Lipid Matters - A Personal Blog
— by William (Bill) W. Christie

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).

September 19, 2018

A new publication examines a range of N-acylethanolamide derivatives to determine whether they are endocannabinoids as defined by an interaction with CB1 and/or CB2 receptors (Alharthi, N. et al. n-3 polyunsaturated N-acylethanolamines are CB2 cannabinoid receptor-preferring endocannabinoids. Biochim. Biophys. Acta, 1863, 1433-1440 (2018);  DOI.). Saturated and monoenoic N-acylethanolamides are not endocannabinoids, but those derived from other members of the n-6 family of polyunsaturated fatty acids (docosatetraenoic and docosapentaenoic acids in addition to arachidonic) activate both CB1 and CB2 receptors, as well as TRPV1 channels, so these should be considered true endocannabinoids (and 'endovanilloids'). Similarly, N-acylethanolamides derived from the n-3 family of polyunsaturated fatty acids (eicosapentaenoic, docosapentaenoic and docosahexaenoic acids) activate CB2 receptors, and of these, the C22 derivatives also activate TRPV1 channels but not the CB1 receptor. The authors suggest that the preferential activation of CB2 receptors by N-acylethanolamides of the n-3 family of polyunsaturated fatty acids contribute in part to the broad anti-inflammatory profile of the latter.

Scottish thistleThe journal Current Opinion in Cell Biology has a special issue (open access) dealing with the topic of "Membrane Trafficking" (edited by Satyajit Mayor and Anne Spang): Volume 53, Pages A1-A4, 1-110 (August 2018).

A correspondent has drawn to my attention an article in the Guardian Newspaper that is relevant to my comment on open access publication in last week's blog. The author suggests that scientific publication is a rip-off and has no qualms about using the Sci-Hub web site. I have looked at this web site in the past, although my service provider does not now permit access. My own feeling is that while I don't mind bending the copyright law from time to time, I would feel guilty about breaking it in a more comprehensive manner. Also, I would worry about the security of my computer if I were to download material from this source.

September 12, 2018

Another new fatty acid caught my eye this week that is novel in terms of both structure and function, i.e. one containing a tetrahydrofuran ring, i.e. (+)-(2S, 3S, 5R)-tetrahydro-3-hydroxy-5-[(1R)-1-hydroxyhexyl]-2-furanoctanoic acid, which is shown to be a secreted pheromone that controls the migratory behaviour of a fish species, the sea lamprey. This is secreted by the fish larvae and draws the mature fish towards the spawning grounds. (Li, K. et al. Fatty-acid derivative acts as a sea lamprey migratory pheromone. Proc. Natl. Acad. Sci. USA, 115, 8603-8608 (2018);  DOI - open access). The compound is potentially useful for both control and conservation of sea lamprey populations. As far as I am aware, this is the first natural fatty acid to have been found with a tetrahydrofuran ring, i.e. produced by enzyme systems, although isofurans with a ring structure of this kind are formed adventitiously together with other isoprostanes by autoxidative processes in animal tissues. Fatty acids with a furan ring are common minor components of fish oils, although they are presumed to come from algae and phytoplankton in the diet.

Tetrahydrofuranoid fatty acid from sea lampreys

A news item in Nature reports that a number of funding organizations are moving towards a policy of free access to all publications for work that they have supported. I am happy to see an increase in the number of open access publications, but I have the one caveat as to how is it to be decided which open access publications are reputable in the light of innumerable reports that there are a host of frankly fraudulent publications on line. Incidentally, the Nature article has some interesting statistics on the growth of open access publishing. Between 2012 and 2016, the proportion of publications in subscription-only journals fell from 49.2 to 37.7%, though those in fully open access publications only rose by 3%, and there was virtually no change in the number of papers published in journals that permit open access after a fixed period.

It barely touches upon lipids, but who could resist this title (Cao-Pham, A.H. et al. Nudge-nudge, WNK-WNK (kinases), say no more? New Phytologist, 220, 35-48 (2018);  DOI).

September 5th 2018

It is rare to see an announcement of the discovery of novel fatty acids in the popular science news websites, but both Sci-News and Science-Daily have picked up on nebraskanic (illustrated) and wuhanic acids (as the previous but with an additional double bond in position 22) from a seed oil from a Chinese plant. Both reports carry an interview with Prof. Edgar Cahoon, who describes the scientific interest in that biosynthesis involves a break in the cycle of two-carbon additions involved in the assembly of the acyl chain in a manner usually seen only in the synthesis of bacterial fatty acids. Also, the fatty acids seem to form estolide linkages to each other as well as being esterified to glycerol. From a practical standpoint, the oil may have value as a lubricant of natural origin. The names are of course derived from the institutions of the lead authors. This is a long and honorable tradition, as I recall from my days as a post-doc at the Hormel Institute in the 1960s that Helmut Mangold gave the name 'hormelic acid' to a new cyclopentenyl fatty acid. The 60s and 70s were a golden age in the discovery of novel fatty acids, when the Northern Regional Laboratory of the USDA in Peoria, especially, had a major research programme the aim of which was to discover new seed oils of potential industrial value.

