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. The older entries are archived for at least a year in a separate web page here..

June 28th, 2017

Scottish thistleThe journal Biochim. Biophys. Acta - Molecular and Cell Biology of Lipids has a special Issue for August just online entitled "BBALIP_Lipidomics Opinion Articles" and edited by Sepp Kohlwein. At first glance, there seems to be a wide and diverse range of topics going beyond the technical aspects into the biology. While, I am fascinated and a little envious of the new methodology, I am more interested in the results. So far, I have only had time to look at one of the reviews, which is highly relevant to my Lipid Essentials pages here in relation to presentation of data (Liebisch, G. et al. Reporting of lipidomics data should be standardized. Biochim. Biophys. Acta, 1862, 747-751 (2017);   DOI). Many of the points made seem sensible, including the suggestion that data should be reported in terms of absolute amounts although I am not clear whether they mean by weight or in terms of molar amounts. They also suggest that data should be available in spreadsheets rather than Word documents or pdf files to make inter-laboratory comparisons easier.

In my articles here, I do not quote any analytical data made by modern mass spectrometric methods - all come from papers published in the 70s and 80s when the methodology was more time consuming but capable of high precision. The problem is that data obtained now in terms of molecular species compositions are in a format that does not lend itself to simple presentation. A phospholipid with 10 fatty acids can exist in the form of 90 molecular species, including positional isomers on the glycerol moiety, while a similar triacylglycerol can have 500 species not including enantiomers. When I came into lipid science, we were more concerned with positional distributions of fatty acids as determined following hydrolytic cleavage with specific lipases; analysis of molecular species was often secondary. It was a simple task to tabulate data for the fatty acid composition of each position in a phospholipid as two columns of fatty acids normalized to 100 mol% with roughly 10 numbers in each. Comparison of data from other laboratories was straight forward, and if you need examples look at almost any of the tables in my web page here on triacylglycerol compositions where data from several sources are presented in a single table.

Such positional data are relevant to biosynthetic processes, hydrolysis by enzymes and lipid remodelling. To give just two examples, arachidonic acid from position sn-2 of phospholipids is used for eicosanoid production while that from position sn-1 is used for anandamide biosynthesis. Of course, molecular species data are important also but this may not be as immediately obvious.

Although mass spectrometric methodology produces data in the form of amounts of the various molecular species, is it necessarily to present it in this form only? Lipidomics methodology is available to determine positional distributions of fatty acids on the glycerol moiety in each species, and while I am not up to date on the mechanics of this there are certainly plenty of papers on the topic. I suspect that the older methods may be capable of greater precision, but mass spectrometry may be good enough for comparative purposes. If so, would it not be possible to add simple mathematical formulae to the spreadsheets to generate tables of positional data for the fatty acids in each lipid class from the molecular species data? Data in both formats are important, but a simple comparison of positional data for each lipid as a first step in interpretation might point to the areas of the molecular species information that require a closer examination. It would certainly simplify interlaboratory comparisons.

June 21st, 2017

In this blog, I have often discussed the therapeutic potential of particular lipids against human diseases. It may be worth a reminder that lipids can have similar beneficial functions in plants. For example, plants in the Solanacea and other families have glandular trichomes, i.e. secretory organs on the external surfaces that secrete mixtures of sugar esters onto the plant aerial surfaces that act as protective agents against both insect herbivores and pathogenic fungi Luu, V.T. et al. O-Acyl sugars protect a wild tobacco from both native fungal pathogens and a specialist herbivore. Plant Physiol., 174, 370-386 (2017);  DOI). In the tomato, for example, these metabolites consist of a carbohydrate backbone, usually glucose or sucrose, to which two to five fatty acids are esterified. The aliphatic acyl chains vary in length from C2 to C12 and are straight chain or have iso- or anteiso-methyl-branches.

My open access publication of the week is perhaps more mainstream and deals with the role of sphingolipids in brain development (Olsen, A.S.B. and Færgeman, N.J. Sphingolipids: membrane microdomains in brain development, function and neurological diseases. Open Biol., 7, 170069 (2017);  DOI).

In the discussion of the new biologically active lipids 'FAHFA' (Fatty Acid Hydroxy Fatty Acid), I do not recall the term "estolide" mentioned although this has been in use since at least the 1950s (according to Google scholar). The definition from the review cited here is "they are intermolecular esters comprised of at least two fatty acid molecules". In animals, the best known example is skin ceramides, but they are also present in bacteria (ornithine lipids and lipid A), many seed oils and yeast. However, the FAHFA are distinctive and differ from the rest in that they have a free carboxyl group. As an example, it may seem something of a misnomer, but hexaacyl triacylglycerols were reported from ergot oil, i.e. with three moles of ricinoleate attached to glycerol each of which is esterified with a long chain fatty acid (Morris, L.J. and Hall, S.W. Structure of glycerides of ergot oils. Lipids, 1, 188-196 (1966);  DOI). In fact, estolides are important industrial products with applications in lubricants (Zerkowski, J.A. Estolides: From structure and function to structured and functionalized. Lipid Technology, 20, 253-256 (2008);  DOI). Incidentally, this review suggests that the first description of an estolide may have been "a 1915 report in Die Naturwissenschaften mentioning their isolation from conifer needles".

