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).


August 21st, 2019

Scottish thistleIt 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!

July 31th, 2019

Scottish thistleAlthough they may be outside the mainstream of lipid research, I like to keep abreast of what is happening in the world of bacterial lipopeptides, as these appear to be one of our best hopes for the discovery of novel antibiotics to combat the development of resistance of bacterial pathogens to the current spectrum of antibiotics. A new review has helped to clarify my understanding of how these molecules work (Balleza, D. et al. Role of lipid composition, physicochemical interactions, and membrane mechanics in the molecular actions of microbial cyclic lipopeptides. J. Membrane Biol., 252, 131-157 (2019);  DOI). It appears that variety of different mechanisms may be involved, and this will hopefully be advantageous therapeutically. Bacterial lipopeptides, both linear and cyclic constitute a diverse range of amphiphilic agents that not only interact electrostatically with the charged head groups of membrane lipids, but also with the hydrophobic region of lipid bilayers. This can result in electrostatic and mechanical changes, reduction in surface tension, promotion of metal ion sequestration, and a disturbance of the structures of lipid bilayers in bacterial and fungal membranes. Often, there appears to be a general tendency to induce pore formation. As I understand it, toxicity problems remain that limit therapeutic use at present, but hopefully time and hard work will reduce these. It is noteworthy that surfactins kill the larval and pupal stages of mosquito species and even have anti-viral properties; some have already reached commercial application as biocontrol agents in agriculture.

July 24th, 2019

Leukotriene B4 is usually considered one of the harmful inflammatory oxylipins, but it also has its good points, for example by triggering functional responses important for host defence including the elimination of certain pathogens. A new publication reports that a single dose ameliorates the symptoms of influenza and improve tolerance to the disease in mice by limiting the accumulation of inflammatory monocyte-derived macrophages, controlling tissue damage and increasing survival (Pernet, E. et al. Leukotriene B4-type I interferon axis regulates macrophage-mediated disease tolerance to influenza infection. Nature Microbiol., 4, 1389–1400 (2019);  DOI). More than 300 died from the disease in the U.K. in the winter of 2017, so anything that may help will be welcome.

The definition of what constitutes an endocannabinoid is looking rather tenuous. Usually the term is taken to mean those lipids that function as agonists for the two primary G protein-coupled receptors for the plant cannabinoids, i.e. those designated CB1 and CB2, but it is now recognized that other receptors may be involved in their functions. Some N-acylethanolamides interact with the other receptors but not with CB1 or CB2, or they may interact with only one of them. The picture is complicated increasingly by findings that derivatives of polyunsaturated fatty acids of the n-3 family are also endocannabinoids or endocannabinoid-like, and then there are the forms that are enzymatically oxidized. For example, some epoxy-endocannabinoids interact much more strongly with the endocannabinoid receptors than does anandamide per se. Two new reviews in this area from different stand-points have helped me to update my web pages here (Watson, J.E. et al. Emerging class of omega-3 fatty acid endocannabinoids and their derivatives. Prostaglandins Other Lipid Mediators, 143, 10633 (2019);  DOI, and de Bus, I. et al. The role of n-3 PUFA-derived fatty acid derivatives and their oxygenated metabolites in the modulation of inflammation. Prostaglandins Other Lipid Mediators, 144, 106351 (2019);  DOI).

July 17th, 2019

Some amazing results can now be obtained by modern mass spectrometric methods, and in particular it is possible to determine double bond positions in the fatty acid components and positional distributions on the glycerolipid backbone for phospholipids. I have been impressed by a new review dealing with what can now be accomplished by such techniques with minute amounts of sample (Siegel, T.P. et al. Reshaping lipid biochemistry by pushing barriers in structural lipidomics. Angew. Chem.-Int. Ed., 58, 6492-6501 (2019);  DOI - open access). For example, it seems to be possible to determine the ratio of n‑9 to n‑7 monoenes in a lipid class, or the ratio of the 16:0/18:1 to 18:1/16:0 species. On the other hand, it does seems that the correct choice of instrumentation may be critical, and that not every system bought off the shelf is suitable for such analyses. If you are planning a purchase, this review will be essential reading.