Formula of nebraskanic acid

Coincidentally, a tweet to LIPID MAPS® alerted me to a report of the presence in plant tissues of other estolide-linked fatty acids, i.e. fatty acid esters of hydroxy fatty acids, which are proving to have some surprising biological properties in animal tissues (Zhu, Q.-F. et al. Comprehensive screening and identification of fatty acid esters of hydroxy fatty acids in plant tissues by chemical isotope labeling-assisted liquid chromatography–mass spectrometry. Anal. Chem., 90, 10056-10063 (2018);  DOI).

If I had to pick the most neglected of all lipid classes, I would suggest the non-acidic glycosyldiacylglycerols of animal tissues for which I have to depend on a review from 1987 in my account of the topic in the LipidWeb. I suspect that one reason is that they may suffer degradation in some methods for the isolation of the oligoglycoceramides with which they have similar physical and chromatographic properties. Even the acidic seminolipid or sulfogalactosyldiacylglycerol does not rate a mention in many lipid text books, although it is essential for male reproduction. Hopefully, a new review will rekindle interest in the the latter lipid at least (Tanphaichitr, N. et al. Properties, metabolism and roles of sulfogalactosylglycerolipid in male reproduction. Prog. Lipid Res., 72, 18-41 (2018);  DOI.).

August 29nd 2018

Scottish thistleA new review (open access) covers the topic of glycosylphosphatidylinositol anchored proteins in plants (Yeats, T.H. et al. Plant glycosylphosphatidylinositol anchored proteins at the plasma membrane-cell wall nexus. J. Integr. Plant Biol., 60, 649-669 (2018);  DOI). As might be expected, these are vital for a host of functions in plant development and signalling especially at the interface of the plasma membrane and cell wall. However, although the synthesis and structure of GPI anchors is believed to be conserved across eukaryotes, this appears to be based on a number of assumptions as far as plants are concerned, as it seems that the O-glycan component of only one species has been determined to date, i.e. that of Pyrus communis (pear), in a publication from 1999. In this instance, the O-glycan was relatively simple with no phosphoethanolamine side chains and sometimes a β-linked galactose side chain on the first mannose. The lipid component was a ceramide, as that in many fungi, rather than a diacylglycerol.

The microbial lipopeptides are fascinating molecules in that they often contain unique fatty acids together with distinctive amino acids, sometimes with the "wrong" stereochemistry. They are usually powerful surfactants, often with anti-bacterial and antifungal properties. Importantly, they are also considered one of the best hopes in the search for novel antibiotics that may replace those to which pathogenic bacteria are becoming resistant. They may be of equal value against plant pathogens. The polymixins are already licensed for topical use against Gram-negative bacterial infections, but they can only be used internally as a last resort because of toxicity problems. A new review discusses the progress that is being made in the synthesis of polymixin analogues that are better tolerated and hopefully will have a greater range of activities (Vaara, M. New polymyxin derivatives that display improved efficacy in animal infection models as compared to polymyxin B and colistin. Med. Res. Rev., 38, 1661-1673 (2018);  DOI). It seems that we are no nearer to finding a magic bullet, although individual compounds are showing promise, especially as they may act in synergy with existing antibiotics. Similarly, there is hope for novel lipopeptides produced by Pseudomonas species as also discussed in another new review (open access) (Geudens, N. and Martins, J.C. Cyclic lipodepsipeptides from Pseudomonas spp. - biological Swiss-army knives. Front. Microbiol., 9, 1867 (2018);  DOI). Some of these have anticancer activities in vitro in cancer cell lines.

August 22nd 2018

It seems a highly ambitious undertaking to use lipidomics to assess how the lipidome has changed during evolution even in mammalian species. From the internet - "According to Mammal Species of the World, 3rd Edition (Wilson and Reeder 2005), the most recent authoritative published checklist of modern mammal species, there are 5,416 different species of mammals". A beginning can be made at least to such a study, and a new publication reports data from six tissues of 32 species of mammals representative of primates, rodents, and bats (Khrameeva, E. et al. Lipidome evolution in mammalian tissues. Mol. Biol. Evolution, 35, 1947-1957 (2018);  DOI). It appears from this selection that the lipidome has not evolved appreciably except in humans, where many of the unique features were found in the brain cortex, suggesting that there has been an accelerated lipidome evolution in the human brain. The paper is open access.

Another pedantic rant: It is now more than 50 years since IUPAC-IUB published their first set of nomenclature recommendations for lipids in which the stereospecific numbering (sn) system was introduced for triacylglycerol positional distributions. My recollection from that time was that this part of the proposal was approved universally, as a sensible and practical way to characterize the chirality of glycerolipids instead of the R/S or D/L nomenclatures, which could cause confusion especially when applied to more complex lipids. It was fondly assumed that the term 'triglyceride' would fall into disuse, although I can understand why it continues to be used in industry and perhaps more surprisingly in medicine (Sigma-Aldrich sell "Serum Triglyceride Determination Kits"). As I may have mentioned before, my pet hate is the hybrid term "triacylglyceride", which still gets passed by referees and editors of reputable journals. Google Scholar tells me that it has been used in more than 2000 publications since 2017. I don't suppose that many read the original IUPAC-IUB publications nowadays (although you can find links here), but all the text books in my library use triacylglycerol. By all means continue to use 'triglycerides' if you wish, but please not 'triacylglycerides'.