I was not around in 1915, but I do remember Lindsay Morris - the author of the 1966 paper. He was a few years ahead of me first as a PhD student with Frank Gunstone and then as a post doc with Ralph Holman, so I knew him first simply as a legendary figure for his activities both within and out of the lab. He will be best remembered as one of the inventors of silver ion chromatography. When we did eventually meet, I found him an engaging person with boundless energy and enthusiasm. I understand that he moved back to Scotland when he retired from Unilever Research, and sadly he died a few years ago.

June 14th, 2017

In my essays here, I have used a rather strict definition of what constitutes an endocannabinoid, i.e. that they must interact with the cannabinoid receptors CB1 and CB2. Thus of the amides, anandamide is obviously an endocannabinoid as is oleamide, but oleoylethanolamide is not. For many purposes this is a useful practical distinction, but there are grey areas and I wonder if I have been too pedantic especially as the 'true' endocannabinoids interact with a number of other receptors. Perhaps we need a new collective term that embraces all the fatty acid amides and simple lipaminoacids - 'amidolipins'? For example, of the other amides palmitoylethanolamide does not interact with the CB1 and CB2 receptors to a significant extent, but it has does have synergistic or "entourage" effects with the 'true' endocannabinoids. This interesting lipid exerts many biological effects in its own right, apparently by a multiplicity of mechanisms and receptors that impinge upon the activities of the other acyl amides. It is undergoing clinical trials for the relief of chronic pain and is the subject of a new review (Petrosino, S. and Di Marzo, V. The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. Brit. J. Pharmacol., 174, 1349-1365 (2017);   DOI).

The N-acylserotonins are another class of fatty amides that also fall into a grey classification area, simply because we do not yet appear to know with which receptors they interact. In particular, it is now clear that N-docosahexaenoylserotonin is present in human intestinal tissue and is a potent anti-inflammatory mediator that may be relevant to intestinal inflammatory conditions such as Crohn's disease and ulcerative colitis. It is a fascinating addition to the list of lipids containing polyunsaturated fatty acids of the (n-3) family with beneficial properties (Wang, Y. et al. Docosahexaenoyl serotonin emerges as most potent inhibitor of IL-17 and CCL-20 released by blood mononuclear cells from a series of N-acyl serotonins identified in human intestinal tissue. Biochim. Biophys. Acta, 1862, 823-831 (2017);   DOI).

In relation to the 'true' endocannabinoids, a new review suggests that some of their biological properties may be mediated through the production of nitric oxide, which functions as a versatile signalling intermediate and is ubiquitous in tissues (Lipina, C. and Hundal, H.S. The endocannabinoid system: ‘NO’ longer anonymous in the control of nitrergic signalling? J. Mol. Cell Biol. 9, 91-103 (2017);   DOI).

June 7th, 2017

The presence of α-galactosylceramide as opposed to the β-form in human tissues and its astonishing biological activity as an anti-tumor immunotherapeutic agent has been one of the pleasant surprises of this year (and has featured earlier this year in this blog). Indeed, I understand that it is undergoing clinical trials as an anti-tumor agent. One major difficulty in studying its metabolism and function is the low levels at which it occurs naturally in tissues (0.02% of the total galactosylceramides in RBL-CD1d cells, for example). A new LC-MS2 separation of the stereoisomers has now been described that appears to solve the problem (von Gerichten, J. et al. Diastereomer-specific quantification of bioactive hexosylceramides from bacteria and mammals. J. Lipid Res., 58, 1247-1258 (2017); DOI). As this lipid is produced by intestinal bacteria, it is a useful reminder after my previous two blogs that bacteria have many virtues and they are not always harmful. It is a truism that advances in methodology often lead to advances in the science, so watch this space. If I want to be picky, I would raise my old chestnut that the term "hydrophilic interaction chromatography" applied to the separation is meaningless unless we know more about the nature of the stationary phase. In fairness to authors, the manufacturers are often silent on this point.

The Journal of Steroid Biochemistry and Molecular Biology has published a special issue on the topic of "Oxysterols: Players in Different Metabolic Leagues" (Volume 169, Pages 1-234 (May 2017)) and edited by Luigi Iuliano, Dieter Lütjohann, Gérard Lizard and Ingemar Bjorkhem.