My main worry as always is that older "classical" techniques may be forgotten. As I have pointed out before, I don't ever recall seeing a study in which positional distributions on the glycerol backbone obtained by mass spectrometry were compared with older methods using phospholipase methodology. It is possible that high precision is not always necessary, but it would be useful to know the potential error, and I suppose that the same may be true for fatty acid isomer distributions. I was once asked to adjudicate on a paper, where the method for methylation of GC analysis might introduce an error of 0.5% in one component of interest, but I pointed out that the standard of accuracy demanded by one referee was much higher than that expected in most fields of biochemistry.

If you would like to read of a further challenging aspect of lipidomics methodology, I can recommend a review that deals with structural analysis of Archaeal lipids. These have isoprenoid alkyl moieties linked by ether bonds to one or two glycerols of the "wrong" stereochemistry, often with ring structures in the alkyl chains and two polar head groups (Law, K.P. and Zhang, C.L.L. Current progress and future trends in mass spectrometry-based archaeal lipidomics. Org. Geochem., 134, 45-61 (2019);  DOI).

July 10th, 2019

A few years ago in this blog, I commented on discovery of 9-hydroxy-stearic acid its isomers with a free carboxyl group and a centrally located hydroxyl group to which a further fatty acid was linked as an estolide or 'FAHFA' (Fatty Acid ester of Hydroxy Fatty Acid). At the time, I thought it simply a novelty, but a number of publications since have demonstrated that these lipids are important anti-inflammatory mediators. The most recent has used the naturally occurring lipids of this type in oat oil to demonstrate that they suppress "lipopolysaccharide-stimulated secretion of cytokines and expression of pro-inflammatory genes. These studies identify LAHLAs as an evolutionarily conserved lipid with anti-inflammatory activity in mammalian cells" (Kolar, M.J. et al. Linoleic acid esters of hydroxy linoleic acids are anti-inflammatory lipids found in plants and mammals. J. Biol. Chem., 294, 10698-10707 (2019);  DOI). If the topic continues to expand, it may need its own web page on this site one day. Incidentally, many years ago I was involved in a minor collaboration with a company promoting the perceived benefits of oat oil as a nutraceutical, unaware of any special value in the estolide components (although we were aware of them).

By some calculations there can be as many as 1000 distinct molecular species of lipids in an animal membrane, so it is surprising that a single one of these can stand out from the rest. This seems to be true for the 18:0/18:1 species of phosphatidylserine in the inner leaflet of the membrane, which has a range of properties that enable transfer of signals to the cytosol. A new review suggests that the mechanism for this may be an interaction with the very-long chain acyl groups of sphingolipids (interdigitation or a "hand-shake") in the outer leaflet in raft-like domains. The result is an accumulation of the anionic phospholipid and negative surface charge to which specific poly-cationic proteins in the membranes can bind (Skotland, T. and Sandvig, K. The role of PS 18:0/18:1 in membrane function. Nature Commun., 10, 2752 (2019);  DOI - open access).

I hate to carp when the first author has such a fine surname, but in view of my recent comments on overuse of abbreviations was it really necessary to use "PS" instead of the full name in the title. Perhaps I am simply becoming a G.O.M. (Grumpy Old Man).

Acronyms may be used to spare embarrassment, and it seems that B.O. and the resulting local pollution is due to oxidation of skin lipids especially on clothing (Lakey, P.S.J. et al. The impact of clothing on ozone and squalene ozonolysis products in indoor environments. Commun. Chem., 2 (1) (2019);  DOI).

July 3rd, 2019

Of all the lipids that now appear to have therapeutic potential, I suspect that nitro fatty acids must be front runners in terms of reaching clinical acceptance. As they are formed relatively easily by non-enzymatic methods, their stereochemistry is relatively simple in comparison to say eicosanoids or docosanoids, so they can be produced on a relatively large scale as pharmaceuticals. They are known to exert protective effects against chronic unresolved inflammation in numerous pre-clinical animal models of disease including cardiovascular, pulmonary and renal fibrosis. A new brief review is worth a look (Khoo, N.K.H. and Schopfer, F.J. Nitrated fatty acids: from diet to disease. Curr. Opinion Physiol., 9, 67-72 (2019);  DOI). Nitrated conjugated linoleic acid is the most active form. In contrast to linoleic acid, α-linolenic acid (18:3(n-3)) is present at low levels only in human tissues, and conjugated forms are not usually detectable. However, naturally occurring conjugated C18 trienes found in certain seed oils are reported to be potent anticancer agents, so it would be interesting to know whether this activity is mediated via nitro adducts.