My open access bargain of the week is a 30 page review on protein S-acylation (Zaballa, M.E. and van der Goot, F.G. The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics. Crit. Rev. Biochem. Mol. Biol., 53, 420-451 (2018);  DOI).

August 15th 2018

Although the immune system is essential to protect the body from infection, some immune responses can harm tissues. The eye is especially sensitive to immune reactivity, and it has now been determined that cholesterol sulfate is a key protective factor (Sakurai, T. et al. Cholesterol sulfate is a DOCK2 inhibitor that mediates tissue-specific immune evasion in the eye. Science Sign., 11, eaao4874 (2018);  DOI). This is produced by the Harderian gland, which secretes the lipids that form a protective layer in the tear film that covers the eye. Experiments with mice in vitro demonstrated that cholesterol sulfate selectively inhibits the guanine nucleotide exchange factor DOCK2 and by this means suppresses the migration of neutrophils and T cells. When the sulfotransferases responsible for the synthesis of this lipid were inhibited, inflammation occurred that could be cured by administering eye drops containing cholesterol sulfate. As it is produced by most animal cells and circulates in plasma, it seems to me that the next important question is whether cholesterol sulfate might be an endogenous factor that suppresses the immune system in other circumstances, and possibly in a less benign manner in tumours, for example.

The journal Nitric Oxide continues its series of review articles on the chemistry and biochemistry of the potent anti-inflammatory nitro fatty acids in volumes 78 and 79. A separate publication describes the anticancer effects of nitro fatty acids and proposes a mechanism (Kühn, B. et al. Anti-inflammatory nitro-fatty acids suppress tumor growth by triggering mitochondrial dysfunction and activation of the intrinsic apoptotic pathway in colorectal cancer cells. Biochem. Pharm., 155, 48-60 (2018);  DOI). The authors suggest that "these naturally occurring lipid mediators are a new class of well tolerated chemotherapeutic drug candidates for treatment of colorectal cancer or potentially other inflammation-driven cancer types." Good news indeed!

I am always interested in lipid oddities, and it is hard to think of anything more unusual than a triacylglycerol with acetate in position sn-2, as in the seed oils from Polygala species. This was first reported briefly in 1977 but has now been confirmed by mass spectrometry (Smith, M.A. et al. 2-Acetyl-1,3-diacyl-sn-glycerols with unusual acyl composition in seed oils of the genus Polygala. Eur. J. Lipid Sci. Technol., 120, 1800069 (2018);  DOI). Curiosity aside, if any species from the genus can be developed as a commercial crop, the oil may have potential as a low-viscosity biofuel/lubricant or reduced calorie food ingredient.

August 8th, 2018

The uncontrolled inflammatory response that is seen in sepsis is now recognized to be a major cause of death in the UK and I am sure elsewhere. One of the best hopes for novel therapeutic responses lies with the specialized pro-resolving mediators - resolvins, protectins and maresins, but how are such highly stereospecific structures to be produced on a scale that permits clinical testing? A new total synthesis of resolvin D4 (RvD4), which has three chiral hydroxyl groups and three cis- and three trans-double bonds, has just been published that has the potential to be developed on a commercial scale (Winkler, J.W. et al. Structural insights into Resolvin D4 actions and further metabolites via a new total organic synthesis and validation. J. Leukocyte Biol., 103, 995-1010 (2018);  DOI). The product was tested successfully against ischemia models in mice, and in so-doing the importance of the correct stereochemistry was emphasized. An editorial in the same issue of the journal provides a further perspective on the topic.

Resolvin D4

Every Saturday morning, I scan rapidly through the titles of around 500 publications dealing with lipid science to pick out a relative few that are useful to me for my web endeavours, and which are subsequently listed in my Literature survey pages. Inevitably, I miss many that are not picked out by the algorithm I use, or whose significance I do not recognize at first glance. One that I greatly regret missing when it first appeared deals with how lipids are distributed in membranes (Murate, M. and Kobayashi, T. Revisiting transbilayer distribution of lipids in the plasma membrane. Chem. Phys. Lipids, 194, 58-71 (2016);  DOI). I am now using it to update my web pages. When I was a young scientist, the work of van Deenen and colleagues in the Netherlands in which specific lipases were used to determine the sidedness of membranes attracted great interest. However, by today's standards, these methods seem relatively crude and new procedures involving immunoelectron microscopy are providing much greater selectivity and precision. Perhaps surprisingly, the one lipid for which we still lack reliable data is cholesterol, and it seems that new cholesterol-specific probes are required before it will be possible to reliably determine its transbilayer distribution.