May 31st, 2017

Scottish thistleWe can never fully free ourselves of the national and occupational stereotypes that are part of our cultural heritage, and I am sure my readers will have an idea at the back of their mind of a "typical" Scotsman. Our view of Russians and scientists is of a very serious and possibly humorless people, so it was a rather pleasant surprise to find an item in Nature NewsDOI ) regarding a 'Monument to an Anonymous Peer Reviewer' outside the Higher School of Economics in Moscow. Immortalized in concrete, "the sculpture takes the form of a die displaying on its five visible sides the possible results of review - 'Accept', 'Minor Changes', 'Major Changes', 'Revise and Resubmit' and 'Reject'." One more stereotype bites the dust.

Phosphatidylserine is known to have an important role in the regulation of apoptosis or programmed cell death, the natural process by which aged or damaged cells are removed from tissues before they can exert harmful effects. A new review (open access) gives a clear explanation of the process in relation to erythrocytes, where phosphatidylserine is located in the inner leaflet of the membrane bilayer under low Ca2+ conditions when a phospholipid scramblase is suppressed by membrane cholesterol, but it is exposed to the outer leaflet under elevated Ca2+ concentrations which activate the scramblase (Arashiki, N. and Takakuwa, Y. Maintenance and regulation of asymmetric phospholipid distribution in human erythrocyte membranes: implications for erythrocyte functions. Curr. Opinion Hemat., 24, 167-172 (2017); DOI). The phosphatidylserine on the outer leaflet of the cell is then recognized by a receptor on the surface of macrophages and related scavenger cells, and these proceed to remove the apoptotic cells in a non-inflammatory manner.

Last week, I discussed two reviews that dealt with the sneaky ways pathogens made use of the lipids of their hosts for their own nefarious purposes. A new review that has the virtue of being open access discusses this in relation to cholesterol specifically (Samanta, D. et al. Manipulation of host cholesterol by obligate intracellular bacteria. Front. Cell. Inf. Microbiol., 7, 165 (2017); DOI). To gain entry into cells, pathogens utilize the cholesterol-rich microdomains in membranes known as rafts. Then, it is apparent that they can manipulate host cholesterol metabolism, including uptake, efflux, and storage, to access nutrient-rich vesicles or acquire membrane components. They also hijack the host cell signaling pathways involving cholesterol that are favorable for their intracellular survival.

The Journal of Experimental Botany has a special issue devoted to the "The Flowering of Jasmonate Research" (1 March, 2017).

May 24th, 2017

A week in the Canary Islands has taken my mind off lipid science for a time, but now I have twice as many papers as usual to read. A catchy title to a review often heralds a more entertaining discussion to follow as in this instance (Pathak, D. and Mallik, R. Lipid - motor interactions: soap opera or symphony? Curr. Opinion Cell Biol., 44, 79-85 (2017); DOI). Motor proteins are here defined as "ATPases that convert chemical energy into mechanical energy to drive many cellular functions including intracellular transport of vesicles". These enzymes require interactions with specific lipids, especially the phosphoinositides and cholesterol, to direct them to specific membranes. As to "soap opera etc", read the first paragraph for an elegant explanation of the analogy. The protein can have highly specific binding sites for particular lipids or it can indirectly react to membrane curvature induced by characteristic lipid head groups. Here much of the discussion focuses on the endosome/phagosome compartment partly because of the importance to normal cellular metabolism, and partly because pathogens in phagosomes use the lipid interactions to survive in host cells. Incidentally, there is a rather substantial new (if relatively inaccessible) book chapter that relates to the latter process (Fozo, E.M. and Rucks, E.A. The making and taking of lipids: the role of bacterial lipid synthesis and the harnessing of host lipids in bacterial pathogenesis. Adv. Microb. Physiol., 69, 51-155 (2016); DOI).

I am a spectator only to modern mass spectrometric techniques, but I have the impression that advances in software and data management are as important as those in instrumentation in driving what can now be achieved. For example, LipidFinder optimizes analysis based on users' own data, and a new open access publication describes its use to identify three 12-hydroxyeicosatetraenoic acid phosphoinositides in thrombin-activated platelets (O'Connor, A. et al. LipidFinder: A computational workflow for discovery of lipids identifies eicosanoid-phosphoinositides in platelets. JCI Insight, 2, e91634 (2017); DOI). Another research group describes the use of the software IE-Omics to automate data acquisition by MS/MS in sequential injections to improve the coverage of the lipidome especially with regard to trace species (Koelmel, J.P. et al. Expanding lipidome coverage using LC-MS/MS data-dependent acquisition with automated exclusion list generation. J. Am. Soc. Mass Spectrom., 28, 908-917 (2017); DOI).

The therapeutic potential of docosanoids such as the resolvins is increasingly becoming evident, and an application of 17(R)-hydroxy-docosahexaenoic acid to the relief of pain in osteoarthritis, if not yet the underlying cause, in animal models is described in a new publication hopefully as a prelude to clinical studies (Huang, J.T. et al. Targeting the D series resolvin receptor system for the treatment of osteoarthritis pain. Arthritis Rheumatol., 69, 996-1008 (2017); DOI).