Another lipid with potential pharmaceutical value is N-oleoylethanolamide with beneficial effects towards non-alcoholic fatty liver disease (NAFLD), the most prevalent of chronic liver diseases. A new systematic review supports the claims and suggests that further clinical are warranted (Tutunchi, H. et al. The effects of oleoylethanolamide, an endogenous PPAR-α agonist, on risk factors for NAFLD: A systematic review. Obesity Rev., 20, 1057-1069 (2019);  DOI). Of course, it is also of interest as an endogenous regulator of food intake, where it is believed to act as a local satiety signal rather than as a blood-borne hormone.

The journal Trends in Analytical Chemistry has a virtual special section on "Ion Mobility Spectrometry" (Volume 116, July (2019) edited by Janusz Pawliszyn) in which many of the articles deal with lipids. The Springer book series Advances in Experimental Medicine and Biology (for those who have access) has two recent volumes dedicated to lipids - "Cholesterol Modulation Of Protein Function: Sterol Specificity And Indirect Mechanisms" and "Bioactive Lipids In Health And Disease".

June 26th, 2019

Scottish thistleThe most unusual lipid of the month and perhaps of the year is N-palmitoyl-O-phosphocholineserine (the most abundant species in its class), which has been found in patients with the genetic disorder Niemann-Pick disease type C1 (Sidhu, R. et al. N-Acyl-O-phosphocholineserines: structures of a novel class of lipids that are biomarkers for Niemann-Pick C1 disease. J. Lipid Res., in press (2019);  DOI). Nothing is yet reported of the biosynthesis and function of this novel lipid, and we do not even know whether it has any specific role in cells or is merely a byproduct, but no doubt we will learn more soon.

Formula of N-palmitoyl-O-phosphocholineserine

I tend to believe that all lipids have some distinctive function in tissues, if only as an intermediate in the deactivation of some more vital lipid. It is fun to speculate on biosynthesis and the obvious possibility is that it is produced by the promiscuous action of a sphingomyelin synthase upon N-acylserines, instead of upon ceramide, with phosphatidylcholine as the phosphocholine donor (speculations are not always a good idea, as I have on occasion seen them cited by others later as facts). N-Acylserines are known constituents of animal tissues, although N-arachidonoylserine has been most studied. However, N-palmitoylserine per se has been detected in brain, and it is reported to have neuroprotective effects against traumatic brain injury. LipidMaps will have to decide how they will classify this new phospholipid, but I have included a brief note in my web page on lipoamino acids on the assumption that it is derived biosynthetically from such lipids.

June 19th, 2019

From time to time I have a diatribe here about the excessive use of abbreviations in publications, and especially in their titles. In my weekly literature search, I have just come across the use of 'HETE' in the title of a paper, which every good lipid scientist knows means 'hydroxyeicosatetraenoic acid' - except that in this instance it apparently stood for 'hydroxyethylthioethyl'. Of course, we cannot control the use of acronyms in other disciplines. I understand that it is necessary to use acronyms for specific genes and proteins in publications, but more details in titles would be often be invaluable. For example, a title such as 'Activation of XYZ123 by abc789' may means something to an expert in a particular field, but to those of us who may be only peripherally involved it may be gobbledygook, and we may not know if it is even related to lipid science. Please give some thought to more explanatory titles for those of us who have difficulty remembering all the acronyms for lipids, never mind genes, enzymes, etc.

In my web pages on oxylipins, I concentrate on mammalian metabolism, although I do not overlook higher plants. However, it is easy to forget that some more primitive organisms produce oxylipins, including hydroperoxides, prostaglandins, and even resolvins, by utilizing enzymes that may only be distantly related in structure to those found in animals. It can be difficult to pull all this information together, so I was grateful for a new review on the topic (Niu, M.Y. and Keller, N.P. Co-opting oxylipin signals in microbial disease. Cell. Microbiol., 21, e13025 (2019);  DOI - open access)

The open access bargain of the week has a title that seems encompass the whole of the biochemistry of complex lipids, but in only 30 pages, they appear to make a creditable job of it (Casares, D. et al. Membrane lipid composition: effect on membrane and organelle structure, function and compartmentalization and therapeutic avenues. Int. J. Mol. Sci., 20, 2167 (2019);  DOI). Students and newcomers to the subject will find it especially useful, but those of us who are a bit more jaded may enjoy a refresher session.