August 1st, 2018

I have belatedly come across two fascinating and important papers on the subject of 12,13-dihydroxy-9Z-octadecenoic acid or 12,13-diHOME. This is a further example of a fatty acid with important biological functions that is not an eicosanoid or a docosanoid but an octadecanoid, derived in this instance from linoleic acid via the action of a CYP epoxygenase followed by an epoxide hydrolase. Last year, this was reported to promote fatty acid transport into brown adipose tissue during cold exposure, while the more recent publication suggests that it is a "novel exercise-stimulated circulating factor that may contribute to the metabolic changes that occur with physical exercise" both in humans and laboratory animals (Stanford, K.I. et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metabolism, 27, 1111-1120.e3 (2018);  DOI). While these effects seem beneficial, there are earlier reports of adverse properties, for example that such oxidized linoleate metabolites may be atherogenic through the induction of pro-inflammatory cytokines and by formation of foam cells from macrophages by PPAR activation. Life is complicated!

Excuse a moment of pedantry, but I have often complained about the excessive use of abbreviations in publications, and the reason I missed these articles in my weekly searches was because of the use of the abbreviated name of the lipid in the title; this was not recognized by the search algorithm I use. The authors did use the word "lipokine" in the title and I could add this to my search algorithm, but a quick search in the Web of Science suggests that this term has only been used 14 times in the last five years and then mainly for palmitoleic acid for which it was originally coined. Should it be used more?

July 25th, 2018

Scottish thistle While animals have eicosanoids and docosanoids and plants have jasmonates and other oxylipins as lipid mediators of innumerable biological reactions, nematodes, including a number of human parasites, have ascarosides. These are glycolipids that consist of the mono-saccharide α-L-3,6-dideoxymannose or ascarylose, which occurs in few other organisms, linked glycosidically to the hydroxyl group of a 2-hydroxy alcohol or of an (ω-1)-hydroxy fatty acid. The nature of the alkyl moiety can vary appreciably and the free hydroxyl and carboxyl groups can be derivatized in various ways. For example, more than 200 ascarosides have been characterized from the model nematode species Caenorhabditis elegans with presumably many different functions.

Formulae of two representative ascarosides

Some of these are structural and provide an impermeability to the shell that protects eggs of certain nematode species from the harsh conditions in the intestines of host animals. Others function as pheromones as well as signalling molecules that regulate development and behaviour. For example, they control the entry and exit of nematodes from a dormant or 'dauer' stage. A new review (open access) describes the properties of these fascinating molecules (von Reuss, S.H. Exploring modular glycolipids involved in nematode chemical communication. Chimia, 72, 297-303 (2018);  DOI).

In my blog last week, I cited a review claiming benefits towards heart disease from eating fish (and presumably their fish oils), and since then two other reviews have appeared one claiming no such benefits and the other the opposite including increased longevity. Is it any wonder that I am confused by nutritional advice, even though the Fats of Life newsletter does its best to enlighten me. Of course fish oils have the potential to help with many more inflammatory conditions other than heart disease. Whether or not it will give me any health benefit, I will enjoy my smoked salmon sandwich at lunchtime.

July 18th, 2018

In my notes on proteolipids in the LipidWeb, I had quoted from a paper suggesting that there were approximately 300 myristoylated proteins in humans and a similar number in Arabidopsis. This figure has now been revised to more than 600 in each (Castrec, B. et al. Structural and genomic decoding of human and plant myristoylomes reveals a definitive recognition pattern. Nature Chem. Biol., 14, 671-679 (2018);  DOI). The results came after the crystal structure of the N-myristoyltransferase-1 was determined. This showed that the enzyme has a characteristic binding cleft that is involved in the recognition of potential substrates for myristoylation (with some overlap with targets for N-acetylation); it also revealed potential sites for further S-palmitoylation, allowing recognition of sequences exhibiting both acylations.

I tend to pay little heed to dietary recommendations in terms of fats and oils as opinions seem to change with the seasons. On the other hand, when the American Heart Association publishes its recommendations, I feel that I must take note at least (Rimm, E.B. et al. Seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease: a science advisory from the American Heart Association. Circulation, 138, E35-E47 (2018);  DOI - open access). The last line of the abstract succinctly states the AHA position with which I can happily live - "We conclude that 1 to 2 seafood meals per week be included to reduce the risk of congestive heart failure, coronary heart disease, ischemic stroke, and sudden cardiac death, especially when seafood replaces the intake of less healthy foods." Following dietary recommendations that appeal to your taste buds may not be the best policy, but I am sure there are worse.

Aficionados of sphingolipids in general and gangliosides in particular will no doubt appreciate a new book on the topic (Ronald L. Schnaar and Pablo H.H. Lopez (editors) Gangliosides In Health And Disease. Progress in Molecular Biology and Translational Science, Volume 156, Pages 1-462 (2018) available from Science Direct). I have not seen it myself.