May 10th, 2017

There is a short series of reviews on the theme of 'Lipid Methodology' (edited by Howard Goldfine and Ziqiang Guan) in a recent issue of Analytical Biochemistry (Volume 524, Pages 1-76 (1 May 2017)). One of these dealing with cholesterolomics is open access, but the one that caught my eye especially deals with the various modes of high-performance liquid chromatography that can be applied for the separation of regio- and stereoisomers of triacylglycerols (Rezanka et al. Regioisomeric and enantiomeric analysis of triacylglycerols. Anal. Biochem., 524, 3-12 (2017); DOI). Modern mass spectrometric methods dominate the recent analytical literature, but they cannot accomplish stereospecific analysis of triacyl-sn-glycerols, so I am always encouraged to see that alternative methods are still being pursued.

Some months ago, my attention was drawn to the fact that some subjects were being reviewed to exhaustion, with more than 20 reviews a year devoted to each of the topics of phosphoinositides and sphingosine-1-phosphate in particular. Of course, the reason these topics receive so much attention is because they are so dynamic and there is much important new research to discuss. Therefore, I make no apology for drawing your attention to a new review dealing with sphingosine-1-phosphate, which among its many virtues is open access (Pyne, N.J. and Pyne, S. Sphingosine 1-phosphate receptor 1 signaling in mammalian cells. Molecules, 22, 344 (2017); (2017); DOI).

May 3rd, 2017

One of the more surprising lipid discoveries in recent years has been fatty acids with a centrally located hydroxyl group to which a further fatty acid is linked as an estolide or 'FAHFA' (Fatty Acid Hydroxy Fatty Acid), such as the palmitoyl ester of 9-hydroxy-stearic acid (note that both component fatty acids are fully saturated), which was first found in the adipose tissue of mice. These have anti-diabetic and anti-inflammatory effects, even when administered orally, and they protect against colitis by regulating gut innate and adaptive immune responses. Although details of the biosynthesis have still to be established, there seems little doubt that they are formed endogenously as a new study has established that the hydroxyl group has defined stereochemistry, i.e. it is of the R-configuration (Nelson, A.T. et al. Stereochemistry of endogenous palmitic acid ester of 9-hydroxystearic acid and relevance of absolute configuration to regulation. J. Am. Chem. Soc., 139, 4943-4947 (2017);   DOI). Unfortunately, I am dependent on the abstract for this information as access is closed to non-subscribers.

I try to keep up with with the plethora of new eicosanoids and docosanoids that continue to be discovered, but I did not realize that more than 70 oxygenated metabolites of docosahexaenoic acid (DHA) had been discovered to date as summarized in a new review (Kuda, O. Bioactive metabolites of docosahexaenoic acid. Biochimie, 136, 12-20 (2017);  DOI). Included among these are FAHFA derived from essential fatty acids, i.e. with 14-hydroxydocosahexaenoic acid (14-OH-DHA) esterified to 9- and 13-hydroxyoctadecadienoic acids, for example; these have profound anti-inflammatory effects.

A few weeks ago, I pointed out here that the Journal of Lipid Research had taken a retrograde step in closing access to papers that had been accepted but were still in manuscript form. Either this was a technical error or they have seen the error of their ways and this policy has now been reversed.

April 26th, 2017

Scottish thistleUrine samples are usually regarded as the easiest non-invasive method of obtaining samples for analysis, but then any metabolites have passed through the kidney and may have been substantially altered. I had not considered human tears for this purpose, but it seems that tear fluid can serve as a means to identify and monitor novel biomarkers in ocular and systemic disease, and in particular the specialized pro-resolving mediators (SPMs). For example, resolvin D1, protectin D1, lipoxin A4, and resolvin E1 are accessible in this way in quantities that are known to be active biologically (English, J.T. et al. Identification and profiling of specialized pro-resolving mediators in human tears by lipid mediator metabolomics. PLEFA, 117, 17-27 (2017);   DOI). When I first saw the title, it brought to mind the old Julie London song "Cry me a River", but it seems that only 100μl of tears obtained "through an induction of an emotional response" were required for the identification and quantification of 21 different metabolites. This seems an astonishing example of the sensitivity of modern mass spectrometric methodology. The results are also surprising in that while SPMs were detected in male donors, they were essentially absent in females. Incidentally, if any of my younger readers don't know the above song (or the Barbra Streisand version), a treat awaits you.

Another record appears to have been broken in that trace levels of highly unsaturated fatty acids of the (n-3) family suggested to be 38:7(n-3) to 44:12(n-3) have been reported from brains of patients with genetic impairments of peroxisome function. The last must be the most highly unsaturated fatty acid of conventional origin known (Takashima, S. et al. Detection of unusual very-long-chain fatty acid and ether lipid derivatives in the fibroblasts and plasma of patients with peroxisomal diseases using liquid chromatography-mass spectrometry. Mol. Gen. Metab., 120, 255-268 (2017);  DOI).