June 12th, 2019

Formula of DiEpHEDEThree years ago in this blog, I highlighted a publication describing a novel eicosanoid with an unusual structure. It was termed dioxolane DXA3 and subsequently was found to have fascinating biological properties. The latter have not changed, but it appears that the structure proposed originally was wrong, and it has now been established that it is in fact a di-epoxide or 8,9‑11,12‑diepoxy-13-hydroxyeicosadienoic acid (8,9-11,12-DiEp-13-HEDE or DiEpHEDE). Of course, this is just as interesting from a biosynthetic standpoint as a dioxolane structure, especially as the cyclooxygenase 1 is the key biosynthetic enzyme (Kornilov, A. et al. Revising the structure of a new eicosanoid from human platelets to 8,9‑11,12-diepoxy-13-hydroxyeicosadienoic acid. J. Biol. Chem., 294, 9225-9238 (2019);  DOI - open access as author's choice).

A further open access bargain deals with the recent developments in oxysterol research (Griffiths, W.J. and Wang, Y.Q. Oxysterol research: a brief review. Biochem. Soc. Trans., 47, 517-526 (2019);  DOI). It has become apparent that these are intimately involved in innumerable biochemical processes of which many are relevant to human diseases, including neurodegenerative diseases and cancer. They are also important in tissue development through their involvement in the regulation of the activities of hedgehog proteolipids, among my favourite lipid molecules as they contain both cholesterol and palmitic acid, which are covalently bound. Technically, these oxysterols can be hard to study because they tend to be minor components in the presence of relatively large amounts of cholesterol, which is liable to autoxidation during processing. It may be a while before we can hand over their analysis to robots, so lipid analysts will continue to be gainfully employed.

June 5th, 2019

It has long been known that palmitoleic acid or cis-9-16:1 is a bit special and indeed has been termed a lipokine. For example, it is essential for the function of Wnt proteins in animal development. Now, another isomer, i.e. cis-10-16:1 isolated from a bacterial species, has been found to have distinctive anti-inflammatory properties (Smith, D.G. et al. Identification and characterization of a novel anti-inflammatory lipid isolated from Mycobacterium vaccae, a soil-derived bacterium with immunoregulatory and stress resilience properties. Psychopharmacology, in press (2019);  DOI). It is shown to upregulate many genes associated with signalling via its action upon peroxisome proliferator-activated receptor alpha (PPARα). Double bonds in even-numbered positions in monoenes are rather unusual, and one in position 10 may be unique (please correct me if I am wrong). Another interesting feature is that the fatty acid appears to be esterified into triacylglycerols as a single molecular species in the organism.

I mentioned a fascinating short review on aspirin in a recent blog, including its effects upon prostaglandin synthesis. It also a factor in the biosynthesis of the so-called aspirin-triggered specialized proresolving mediators produced from docosahexaenoic acid, i.e. the aspirin-triggered resolvins (AT-RvDs) and lipoxins (AT-LXs). It has now been demonstrated that AT-RvDs mediate the anti-tumour activity of aspirin. I can do no better than quote from the abstract - "Thus, the pro-resolution activity of AT-resolvins and AT-lipoxins may explain some of aspirin's broad anticancer activity. These AT-SPMs are active at considerably lower concentrations than aspirin, and thus may provide a nontoxic approach to harnessing aspirin's anticancer activity" (Gilligan, M.M. et al. Aspirin-triggered proresolving mediators stimulate resolution in cancer. PNAS, 116, 6292-6297 (2019);  DOI). We can but hope that clinical studies will soon prove their efficacy.

The British Journal of Pharmacology, Volume 176, Issue 8 has a themed Section: "Eicosanoids 35 years from the 1982 Nobel: where are we now?" with guest editors: Roderick J. Flower and Timothy D Warner.

May 29th, 2019

Scottish thistleMy recent blog-free holiday in Gran Canaria has provoked some reflection. When I started writing for the WWW in my supposedly retirement years, my first task was to set up my mass spectrometry pages. Then, I was aware that at the time (pre Lipid Maps) there was little else of value to students of lipid science - chemistry, biochemistry, physiology - that was open access. I had written a review of triacylglycerol composition and metabolism some years earlier, so it was not difficult to update and reformat this in a manner suited to the internet, and I hoped to make a small contribution in this way. However, on reflection, I thought that this should be balanced by a similar web page on a phospholipid, so I produced a similar web page on phosphatidylcholine. I was clear at the outset that I was aiming to help students and young scientists - not experts in the field - though I hoped that the reading list provided would assist the latter.

