabolism of arachidonic acid and thence of the eicosanoids, one enzyme that has been somewhat neglected is the acyl-coenzyme A synthetase 4, which preferentially converts unesterified arachidonic acid to its CoA ester for incorporation into phospholipids when remodelling occurs. This enzyme is important in the earliest stages that might ultimately lead to the eicosanoid cascade, and a new study describes how it is required to maintain the content of highly unsaturated fatty acids to aid the inflammatory response (Kuwata, H. et al. Long-chain acyl-CoA synthetase 4 participates in the formation of highly unsaturated fatty acid-containing phospholipids in murine macrophages. Biochim. Biophys. Acta, 1864, 1606-1618 (2019);  DOI).

October 16th, 2019

Milk is fascinating stuff as the only animal food designed by evolution for oral consumption by other animals. It is not only nutritious but dairy products taste good. Of course, cow's milk is ideal food for calves, but it has its drawbacks for human nutrition, especially because of the low content of essential fatty acids. I can't comment on the taste of human milk (it is a long time since I was a baby!), but it obviously contains the perfect balance of nutrients for human infants. The lipids from the two sources are very different in composition, and both must be among the most studied of all natural products. However, surprises still occur. Now the emphasis is not on the bulk constituents, but on minor lipids that may be biologically active and perhaps should be added to infant formulae.

The nature of the specialized proresolving mediators in human milk, were the subject of my blog 2-3 years ago. Now a new paper discusses the properties of glycerol monolaurate in milk (Schlievert, P.M. et al. Glycerol monolaurate contributes to the antimicrobial and anti-inflammatory activity of human milk. Sci. Rep., 9, 14550 (2019);  DOI - open access). This lipid occurs at a concentration twenty times greater in milk of humans (3000μg/ml) compared to cows (and not at all in infant formulae) and has antimicrobial activity against a number of common bacteria. A second paper reports the presence of side-chain oxysterols in human milk, i.e. 24-, 25- and 27-hydroxycholesterol, throughout lactation with the last of these especially abundant in colostrum (Civra, A. et al. Antiviral oxysterols are present in human milk at diverse stages of lactation. J. Steroid Biochem. Mol. Biol., 193, 105424 (2019);  DOI). This was shown to be active against the pathogenic human rotavirus and rhinovirus of importance in pediatrics. What next for milk lipids?

October 9th, 2019

Carnivorous plants are fascinating biological oddities to botanists and laymen alike, and I suppose that many of us have wondered how they could have evolved to use insects as a source of nutrients - even plants don't have to be vegans! The answer it seems is to do with their lipids, as the capacity to induce digestive enzymes uses a form of the same signalling machinery as that for plant defence against insect predators, i.e. jasmonates (Pavlovič, A. and Mithöfer, A. Jasmonate signalling in carnivorous plants: copycat of plant defence mechanisms. J. Exp. Botany, 70, 3379-3389 (2019);  DOI). In addition, it appears that jasmonate signalling is connected to the electrical signals that induce plants such as the Venus fly trap to close and trap their prey. There are further valuable review articles on jasmonates in the same journal issue, and if you need a brief introduction I can recommend the editorial to the topic (Farmer, E.E. and Goossens, A. What allene oxide synthase does for plants. J. Exp. Botany, 70, 3373–3378 (2019):  DOI - open access). It is the oddities that fascinate a dilettante such as myself, but jasmonates are fascinating oxylipins with structural similarities to the prostaglandins that are presumably of evolutionary significance.

Up until now, jasmonoyl-L-isoleucine was the only metabolite known to be an endogenous ligand of the jasmonate co-receptor, but it has now been demonstrated that the omega-hydroxy analogue, hitherto thought to be inert, differentially activates a subset of the same receptor complex to modify particular jasmonate-dependent responses to improve plant resilience to stress (Jimenez-Alemana, G.H. et al. Omega hydroxylated JA-Ile is an endogenous bioactive jasmonate that signals through the canonical jasmonate signaling pathway. Biochim. Biophys. Acta, 1864, 158520 (2019);  DOI).

October 2nd, 2019

In all of my research career, I threw away the ganglioside fraction, because it remained in the aqueous rather than the organic component after Folch lipid extraction. However, I am grateful for those who have had the persistence to tackle ganglioside biochemistry and analysis as they are proving to have many vital functions in human metabolism. Increasingly, it has emerged that they can be important factors in the development of cancers, and specific gangliosides can have either positive or negative effects upon the regulation of the malignant properties of cancer cells as described in a recent review (Cavdarli, S. et al. Gangliosides: the double-edge sword of neuro-ectodermal derived tumors. Biomolecules, 9, 311 (2019);  DOI - open access). In regard to the latter, the good news is that antibodies to specific gangliosides are proving to be a useful element in therapy for specific cancers, with some current interest focussed upon O-acetylated GD2 (OAcGD2) in breast cancer. Incidentally, the ganglioside GM3 is elevated in the serum of patients with breast cancer and may be a marker for the disease (Li, Q.Y. et al. Gangliosides profiling in serum of breast cancer patient: GM3 as a potential diagnostic biomarker. Glycoconjugate J., 36, 419-428 (2019);  DOI).