April 19th, 2017

Some years ago, I took issue with the LipidMaps consortium over some aspects of their lipid classification system. In particular, I though they were wrong to create a distinct class for glycerophospholipids while lumping glycosyldiacylglycerols in with triacylglycerols. As glycosyldiacylglycerols can substitute for phospholipids under conditions of phosphate deprivation in plants and both function exclusively in membranes, I believed that both groups should have the same ranking. Apparently, I did not persuade them as the ranking did not change. One lipid that is particularly anomalous in this classification is the highly polar plant sulfolipid sulfoquinovosyldiacylglycerol, which cannot be compared with storage lipids in any respect; it is the subject of a new review (Goddard-Borger, E.D. and Williams, S.J. Sulfoquinovose in the biosphere: occurrence, metabolism and functions. Biochem. J., 474, 827-849 (2017);   DOI). As access is closed to non-subscribers, I am grateful to a friend for giving me a sight of it. While I was familiar with much of what the authors had to say about the biochemistry and function, I was not aware that it was such an important component of the sulfur cycle in the biosphere. The total annual synthesis of sulfolipid is thought to be of the order of 1013 kg per annum!

The March issue of Biochimie (Volume 134, Pages 1-138 (March 2017)) contains a number of articles with the theme of brown fat metabolism (Edited by Frédéric Bouillaud, Louis Casteilla, Susanne Klaus and Bruno Miroux). The May issue of this journal (Volume 136, pages 1-104) is devoted to "Pleiotropic physiological roles of PPARs and fatty acids: A tribute to Paul Grimaldi" (edited by Nada A. Abumrad, Ez-Zoubir Amri, Serge Luquet and Claude Forest).

Fatty acid binding proteins (FABPs) are a family of small cytoplasmic proteins that are highly conserved and as the name suggests bind long-chain fatty acids; they facilitate the transfer of fatty acids between extra- and intracellular membranes and receptors. Of these, FABP7 is located in astrocytes of the brain and binds DHA with the highest affinity. It is now reported to be required for normal sleep in humans and other animals. There is a brief popular report in Sci News with a link to the original article.

I have come across the Latin expression "in silico" in the titles of several recent publications, and I now understand that this means "in silicon" strictly speaking but is used to mean "performed on computers or via computer simulation". Those ancient Romans were cleverer than I would have believed if they knew of silicon and anticipated the use of computers.

April 12th, 2017

An item in Nature News drew my attention to Unpaywall - a free web-browser extension that hunts for papers in more than 5,300 repositories worldwide, including preprint servers and institutional databases, to find freely accessible (and legal) copies of research articles. It is an add-on to Firefox or Google Chrome that is quick and easy to install and use. In a brief trial, it found me one paper quickly that I needed to update these pages, and just as importantly found that two of interest were not available yet as open access so saving time in fruitless searching. The article in Nature suggests that more such tools are on the way.

The titles of some publication simply shout for attention (e.g. Li, X.B. et al. The slim, the fat, and the obese: guess who lives the longest? Current Genetics, 63, 43-49 (2017);   DOI). It appears that there is a phenomenon called the "obesity paradox" in that the overweight population enjoys the lowest rate of mortality from all causes in contradiction to everything that scientists and clinicians think they know. The authors believe that the answer may lie in a new cytoprotective function of triacylglycerols. As a relatively lean 140 pounder, should I be worried? Certainly, I wont feel guilty next time I am offered a big sugary doughnut with my morning coffee.

Fascinating new lipids are discovered all the time, but occasionally nature springs a nasty surprise. The latest in this category are alkyl cyanides produced by bacterial species. These can be either unbranched saturated or unsaturated with an omega-7 double bond, such as (Z)-11-octadecenenitrile, or methyl-branched unsaturated cyanides with the double bond located at C-3, such as (Z)-13-methyltetradec-3-enenitrile. Fatty acids are the biosynthetic precursors, and these are first converted into their amides and then dehydrated. While their functions are not yet known, some of these nitriles showed bactericidal activity; any possible homicidal properties were not investigated (Vidal, D.M. et al. Long-chain alkyl cyanides: unprecedented volatile compounds released by Pseudomonas and Micromonospora bacteria. Angew. Chem.-Int. Ed., 56, 4342-4346 (2017);   DOI). Some plant species contain cyanolipids but of a very different kind.