The Lipid Essentials section of the web site came into existence then in a relatively unplanned way as I continued to tackle individual lipid classes one at a time over a number of years. Of course, I was not omniscient then (or now), so I learned a great deal myself during this process. Writing for the WWW turned out to be an iterative process, as it is so easy to update web pages as I become aware of further information or new publications on my topics, or simply find a better way to explain some aspect. Nearly 20 years into my task, I continue to find stimulation in this activity, and I still have plenty of time for my family, garden, etc.

My background in lipid chemistry governed my approach, but I occasionally look back to consider whether I could have tackled it in a different way. For example, it is evident that there is a complex interplay among the innumerable lipid species in cells, and it can be difficult to convey this adequately in a web page devoted largely to a single lipid class, even with the use of hyperlinks between pages. While this is especially true for the oxylipins, it is also relevant for all complex lipids in membranes. These thoughts were stimulated in part by a review dealing with lipids as cells divide (Storck, E.M. et al. Lipid cell biology: a focus on lipids in cell division. Annu. Rev. Biochem., 87, 839-869 (2018);  DOI). In this process, a host of different lipids with different functions are involved in an integrated manner, and I am somewhat at a loss to see how I can incorporate this information adequately into so many different web pages on this site. A further paper to show the complexity of lipid interactions that is difficult to fit into my approach deals with the sneaky way viruses hijack many aspects of cellular lipid metabolism for their own nefarious purposes (Vieyres, G. and Pietschmann, T. HCV pit stop at the lipid droplet: refuel lipids and put on a lipoprotein coat before exit. Cells, 8, 233 (2019);  DOI).

I am content to continue with my existing plan for this website, but there must be many scientists out there who are nearing retirement and might consider the production of complementary websites with deeper insights into aspects of lipid science or with a more integrated approach to the subject. Over to you!

May 8th, 2019

If I have to select a single lipid that is attracting particular interest at present, it would have to be the epoxides of polyunsaturated fatty acids, both eicosanoids and docosanoids. Any number of publications have crossed my desk in recent weeks, and the most recent is a review article (Sausville, L.N. et al. Cytochrome P450 epoxygenases and cancer: A genetic and a molecular perspective. Pharmacol. Therapeut., 196, 183-194 (2019);  DOI). In many of their functions, epoxy-eicosanoids derived from arachidonic acid are believed to be beneficial towards human health, but not in relation to cancer where they are pro-angiogenic and promote tumor development and growth. The dihydroxy acids formed by ring opening of such epoxides seem to be regarded universally as harmful. On the other hand, the epoxy-fatty acids derived from eicosapentaenoic and docosahexaenoic acids inhibit angiogenesis and are protective against certain pathological conditions that include cancer. Life is complicated.

Next, a publication in which the title contains the worst pun of the year (Dixit, D. et al. Secrets and lyase: Control of sphingosine 1-phosphate distribution. Immun. Rev., 289, 173-185 (2019);  DOI). All joking aside, this seems to be a fascinating approach to the understanding of the complex problem of the multiple functions of sphingosine 1-phosphate in tissues.

My last publication today is surely a sign of the times (Lee, C.W. et al. Lipidomic profiles disturbed by the internet gaming disorder in young Korean males. J. Chromatogr. B, 1114, 119-124 (2019);  DOI). While a companion study of cell phone addiction and plasma lipids might now be relevant, where would we get an appropriate control group? I am not sure of any real relevance to lipids, and I confess that I should not be flippant about what is obviously a real problem for some.