Gangliosides are also involved in the action of interactions between microbes and host cells during infections, and cholera toxin, which is an enterotoxin produced by Vibrio cholerae, is a much studied example. The five B-chains of cholera toxin each bind one molecule of ganglioside GM1 and this enables it to enter cells to exert its dire effects. Now it has been established that the botulinus toxin binds to a complex of a polysialoganglioside with the protein synaptotagmin, which together act as a high-affinity receptor complex to enable the neurotoxic effects (Flores, A. et al. Gangliosides interact with synaptotagmin to form the high-affinity receptor complex for botulinum neurotoxin B. PNAS, 116, 18098-18108 (2019);  DOI). Of course, the better we understand these mechanisms, the more likely are we to be able to counter the ill effects. While these make the news, it should not be forgotten that gangliosides have innumerable beneficial functions.

September 25th, 2019

Scottish thistleThe word "thraustochytrid" hardly trips off the tongue and I must confess that I was unaware of it until a new review appeared (Morabito, C. et al. The lipid metabolism in thraustochytrids. Prog. Lipid Res., 76, 101007 (2019);  DOI). Apparently, they are a group of unicellular marine organisms, which are considered to be non-photosynthetic microalgae (I rapidly got lost trying to understand their phylogeny). They are distinctively metabolically in that they produce a high proportion of their fatty acids as docosahexaenoic acid (DHA), as much as 20-25% of the dry weight, with most of the remainder as palmitic. We all know that DHA is a vital component of membrane lipids in animals, especially in brain, the eye and reproductive tissues, as well as being an essential precursor of the oxylipins resolvins, protectins and maresins - the specialized pro-resolving mediators (SPMs). But why is it so essential to this family of algae that it has evolved a distinctive mechanism for its synthesis, i.e. the anaerobic or polyketide pathway, which coexists in the organisms with a type 1 fatty acid synthase? Presumably the DHA is a component of the membrane lipids, but is it also a precursor for oxylipins and are there any other distinctive functions? It seems the answers to these questions are not known.

I have reached an age where I no longer worry about owning things, so instead I collect novel lipids and their functions (as computer files). I have long been aware of ascarosides, the complex glycolipids that protect the cell walls of the eggs of nematodes, but I was less aware of their functions as pheromones. A new review discusses them at length (Park, J.Y. et al. Ascaroside pheromones: chemical biology and pleiotropic neuronal functions. Int. J. Mol. Sci., 20, 3898 (2019);  DOI - open access). I have also been collecting mass spectra to add to the various Archive pages in the Mass Spectrometry section of these web pages, and I have recently added a further 21 to bring the total to 2128. However, these may be my last as my access to novel samples and mass spectrometry is diminishing.

September 11th, 2019

In my long-departed research career, I made good use of the evaporative light-scattering detector (ELSD) for HPLC. For those of you unfamiliar with the instrument, the principle involves evaporation of the mobile phase in a stream of air with lipid molecules forming an aerosol of minute droplets, which are passed through a light source and scatter the light in a manner that reflects the amount of sample. The proportionality of the response was always questionable, especially with minor components, and I made best use of it for micro-preparative purposes with a stream-splitter to divert a proportion of each peak for collection and further analysis. In this mode, the instrument is robust and very easy to use. I can't comment on any current models.

I have had high hopes for the Charged Aerosol Detector (CAD) in which aerosol particles are created in the same way, but then given an electrical charge for detection using an electrometer. Linearity of response is greatly improved over the ELSD, but I have not seen the numbers of published applications that I expected. Of course, I have no personal experience, but I have heard that minor impurities in the mobile phase can affect the response appreciably. That said, a few interesting applications to lipids have appeared, notably a recent one in which supercritical fluid chromatography rather than HPLC is used (Takeda, H. et al. Improved quantitation of lipid classes using supercritical fluid chromatography with a charged aerosol detector. J. Lipid Res., 60, 1465-1474 (2019);  DOI). Perhaps the greater availability of lower-cost bench-top mass spectrometers has dampened the interest in other HPLC detectors.

The Web of Science is now listing papers that appear online before being assigned a volume or page numbers. In many ways, this is useful in informing us of the latest developments, but it does cause a minor headache in recording the data. If this is inserted into a database, it will be necessary to return to journals from time-to-time to check not only on the eventual page numbers but also on the actual year of formal publication - a chore that I for one could do without for my Literature survey pages here. The DOI addresses remain constant at least.