Formula for an alkyl cyanide

April 5th, 2017

I have commented on the uniqueness of cardiolipin in this blog on many occasions in the past, usually in relation to its special functions in membranes. Perhaps the most distinctive feature is that it possesses a dimeric structure in essence with four acyl groups arranged in a very limited range of molecular species. In heart muscle, for example, linoleate makes up 80% of the total fatty acids, so a high proportion of the lipid exists as the tetralinoleoyl species. This composition is attained after its initial synthesis by a remodelling process, catalysed by the enzyme tafazzin, which transfers fatty acids from other phospholipids by a mechanism that does not require a coenzyme A ester as an intermediate, and it is reversible. The question has arisen as to whether the fatty acid specificity is inherent in tafazzin per se or is dependent on thermodynamic considerations. It now appears that the question has been answered definitively by two papers from the laboratory of Professor Michael Schlame (Schlame, M. and Greenberg, M.L. Biosynthesis, remodeling and turnover of mitochondrial cardiolipin. Biochim. Biophys. Acta, 1862, 3-7 (2017);   DOI; Schlame, M. et al. The basis for acyl specificity in the tafazzin reaction. J. Biol. Chem., 292, 5499-5506 (2017);   DOI). It seems now to be established that sufficient energy differences arise from the packing properties of the entire lipid assembly in the membrane to enable tafazzin to catalyse the remodeling of cardiolipin by combinations of forward and reverse transacylations, essentially creating an equilibrium distribution of acyl groups. The shape of tetralinoleoyl-cardiolipin is such that it fits the geometry of negatively curved monolayers particularly well so this structure is favoured.

It seems that we now have a good understanding of the nature of the complex phytoglycosphingolipids from higher plants, although much remains to be learned of their biochemistry and especially their function. However, following the recent discovery of inositol phosphorylceramide glucuronosyltransferase 1, i.e. the first enzyme in the GIPC glycosylation pathway, it has now been shown that these highly polar membrane lipids are essential for normal growth and function in Arabidopsis (Tartaglio, V. et al. Glycosylation of inositol phosphorylceramide sphingolipids is required for normal growth and reproduction in Arabidopsis. Plant J., 89, 278-290 (2017);   DOI).

March 29th, 2017

Scottish thistleProfessor Roscoe O. Brady (1923-2016) will long be revered as one of the pioneers of research into the sphingolipidoses and especially Gaucher's disease. In large part through his efforts, an effective enzyme replacement therapy has been developed for one form of this disease. As part of a Festschrift in his honour in the journal Molecular Genetics and Metabolism, his many colleagues have published their personal reminiscences and insights into his accomplishments (Desnick, R.J. et al. Roscoe Owen Brady, MD: Remembrances of co-investigators and colleagues. Mol. Gen. Metab., 120, 1-7 (2017);  DOI). This tribute is accompanied by a number of further papers relevant to this topic.

According to Nature News ([Link]), the Gates Foundation has announced a new open-access publishing venture modeled on that of the Wellcome Trust. The open-access movement in general seems to be gaining momentum, a boon to someone like myself who has more limited access to journals than those with university positions. In the biological sciences, we tend to be more fortunate than those whose primary interest is chemistry, but there are occasional backward steps. For example, the Biochemical Journal used to allow full access after one year - now 2013 is the last year to which this applies. The Journal of Lipid Research has just stopped access to papers in manuscript form ahead of publication, although I assume that they will still be available one year after publication. I don't recall seeing any formal announcements of these changes.

March 22nd, 2017

Proteolipids are protein lipid conjugates in which the lipid portion is necessary to direct the protein to a membrane where it is required for a specific function. Many of these are signalling proteins (e.g. receptors, G-proteins, protein tyrosine kinases) with implications for the relevant signalling events at the cell surface, and many influence human disease states and are potential pharmacological targets. For example, deregulation of S-palmitoylation has been associated with heart disease, cancer, mental retardation and schizophrenia. A correspondent has brought to my attention a new website that is both informative and elegantly designed that covers the topic of S-palmitoylation, i.e.

HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) is a very different type of protein-lipid complex. The protein component is α-lactalbumin, which is the most abundant protein in human breast milk and normally exists in a tightly packed globular conformation stabilized by four disulfide bridges and a divalent calcium ion. The lipid is oleic acid, and this is not linked covalently but by nonspecific hydrophobic interactions in the loosely organized hydrophobic core of the protein when it is in a molten globular state, as is produced during casein precipitation at low pH. The HAMLET complex can be internalized into cancer cells where it initiates a series of metabolic changes that can result in cell death. In human clinical studies, HAMLET has been shown to be efficacious against skin papillomas and bladder cancers, as well as against many other cancers in animal models. A new review summarises progress with this fascinating molecular complex (Ho, J.C.S. et al. HAMLET - A protein-lipid complex with broad tumoricidal activity. Biochem. Biophys. Res. Commun., 482, 454-458 (2017);  DOI).

A title such as "Masochistic Enzymology: Dennis Vance's Work on Phosphatidylcholine" should catch the eye of most readers. To find what it means, follow this Link to a brief open access commentary in the Journal of Biological Chemistry.