July 11th, 2018

It has become commonplace to see new reports of the biochemistry of oxylipins derived from the C20 and C22 polyunsaturated fatty acids, and it is easy to forget that there are some important metabolites of the more simple C18 fatty acids. In particular, I am thinking of the nitro fatty acids derived from oleate and linoleate, which have attracted increasing interest since the turn of the century. It seems that the story starts with the discovery in the 1990s that NO inhibited the oxidation of membranes and plasma lipoproteins more potently than α-tocopherol and in general had anti-inflammatory, antioxidant and tissue-protective effects. Subsequently, it became apparent that nitro fatty acids had a role in mediating these reactions largely because the nitro-alkene moiety has potent electron-withdrawing properties that favour reversible nitroalkylation reactions (Michael reaction) with proteins. A new brief review provides a fascinating introduction to the subject (Freeman, B.A. et al. The discovery of nitro-fatty acids as products of metabolic and inflammatory reactions and mediators of adaptive cell signaling. Nitric Oxide Biol. Chem., 77, 106-111 (2018);  DOI). The next issue/volume of this journal has a number of review articles on this general topic.

I tend to stay clear of medical and nutritional matters and leave the debate to those better qualified than I in these subjects. Nonetheless, I enjoy reading a provocative article from time to time such as the following, which is open access (Tsoupras, A. et al. Inflammation, not cholesterol, is a cause of chronic disease. Nutrients, 10, 604 (2018);  DOI). The authors suggest that cholesterol has been demonized but that platelet-activating factor, i.e. 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine or PAF, is the true culprit (apart from its main thesis, the paper is a comprehensive review of PAF activities). While I do not feel qualified to endorse the proposal, I have often wondered if the concentration on cholesterol by clinical scientists is in part due to its ease of analysis as one of the most abundant metabolites in molar terms in plasma (only surpassed by glucose). In contrast, PAF occurs in cells and exerts its effects at concentrations as low as 10-14M, and its analysis is technically daunting. It seems that we may need to employ more lipid analysts skilled in advanced mass spectrometry in future clinical studies.

An analytical development that has truly astonished me is the use of a special knife during surgery for ovarian cancer that enables differentiation of cancerous from borderline tumours in real time from differences in their lipid components by analysing aerosolized tissue by a mass spectrometric technique during electrosurgical dissection (Phelps, D.L. et al. The surgical intelligent knife distinguishes normal, borderline and malignant gynaecological tissues using rapid evaporative ionisation mass spectrometry (REIMS). Brit. J. Cancer, 118, 1349-1358 (2018);  DOI). The publication is open access.

July 4th, 2018

The hedgehog proteolipids are fascinating molecules, not least because they require both palmitate and cholesterol in covalent linkage for their essential functions, for example in limb development. Within the cell, they are produced in the endoplasmic reticulum and Golgi but then must be transferred to the exterior leaflet of the plasma membrane. From there, the fully lipidated proteins must travel a distance as much as 15 cell diameters until they encounter their signalling receptors, but exactly how this is accomplished has yet to be determined. Several proteins that are involved in extraction from the membrane and subsequent transport have been characterized, and at least three model systems for this transport have been proposed, although it appears that none is entirely satisfactory. A new review (open access) discusses the alternatives (Manikowski, D. et al. Taking the Occam's razor approach to hedgehog lipidation and its role in development. J. Dev. Biol., 6, 3 (2018);  DOI).

It often surprises me how relatively small changes in enzyme structure can alter the nature of their products, e.g. to switch between desaturation and hydroxylation. Animal tissues contain six ceramide synthases with very different specificities for fatty acid substrates and different tissue locations, and they appear to produce distinct molecular species of ceramides for particular functions. They are membrane bound enzymes with six membrane spanning regions. Now, they have been shown to differ primarily in only an 11-residue sequence in a loop between the last two putative transmembrane domains (Tidhar, R. et al. Eleven residues determine the acyl chain specificity of ceramide synthases. J. Biol. Chem., 293, 9912-9921 (2018);  DOI). As an editors' choice, the paper is open access.

Incidentally, the authors cite the LIPID MAPS® Lipidomics Gateway to the effect that ~40,000 different lipids have been identified to date, ~4000 of which are sphingolipids. I suspect that in the long term many more will be added to the totals, especially as more lipidomic analyses of plant lipids are undertaken. Whatever the true figure, I am sure that lipid scientists are going to be gainfully employed for many years to come - and I am looking forward to recording and celebrating their efforts.

June 27th, 2018

Scottish thistle I encounter publications dealing with new lipidomics studies of animal tissues in all my weekly literature searches, and as these often contain comparisons with human different disease states, it is important to take note of them. On the other hand, lipidomics studies of plants appear relatively infrequently, although it is vital that we understand what keeps plants healthy, especially when phosphate is limiting or when they are under salt stress. In the long term, this knowledge may also be essential to human health and nutrition. Analysis is daunting technically, as in addition to the common phospholipid classes, plants contain a wide range of distinctive lipids not encountered in animals. These include many different classes of glycosylmono- and diacylglycerols, glycosylinositol phosphoceramides and several sterols and sterol glycosides. This complexity is apparent in a new study in which 600 lipid species from 23 lipid classes were identified from a barley root extracts. These included 142 species of glycosyl inositol phosphorylceramides alone (Yu, D.Y. et al. A high-resolution HPLC-QqTOF platform using parallel reaction monitoring for in-depth lipid discovery and rapid profiling. Anal. Chim. Acta, 1026, 87-100 (2018);  DOI).