September 4th, 2019

Bacteria tend to lack sphingolipids of their own so it is perhaps surprising that they have evolved to make use of host sphingolipids and sphingolipid enzymes to promote cellular colonization. In particular, they target the acid sphingomyelinase, leading to an increase of the levels of ceramide in membranes and resulting in the formation of ceramide-enriched membrane domains (rafts). This reorganization of membrane structure facilitates entry of bacteria into cells. There are also effects upon signalling and autophagy that benefit the invader. A new open-access review on the topic is worth a read (Rolando, M. and Buchrieser, C. A comprehensive review on the manipulation of the sphingolipid pathway by pathogenic bacteria. Front. Cell Develop. Biol., 7, 168 (2019);  DOI).

In this blog, I have frequently cited the work done by lipid scientists to discover and exploit lipopeptides derived from microorganisms as antibiotics for use against pathogenic bacteria, which are becoming resistant (see my blog of July 31st). Professor Dame Sally Davies, Chief Medical Adviser to the UK government, has just stated to the UK press that antibiotic resistance is a major threat that "could kill us before climate change does" and "at least 10 million could die every year if we don't get on top of this". Currently, around 70% of the world's antibiotics are given to farm animals (including farmed shrimp) - not for human welfare! I have not read any reports of politicians taking her seriously - but then Professor Davies is not a 16-year old Swedish girl. Please do not think that I am not concerned with climate change, as I applaud relevant work in lipid laboratories in relation to tolerance of plants to drought and excessive heat, for example. We do need to have a sense of perspective sometimes.

A phenomenon known as the "curse of the commentator" occurs when one states that a certain football team is sure to win, followed seconds later by a goal for the other side. I feel that I am suffering from this after my comments on the apparent demise of the sphingomyelin-cholesterol model of raft formation last week, only to find that it is alive and well in a new review just accepted by the Journal of Lipid Research (Morgan, P.K. et al. Hematopoiesis is regulated by cholesterol efflux pathways and lipid rafts: connections with cardiovascular diseases.  DOI). A thematic series on rafts is in the works in this journal.

August 28th, 2019

Scottish thistleIn updating my web pages in the Lipid Essentials section of the LipidWeb, I try to keep the big picture in mind rather than concentrating on the minutiae of a subject. From time to time, there is a substantial change in how a topic is viewed in the lipid community, and I at least have the chance to rectify matters here. I am thinking now of my web page dealing with rafts, the transient nano-domains reportedly present in cell membranes. This has always been a controversial subject, for example whether "detergent-resistant membranes" are truly representative of rafts, or indeed whether rafts do indeed exist. When I first prepared a web page on this subject, it was based entirely on the premise that there was a specific interaction between sphingolipids, especially sphingomyelin, and cholesterol in membranes that determined the existence and function of rafts. This premise now seems out-of-date to say the least. I have been prompted to these thoughts by a review to which I have just received access (Lu, S.M. and Fairn, G.D. Mesoscale organization of domains in the plasma membrane - beyond the lipid raft. Crit. Rev. Biochem. Mol. Biol., 53, 192-207 (2018);  DOI). The authors state - "At this time, we cannot find unequivocal evidence that the classic cholesterol-sphingolipid driven raft does not exist" - hardly a ringing endorsement. Instead, if I understand correctly, the prevailing belief is that there may be a number of factors involved in formation of nano-domains, not merely the miscibility of different lipids and this is especially true for protein-rich domains, where trans-membrane proteins may link to the underlying cortical actin cytoskeleton. Cholesterol and sphingomyelin may both be important, but not necessarily in combination. I was aware of some aspects of this view from earlier publications, but my web page did not reflect this adequately.

I am not an expert on the subject, merely a populariser of lipid science, so I sit on the fence and spectate until hopefully a consensus emerges. So far, I have simply tinkered with my web page to reflect the controversy, but have been watching closely to see what develops. It now appears that I will have to undertake a more substantial revision to reflect current views, but at what point do I discount the earlier concepts entirely?

August 21st, 2019

It has long been known that many marine invertebrates produce prostaglandins, often in amounts that seem far in excess of what is required simply for signalling purposes. It is presumed that they have a defensive role of some kind, perhaps against predators. This may include human predators, as marine prostaglandins are believed to be responsible for some poisoning events in Japan. In addition to the conventional mammalian prostaglandins, there is an astonishing array of different structures, and as well as being in the free acid form they can be esterified, even as methyl esters, and acetylated. More surprising perhaps is the discovery of prostaglandins and the relevant biosynthetic enzymes in brown algae (seaweeds), diatoms and micro-algae. As some of these may have useful pharmaceutical properties, for example as anti-cancer and anti-inflammatory agents, they are attracting increasing interest. A new open access review is a valuable update on the topic (Di Costanzo, F. et al. Prostaglandins in marine organisms: a review. Marine Drugs, 17, 428 (2019);  DOI).