March 15th, 2017

Oxidized phospholipids are important biological mediators, and it is increasingly being recognized that oxylipins of various kinds are esterified to glycerophospholipids, which may serve in part as reservoirs from which they can be released rapidly upon stimulation by various means or the oxidized glycerophospholipids may have biological activities of their own. This is perhaps more surprising when oxylipins formed by non-enzymatic means are concerned, but there appears to be ample evidence that isoprostanes can act in this way. For example, an oxidized species derived from sn-2-arachidonoyl phosphatidylcholine has been shown to modulate the expression of a large number of genes in human aortic endothelial cells, and it is also a potent activator of the peroxisome-proliferator-activated receptor (PPARα).

Similarly, phospholipids that have been oxidatively cleaved to produce "core-aldehydes" have biological activities that resemble those of platelet-activating factor, while other related phospholipids interact with receptors that are normally associated with the recognition of microbial pathogens, as discussed in separate web pages.

Phosphatidylcholine is the most common phospholipid in animal cells, and it is not recognized by any pattern-recognition receptors in native low-density lipoproteins (LDL) or on the surface of cells. However, once oxidized it becomes a key ligand that, for example, mediates the binding of oxidized LDL to receptors, which are normally believed to have very different binding characteristics in relation to microbial pathogens. A concept has been developed of the formation of damage-associated molecular patterns (DAMPs) that arise from the oxidative damage of lipids and lipoproteins. These share common structural motifs with microbial pathogen-associated molecules, and so they activate the same pattern-recognition receptors that are present on the surface of macrophages and of immune and vascular cells. This enables them to initiate many different inflammatory signalling processes. A new review deals with this topic (Miller, Y.I. and Shyy, J.Y.J. Context-dependent role of oxidized lipids and lipoproteins in inflammation. Trends Endocrinol. Metab., 28, 143-152 (2017);  DOI).

Most work on this problem has been concerned with phosphatidylcholine, but a new analytical study has examined the nature of the oxidized phosphatidylinositol in LDL. Of course, there is much less of this phospholipid but it is highly unsaturated so it may make a sigificant contribution to oxidative stress (Hasanally, D. et al. Identification of oxidized phosphatidylinositols present in OxLDL and human atherosclerotic plaque. Lipids, 52, 11-26 (2017);   DOI). Now, the knowledge of what is there should be a stimulous to biological studies

March 8th, 2017

The latest Fats of Life Newsletter was a welcome arrival in my email inbox this week. In addition to the usual section on highlights from the recent literature, it contains two original articles of which I can certainly recommend that entitled "F3-isoprostanes and F4-neuroprostanes: non-enzymatic cyclic oxygenated metabolites of omega-3 polyunsaturated fatty acids: biomarkers and bioactive lipids" (by Galano, G.M. and 7 others), as it will be helpful in updating my web pages here.

When I do my weekly search for new lipid analysis publications, I try to list only those that demonstrate something that is truly new either in terms of the methodology or the sample under analysis. Nowadays, the result is a list of papers dealing mainly with mass spectrometry of lipids, which generally show only minor improvements on what has gone before. Please do not think that I am being disparaging here, as this is how science usually works. Only rarely do I find a publication that marks a step forward simply in chromatography terms these days, but a new paper describing the separation of regio-isomers of triacylglycerols by reversed-phase HPLC seems to fall into this category (Sompila, A.W.G.T. et al. Fast non-aqueous reversed-phase liquid chromatography separation of triacylglycerol regioisomers with isocratic mobile phase. Application to different oils and fats. J. Chromatogr. B, 1041, 151-157 (2017);  DOI). Although such separations have been demonstrated before with model mixtures, the methodology now seems to have reached a stage where it is applicable to natural samples.

I tend to take a cursory note only of new publications that deal with most clinical aspects of lipid science and leave these for others elsewhere to comment, as this topic lies outside my area of expertise. However, I can't resist a mention of a new paper (open access) dealing with sphingosine-1-phosphate (Soltau, I. et al. Serum-sphingosine-1-phosphate concentrations are inversely associated with atherosclerotic diseases in humans. PLOS One, 11, e0168302 (2016);  DOI). The authors demonstrate that decreased serum concentrations of this lipid are better markers of peripheral artery disease and carotid stenosis than is HDL cholesterol. Regretfully, I suspect that it will be some time before HPLC linked to tandem mass spectrometry becomes a routine screening tool for this purpose.

March 1st, 2017

Arachidonic acid is not present in higher plants, other than two species of Gymnosperms; I discount other alleged occurrences as not adequately characterized. However, it is present in lower plants such as algae, mosses and ferns. In a new systematic search for arachidonic acid in the plant kingdom (open access), the earlier findings were confirmed together with an inverse correlation between the concentration of this acid and that of the plant hormone jasmonic acid (Gachet, M.S. et al. Targeted metabolomics shows plasticity in the evolution of signaling lipids and uncovers old and new endocannabinoids in the plant kingdom. Sci. Rep., 7, 41177 (2017);  DOI). A further interesting discovery was the presence of two novel "endocannabinoid-like" molecules derived from 5,11,14,17-eicosatetraenoic or juniperonic acid, an omega-3 structural isomer of arachidonate, namely juniperoyl ethanolamide and 2-juniperoyl glycerol in gymnosperms. I don't like the use of the term "endocannabinoid" in the title as this implies the existence of a specific receptor, but I can accept "endocannabinoid-like" from the abstract. Semantics aside, this seems to be an interesting report that may be relevant to the evolution of signalling pathways in plants.