For similar reasons, it is important that we understand the biosynthesis, metabolism, and action of plant oxylipins, especially the jasmonates, which are so essential to the development of healthy plants as well as their response to stresses, and I can recommend a new review that gives a comprehensive account of this topic (Wasternack, C. and Feussner, I. The oxylipin pathways: biochemistry and function. Annu. Rev. Plant Biol., 69, 363-386 (2018);  DOI).

I have never paid any attention to Twitter, as I had conceived the idea that it was simply a vanity platform for would-be celebrities or a font for trivia. Now, I have had to reconsider this view as the virtues of the Twitter link on the LIPID MAPS website have been pointed out to me. I have not had the courage to send a tweet myself yet, but you never know. Incidentally, the LIPID MAPS site has had a substantial revamp and is certainly much more eye-catching.

June 20th, 2018

An interesting review publication suggests that long-chain polyunsaturated fatty acids, as opposed to linoleic and linolenic acids, are the true essential fatty acids (Anez-Bustillos, L. et al. Redefining essential fatty acids in the era of novel intravenous lipid emulsions. Clin. Nutr., 37, 784-789 (2018);  DOI). Mice fed arachidonic and docosahexaenoic acids exclusively for five generations grew and reproduced normally, and these fatty acids are certainly vital for eicosanoid and docosanoid production and for innumerable other purposes when esterified to lipids in tissues. There is no doubt that we must have adequate amounts to ensure health. On the other hand, linoleic acid is required for skin ceramides and cardiolipin in heart mitochondria, for example. If the skin barrier integrity and energy production were less than optimal (if adequate for life) in the experimental animals, would this have been noticed? The authors suggest that linoleate could be supplied for other functions by retro-conversion of arachidonic acid, but this seems to me a circular argument - linoleate produces arachidonate produces linoleate - the chicken versus the egg. The debate is important in that alternative injectable lipid emulsions low in the C18 precursors are apparently being considered for clinical use. It seems to me that a sensible compromise would be to ensure that there are adequate amounts of all fatty acids that may have essential functions in any artificial feeding regime.

In my last blog, I urged other senior lipid experts to consider keeping active in or near retirement by writing for the web. My web career was initiated by a desire to see that the large repository of mass spectrometric information (electron impact) on fatty acids and other simple lipids, which I had accumulated, was preserved. There are now more than 2,100 spectra available in the LipidWeb. On the other hand, my former colleagues recently asked me to advise on an analytical problem involving plant sterols. As I did not have access to the Wiley Library and had only a few representative spectra of my own, this proved to be a time-consuming and rather tedious task to search the literature. Is there anyone out there who would consider producing a website akin to mine dealing with electron-impact mass spectra of sterols and their derivatives? You would do the lipid community a great service. Again, I would be happy to advise.

Although we are probably stuck with it, I don't particularly like the term "endocannabinoid", as to use yet another cliché - it is putting the cart before the horse. For example, anandamide does not mimic cannabinol, but rather cannabinol mimics anandamide. Whatever we call them, there is no doubt that endocannabinoids have profound biological effects in humans, and drugs that influence their metabolism are undergoing clinical trials. Therefore, it would not be surprising if cannabinoids per se have medicinal properties, although there is currently some controversy in the UK about such applications. It in no way endorses the use of cannabis for recreational purposes if we accept that drugs derived from it may have a legitimate place in pharmacopoeias. Few politicians appear to understand the difference between the two.

June 13th, 2018

Thioxo-arseno lipid I enjoy eating fish, and I am not going to be deterred by the findings that the arseno-hydrocarbons, which they contain albeit at very low levels, are highly toxic. From experiments with human cell lines in vitro, a new publication reports that arsenic-containing hydrocarbons influence gene expression and DNA methylation with the nature and magnitude of the effects dependent on the chain-length of the hydrocarbon (Müller, S.M. et al. Arsenic-containing hydrocarbons: effects on gene expression, epigenetics, and biotransformation in HepG2 cells. Arch. Toxicol., 92, 1751-1765 (2018);  DOI). One surprise was that high proportions of the starting compounds were transformed into thioxo analogues, i.e. with the oxygen atom replaced by sulfur, with trace levels as arseno-fatty acids and alcohols. Thioxo-arseno lipids might be expected to be more lipophilic than the parent compounds, but it is not yet known whether this transformation results in an increase in toxicity.

When I have what my wife calls "a senior moment", it seems that the fault may lie with my lipids and in particular my leukotrienes. Experiments with mice engineered genetically to have excess tau proteins, the second-most important lesion in the brain in patients with Alzheimer's disease, showed that they developed learning and memory problems as they aged. However, the effects were reversed by a drug that inhibits leukotriene formation by blocking the 5-lipoxygenase enzyme. There is a popular account of the work in Science Daily.