May 1st, 2019

There is an interesting exchange of letters between H.S. Hansen and W.L. Smith in the latest issue of the Journal of Biological Chemistry (Issue 17) on the essential functions of linoleic acid in its own right, as opposed to as a precursor of arachidonic acid, and thence of the prostaglandins and other eicosanoids. Both agree on the vital role of linoleic acid as a precursor of hepoxilin-like compounds in skin, though perhaps the role in the specific skin ceramides should also be mentioned. In addition, it perhaps should be noted that oxygenated linoleate metabolites are the most abundant oxylipins in plasma in both free and esterified forms, and these have a range of biological functions - mainly with negative implications as far as I can see. Similarly, nitro-metabolites of linoleate may have important biological functions, though most current research appears to be with oleate isomers as these are more readily accessible by chemical synthesis. Indeed, conjugated linoleate, probably derived from linoleate per se, is by far the most active precursor for nitro fatty acids. N-linoleoyl ethanolamide is one of the main acylethanolamides in animal tissues; does it have any specific functions? All of these linoleate products may potentially be involved in its essentiality.

A subsidiary question is whether arachidonic acid has biological functions other than as a source of eicosanoids, and of course the endocannabinoids are important examples of this. Some years ago, A.R. Brash published a review on the topic (Brash, A.R. Arachidonic acid as a bioactive molecule. J. Clin. Invest., 107, 1339-1345 (2001);  DOI), and perhaps a revised and updated version might be timely (although it is quite possible that I have missed something). Finally, does α-linolenic acid have any essential functions in animal tissues other than as a precursor of long-chain polyunsaturated fatty acids of the n-3 family? As far as I understand it, the consensus at present appears to be no, but I await correction.

Dawn Cotter has been responsible for the weekly appearance of this blog on the LIPID MAPS® Lipidomics Gateway. Soon now, the complete LipidWeb will be duplicated there thanks to her efforts.

April 24th, 2019

Scottish thistleIt is not difficult to understand how so many of the oxylipins derived from essential fatty acids can interact physically with receptors, enzymes and other proteins with such specificity. After all, they contain double bonds, ring structures and/or oxygen molecules in highly stereospecific arrangements to favour specific interactions, and natural selection has designed them for such purposes. Even a relatively simple molecule, such as palmitoleic acid with only a single 9-cis double bond in the chain, is uniquely recognized by the enzymes involved in the function of Wtn proteins. However, when chain-length is the only structural feature of a fatty acid, it is sometimes harder to understand how specificity can be achieved.

The source of octanoic acid for its unique use for activation of ghrelin, has recently been identified as synthesis de novo from long-chain fatty acids by β-oxidation in ghrelin-producing cells, and proximity of the relevant enzymes may contribute to specificity. Then, we now have some understanding of distinctive acylations as in the N-myristoylation or S-palmitoylation of proteins, where it now seems that interactions between binding proteins and acyltransferases may provide an explanation for how these fatty acids are selected (see our web page on proteolipids). Of course, it has long been known how desaturases recognize saturated fatty acid precursors. Now a new, highly specific function for myristic acid has been described (Iwata, K. et al. Myristic acid specifically stabilizes diacylglycerol kinase δ protein in C2C12 skeletal muscle cells. Biochim. Biophys. Acta, 1864, 1031-1038 (2019);  DOI). Early biochemistry text books considered saturated fatty acids as dangerous in nutrition in excess, but otherwise as relatively inert molecules from a physiological standpoint; they were only present in tissues as a source of energy or as building blocks of membrane lipids. Those scientists with an interest in sphingolipids have always known better! I suspect that every fatty acid that we encounter in animal tissues has some vital biochemical function, although we may not yet know it.

April 17th, 2019

A few weeks ago, I expressed surprise that research on sphingosine-1-phosphate covered a span of 50 years. This now pales into insignificance with a new publication (Montinari, M.R. et al. The first 3500 years of aspirin history from its roots - A concise summary. Vasc. Pharm., 113, 1-8 (2019);  DOI). Of course there were no Proceedings of the Sumerian (or Egyptian) Academy of Sciences back then, but the Ebers Papyrus (1534BCE) apparently reports the use of willow bark as a painkiller and antipyretic. A mere 1000 years later, Hippocrates was aware of the medicinal properties of this plant family, but the true science of the salicylates began in the late 1700s. As the review recounts, we now know, thanks to the work of Sir John Vane and colleagues, that the mechanism of action of aspirin and other non-steroidal anti-inflammatory drugs is the dose-dependent inhibition of prostaglandin biosynthesis via its action upon cyclooxygenases. Why not put your feet up and read it during your next coffee break - at least it is a change from Brexit?