Prostaglandins have also been reported from a few higher plants (as opposed to ferns, lichen, algae, etc), though in the past I have been sceptical about whether some of them they do indeed possess the precursor arachidonic acid. Some years ago with a colleague, we established the presence of arachidonic acid in a gymnosperm, Agathis robusta, by GC-mass spectrometry of the 3-pyridylcarbinol (picolinyl) ester and dimethyloxazoline derivatives. There had indeed been a few earlier reports in the literature, but then solely on the basis of relative retention times on GC columns - hence my doubts. As I no longer keep up with this aspect of the literature, I can't comment on more recent publications.

August 14th, 2019

Bis(monoacylglycero)phosphate (BMP) is a fascinating lipid in many ways. It is a minor component of most animal tissues but has a number of important functions. As such, it would be expected that we would know a great deal about its nature and biosynthesis, but there are some surprising gaps in our knowledge. For example, while we know that it has unique stereochemistry in that the phosphodiester moiety is linked only to positions sn-1 and sn-1' of glycerol, rather than to positions sn-3 and sn-3', we are unsure of the positional distributions of the fatty acid components. After isolation from tissues by standard solvent extraction conditions, the fatty acids are in the sn-3 and sn-3' positions, but it is argued from biosynthesis studies that they are in the sn-2 and sn-2' positions when the lipid is first formed. They would be expected to migrate from these to the primary positions under the acidic conditions of the lysosomal compartment of cells or during solvent extraction on analysis. However, the information on biosynthesis is far from complete and the mechanism reported in many publications (including here) is based to some extent on conjecture, especially as to how its ultimate stereochemical configuration is attained. We continue to learn more of its function, so hopefully someone out there is planning to have another attempt to fill in the details of its biosynthesis.

Plant sphingolipids are very different in their structures and functions from those in animal tissues, but as in the latter they are "involved in multiple cellular and regulatory processes including vesicle trafficking, plant development and defence". I can recommend a new open access review on the topic (Huby, E. et al. Sphingolipids: towards an integrated view of metabolism during the plant stress response. New Phytologist, 15597 (2019);  DOI).

August 7th, 2019

Among the more unpleasant lipid classes as far as humans are concerned are the chlorosulfolipids, which were first found and characterized from the phytoflagellate Ochromonas danica, but are now known to occur in marine algae and other organisms. Those isolated from the digestive glands of toxic mussels are causative agents of diarrhetic shellfish poisonings, which tend to be associated with marine algal blooms. For example, mytilipin B isolated from the culinary mussel Mytilus galloprovincialis contains an ester-linked fatty acid in addition to eleven chlorine atoms, six hydroxyls and a sulfate group on a long-chain alkyl moiety. The stereochemistry of this molecule is obviously highly complex, and I have nothing but admiration for those with the courage and persistence to attack the problem (Sondermann, P. and Carreira, E.M. Stereochemical revision, total synthesis, and solution state conformation of the complex chlorosulfolipid mytilipin B. J. Am. Chem. Soc., 141, 10510-10519 (2019);  DOI).

Further novel lipids from an unpleasant source are 6-phosphatidyltrehalose and 6,6'-diphosphatidyltrehalose, which consist of trehalose attached to one or two phosphatidic acid units. These glycophospholipids (not 'phosphoglycolipids - see this web page for an explanation) were isolated from the typhoid fever-causing, Gram-negative bacterium Salmonella Typhi. The positional distributions of the fatty acids have now been determined: long-chain saturated fatty acids in position sn-1 and cyclopropyl fatty acids in position sn-2 (Mishra, V.K. et al. Total synthesis of an immunogenic trehalose phospholipid from Salmonella Typhi and elucidation of its sn-regiochemistry by mass spectrometry. Org. Letts, 21, 5126-5131 (2019);  DOI - open access). As these lipids are potent immunostimulants in an important pathogen, I am sure we will be learning more about them. They also reveal a functional convergence with mycobacteria, which produce a range of acyl trehaloses.

Glycophospholipids of this type, i.e. diacylglycerol-phosphate-carbohydrate, are relatively rare in nature, and the only other direct analogue that comes to mind is phosphatidylglucoside, a minor brain component. Most comparable lipids are derived from phosphatidylglycerol rather than phosphatidic acid. Incidentally, the experts in the field use the term 'phosphatidylglucoside', but I have never been sure why 'phosphatidylglucose' is not correct. Over to you LipidMaps or anyone else who cares to comment!


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Author: William W. Christie Updated: December 11th, 2019 Credits/disclaimer LipidWeb logo