One of the main virtues of writing for the web is its immediacy. Not only do you see the results of your efforts at once, but you also have the opportunities to update anything you write whenever new information becomes available. For example, the figures and comments in this and last weeks' blogs were prepared not for the blog per se but initially for the essays on the appropriate topics in the Lipid Essentials section of this website. I make changes to one or other of these web pages nearly every day - sometimes simply to add or replace a reference and occasionally I regret to say to correct an error. Sometimes, I merely find a better way of explaining a point. If I had intended to use these figures in a review on one of these topics for a print publication, it might be a year before it appeared in a journal - not the same day - and then there would be no opportunities for correction or updating. There are hundreds of senior scientists out there with a wealth of knowledge on lipid science who I am sure would find some fulfillment by setting up their own web sites and writing for the web. It is so easy to do - why not give it a go? I will be happy to offer advice to anyone who wants to try.

June 6th, 2018

Plasmalogen catabolism I have been enjoying the sunshine of Gran Canaria for the last week, and lipid science has not been at the forefront of my thoughts. However, it took only a preliminary look at the literature on my return, to see that I had missed an important paper. The mechanism for the cleavage of the vinyl ether bond in plasmalogens has now been revealed as the result of a master class in elegant mass spectrometric experiments involving the use of stable isotopes (Jenkins, C.M. et al. Cytochrome c is an oxidative stress–activated plasmalogenase that cleaves plasmenylcholine and plasmenylethanolamine at the sn-1 vinyl ether linkage J. Biol. Chem., 293, 8693-8709 (2018);  DOI - open access as an editors' pick, as is an additional useful commentary by Howard Goldfine). Perhaps surprisingly, the key enzyme is cytochrome c, best known for its role in the respiratory chain of mitochondria. This must first be activated to produce peroxidase activity by an interaction with cardiolipin. After a complex series of reactions, the products are a lysophospholipid and an α-hydroxyaldehyde. The carbonyl oxygen is derived from water while that of the α-hydroxyl group comes from molecular oxygen (or possibly from oxidized cardiolipin). As the resulting lysophospholipid is usually enriched in arachidonic acid, this may have interesting implications for eicosanoid production. The findings are also relevant to Alzheimer's disease, as it has long been known that α-hydroxyaldehydes accumulate in the brains of affected patients.

Incidentally, a further new publication is relevant to the suggestion that oxidized cardiolipin may be involved in the reaction (Vähäheikkilä, M. et al. How cardiolipin peroxidation alters the properties of the inner mitochondrial membrane? Chem. Phys. Lipids, 214, 15-23 (2018);  DOI).

May 23rd, 2018

Scottish thistleIt is very rare to see a statue raised to commemorate a scientist, but I was pleased to see that Stephen Hawking was honoured at his death by being interred in Westminster Abbey. I only know of one lipid scientist who has been commemorated by a statue, and that is the great French chemist Michel Chevreul of whom there is a bronze statue in the Jardin des Plantes d'Angers in Paris. Of course that great stalwart of lipid research, the laboratory mouse, is commemorated by a bronze statue in a park in front of the Institute of Cytology and Genetics of the Russian Academy of Sciences in the city of Novosibirsk in Siberia, Russia. He/she is depicted knitting DNA (see the Wikipedia entry). In the main city square here in Dundee, we have a statue of Desperate Dan, a character from children's comics and a superhero of my own childhood. Our priorities must be different.

A candidate for the most unusual new lipid of the year is 1-phosphatidyl-2-acyl-glycero-3-phosphoethanolamine from a Gram-negative bacterial species; the structure has been tentatively identified by tandem mass spectrometric analysis (Luo, Y. et al. Nutrient depletion-induced production of tri-acylated glycerophospholipids in Acinetobacter radioresistens. Sci. Rep., 8, 7470 (2018);  DOI - open access). It is produced together with cardiolipin and lysocardiolipin, presumably from a common intermediate, only in the stationary phase of growth of the organism.

Structure of 1-phosphatidyl-2-acyl-glycero-3-phosphoethanolamine

Issue 8 (Volume 592, April 2018) of FEBS Letters contains a number of review articles on the theme of "Focus on… Yeast Lipid Biochemistry", all of which are open access.

May 16th, 2018

α-D-Galactosylceramides, i.e. cerebrosides with an α-D- rather than the usual β-D-linkage between galactose and ceramide, are present in trace amounts only in human tissues but they have profound biological effects. For example, studies with animal models have suggested that treatment with α-D-galactosylceramides may be effective against lung and colorectal cancers, melanomas and leukemia. Now, a phase I trial with high-risk melanoma patients has given promising preliminary results (Gasser, O. and 19 others. A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients. Cancer Immunology, Immunotherapy, 67, 285-298 (2018);  DOI). It is always pleasing to see that the potential of lipids in therapy is being realized. Unfortunately, not all glycosphingolipids are beneficial and a new short review of the influence of glycosphingolipids on cancer has been published (Zhuo, D.H. et al. Biological roles of aberrantly expressed glycosphingolipids and related enzymes in human cancer development and progression. Front. Physiol., 9, 466 (2018);  DOI - open access).