The effects of the Ebola virus on the lipid metabolism of patients with the disease was also mentioned in an earlier blog. Now a new review describes how this virus (and others) is able to take phosphatidylserine from the inner layer of the host plasma membrane and externalize it on the viral envelope to exploit the host apoptotic clearance machinery to enhance their entry into host cells (Nanbo, A. and Kawaoka, Y. Molecular mechanism of externalization of phosphatidylserine on the surface of Ebola virus particles. DNA Cell Biol., 38, 115-120 (2019);  DOI - open access).

There is currently great interest in oxidized phospholipids in animals, because of their influence on innumerable disease states. However, they are just as important in plants, in which both galactolipids and phospholipids are known to contain specific oxylipins, thanks largely to the marvels of modern mass spectrometry. The best known of these are the arabidopsides, which are formed in leaves upon wounding, but also in distant unstressed leaves so there must be some means of communication between them. A new review summarizes current knowledge (Genva, M. et al. New insights into the biosynthesis of esterified oxylipins and their involvement in plant defense and developmental mechanisms. Phytochem. Rev., 18, 343-358 (2019);  DOI.).

April 10th, 2019

There have been any number of excellent review articles on the topic of lipidomics in recent years that together cover most aspects of the techniques involved in some depth. However, if you are a complete novice to the subject where would you start? I can recommend a new review from the laboratory of Prof. Xianlin Han (Wang, J. et al. Tutorial on lipidomics. Anal. Chim. Acta, 1061, 28-41 (2019);  DOI). The text of the paper is simple, straight-forward and readable, and anything missing is covered by an extensive list of references.

This has been a good week for papers dealing with lipid methodology, and I suspect that one on the topic of oxylipins will prove to be seminal (Watrous, J.D. et al. Directed non-targeted mass spectrometry and chemical networking for discovery of eicosanoids and related oxylipins. Cell Chem. Biol., 26, 433-442 (2019);  DOI). I have yet to get hold of a copy, but from the abstract it appears that there are many more lipid mediators of this type in human plasma than have been adequately characterized to date. The authors are surely having fun exploring the chemistry of these now, especially to determine which are primary metabolites, with studies of the biological properties to follow. "Fun" is probably not the correct word, as I know how frustrating it can be to try to obtain the structures of fatty acid derivatives from minute amounts of material.

In addition, I was intrigued by a paper on derivatization reactions in the solid phase (Atapattu, S.N. and Rosenfeld, J.M. Micro scale analytical derivatizations on solid phase. Trends Anal. Chem., 113, 351-356 (2019);  DOI). There do not yet appear to be many applications to main-stream lipids as yet, but the potential is there. The same journal issue has two further reviews dealing with solid-phase methods for preparing lipid extracts.

The journal Biochimie has a special issue (Volume 159, Pages 1-122, April 2019) devoted to the topic of "Fatty acids and lipopolysaccharides from health to disease" edited by Michel Narce and Isabelle Niot. An eclectic range of topics is covered within the main subject areas.

April 3rd, 2019

It is almost 100 years since the discovery of vitamin E or tocopherol so it is appropriate to see a special journal issue devoted to review articles on the topic - "Vitamin E - Regulatory Roles" edited by A. Azzi and W.J. Whelan (IUBMB Life, Volume 71, Issue 4, Pages: 401-522, April 2019). In the early years, the function of tocopherol as an antioxidant was the focus of most research, then the signalling roles came to the fore, and now there are multiple avenues that are being explored. It seems that I am going to be rather busy now with updates to my tocopherol page, as even a cursory glance at the abstracts shows there is much that I have missed in the last year or two. In particular, I suspect that reading up on the biochemistry of the tocopherol metabolites is going to be a considerable task. For example, I was not aware until now of a publication describing how these interact with 5-lipoxygenase and thence interfere with leukotriene signalling (Pein, H. and 30 others. Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. Nat. Commun., 9, 3834 (2018);  DOI).

However, another important review is demanding my attention at the moment, and this requires updates to several of my web pages - two already (O’Donnell, V.B. et al. Enzymatically oxidized phospholipids assume center stage as essential regulators of innate immunity and cell death. Sci. Signal., 12, eaau2293 (2019);  DOI - open access). Amongst much of interest, it is suggested that the biosynthetic enzymes for free hydroxyeicosatetraenoic acids and their esterified products are colocalized and work cooperatively to the same time scale when cells are activated.


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Author: William W. Christie Updated: August 21st, 2019 Credits/disclaimer LipidWeb logo