The bargain of the week is an open access review of triacylglycerol metabolism (Alves-Bezerra, M. and Cohen, D.E. Triglyceride metabolism in the liver. Comprehensive Physiology, 8, 1-22 (2018);  DOI). There are nearly 300 references, it is very well illustrated and it should be especially useful for teaching purposes. My only caveat is the use of the term 'triglyceride' instead of 'triacylglycerol', which has been recommended by IUPAC-IUB for more than 50 years. Two generations of biochemists have been taught the recommended nomenclature, so I am surprised to find the old used here. At least the authors did not use the hybrid term 'triacylglycerides', which I find much too often in the lipid literature. Am I being pedantic?

May 9th, 2018

In my blog of March 14th, I discussed a paper describing the synthesis of linoleic acid in primitive invertebrates, including insects, nematodes and snails. Hot on its heels, a new paper has just been published demonstrating that a large number of aquatic invertebrates possess the gene for a Δ15-desaturase and so can synthesise α-linolenic acid and polyunsaturated fatty acids of the omega-3 family (Kabeya, N. et al. Genes for de novo biosynthesis of omega-3 polyunsaturated fatty acids are widespread in animals. Science Advances, 4, eaar684902 (2018);  DOI - open access). It was pleasing to see that some of the authors were from the University of Stirling in Scotland. Until now, it had been believed that microorganisms were the main producers of polyunsaturated fatty acids of omega-3 fatty acids in the marine food web, but now it appears that animal species may make a significant contribution. In addition to adding the new information, I have had to make a small but important change to my web page on polyunsaturated fatty acids, by changing phrases such as "animals cannot produce essential fatty acids" to "higher animals cannot, etc".

It is 40 years since, the discovery of glycosylphosphatidylinositol (GPI)-anchored proteins, and thirty since the first complete structure was determined for the parasitic organism Trypanosoma brucei, and it since then it has become evident how important these are for so many aspects of metabolism in Eukaryotes. In their functional site on the outer leaflet of the plasma membrane, the flexible carbohydrate linkage provides GPI-proteins with a much higher degree of rotational freedom than is available to most other membrane proteins, facilitating their functions as signal receptors and host-recognition molecules. They have essential functions in the interaction of cells with their external environment by enabling the receipt of signals and the response to challenges as well as mediating adhesion of extracellular compounds to the cell surface. In parasitic protozoa, yeasts and fungi, GPI-proteins also participate in the structural integrity of the cell wall and with other complex glycans provide a layer of protection to the organisms. A new review is a valuable guide to the latter (Komath, S.S. et al. Generating anchors only to lose them: the unusual story of glycosylphosphatidylinositol anchor biosynthesis and remodeling in yeast and fungi. IUBMB Life, 70, 355-383 (2018);  DOI).

May 2nd, 2018

There has been no shortage of publications dealing with the molecular species of mitochondrial cardiolipin in recent years, but a new publication suggests that most of them suffer from a flaw in that they do not allow sufficiently for overlap with isobaric species (Oemer, G. et al. Molecular structural diversity of mitochondrial cardiolipins. Proc. Natl. Acad. Sci. USA, 115, 4158-4163 (2018);  DOI). I have been too long from the bench to fully comprehend the arguments, but the authors use a combination of HPLC-mass spectral data and a mathematical structural modeling approach to overcome the problems. The data are presented elegantly in graphical form for many different organisms and tissues, but I wish the authors had used the opportunities offered by having appendices to tabulate data at least for the major species, as they have done for fatty acid compositions. I would love to be able to list tabulated data from a modern paper in my web page on this lipid class to replace that from a 25 year old publication.

Do we now fully comprehend the structures of natural cardiolipins? Unfortunately, the answer is no because we know little or nothing about the positional distributions of fatty acids in the molecule. Cardiolipin has two chiral centres, one in each outer glycerol group, and this means that the four positions to which fatty acids are esterified are each metabolically distinct and can have different fatty acid compositions. As far as I am aware, no one has attempted to tackle the problem, which is unlikely to be solved by mass spectrometry. Analysts may have to resurrect enzymatic hydrolysis methods, which are stereo-selective but have been sadly neglected.

An interesting new paper (though I have only seen the abstract) suggests a close relationship between plasmalogen and cardiolipin biosynthesis (Kimura, T. et al. Substantial decrease in plasmalogen in the heart associated with tafazzin deficiency. Biochemistry, 57, 2162-2175 (2018);  DOI)). The authors establish that plasmenylcholine, which is abundant in linoleoyl species in heart mitochondria, is a substrate for tafazzin and may be important for the remodelling of cardiolipin. This may be especially relevant to the debilitating genetic disease Barth syndrome.

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Author: William W. Christie Updated: August 22nd 2018 Credits/disclaimer LipidWeb logo

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