A correspondent has brought a paper to my attention that demonstrates the occurrence of the systemic oxidative stress marker 8-isoprostane in sewage, with the suggestion that it may be a marker for general health in different populations; the authors report a 5-fold change from three sewage collection points supplied by different communities located in the Detroit metropolitan area (Santos, J.M. et al. Could sewage epidemiology be a strategy to assess lifestyle and wellness of a large scale population? Medical Hypotheses, 85, 4080411 (2015);  DOI). Whatever the answer to the question posed by the authors, it is a novel application of lipid analytical methodology and a tribute to its sensitivity.

February 22nd, 2017

Scottish thistle Gangliosides are essential constituents of the central nervous system and of some non-neural tissues. They are arguably the least lipid-like of all animal lipids, by some definitions at least, in that they are as soluble in water as in many of the organic solvents used for extracting lipids from tissues. The hydrophobicity is due to a complex oligosaccharide component to which highly polar sialic acid units are attached, i.e. N-acetylneuraminic acid and its metabolite N-glycolylneuraminic acid, which differ only by the presence of one oxygen atom in the acyl moiety. Both sialic acids are present in nearly all animal species including other primates such as the great apes. Humans are the sole exception in that they lack gangliosides containing N-glycolylneuraminic acid. We have the genes that are required to produce this, but they have been irreversibly silenced. As far as I am aware, this is the only important biochemical distinction between humans and apes, and it is regarded as a major biochemical branch-point in human evolution. It may even be a factor in the superior performance of the human brain. We cannot test evolutionary hypotheses, but the relevance of gangliosides containing N-glycolylneuraminic acid to brain function can be tested in experimental animals at least as in a new publication (Naito-Matsui, Y., et al. Physiological exploration of the long term evolutionary selection against expression of N-glycolylneuraminic acid in the brain. J. Biol. Chem., 292, 2557-2570 (2017);  DOI). The results show that in transgenic mice in which expression of N-glycolylneuraminic acid was enhanced in the brain, the consequence was "abnormal locomotor activity, impaired object recognition memory, and abnormal axon myelination"; the transgenic mice were also lethally sensitive to a specific bacterial toxin. Whatever caused this evolutionary change appears to have done us a favour. The paper is an editor's choice and is open access.

There is a new paper entitled "Localized aliphatic organic material on the surface of Ceres" (De Sanctis, M.C. et al. Science, 355, 719-722 (2017);  DOI). Or see the more accessible report in Sci-News. Are there fatty acids in space?

February 15th, 2017

The isoprostanes are fascinating lipid mediators produced by non-enzymatic mechanisms that closely resemble the prostaglandins in structure. Indeed, so close is the similarity that it has been suggested that during evolution, the first primitive animals found these molecules so useful for signalling purposes that they developed enzymatic methods to produce analogues on demand in response to specific stimuli. Because of their formation by simple chemical reactions, one major difference is that the isoprostanes are produced as many different structural and stereo-isomers, while prostaglandin synthesis is highly stereospecific. Another important difference is that isoprostanes are produced while esterified to complex lipids in membranes, while prostaglandins are synthesised as the free acids. The latter fact is attracting special interest now as it has become apparent that lipid-bound isoprostanes are involved in many biological reactions, in part simply by causing disruption to membranes but also by highly specific interactions with receptors and proteins in general. A new review suggests that phosphatidylcholines containing isoprostanes with an cyclopentenone structural motif are potent pro-resolution mediators like the protectins, resolvins and maresins. In this instance, the cyclopentenone unit, an electrophilic α,β-unsaturated carbonyl moiety, can form covalent adducts with cysteine residues by Michael addition. Then, activation of the antioxidant response factor Nrf2 in this way might be one of a number of reasons for the anti-inflammatory effects (Friedli, O. and Freigang, S. Cyclopentenone-containing oxidized phospholipids and their isoprostanes as pro-resolving mediators of inflammation. Biochim. Biophys. Acta, 1862, 382-392 (2017);  DOI).

This review is part of a special issue of Biochim. Biophys. Acta - Molecular and Cell Biology of Lipids (Volume 1862, Issue 4, Pages 369-440 (April 2017)) dealing with the topic of "Lipid modification and lipid peroxidation products in innate immunity and inflammation" (edited by Christoph J. Binder).

February 8th, 2017

I have mentioned JOVE-Journal of Visualized Experiments before in this blog. It contains laboratory protocols for many types of analytical method, and is unique in that it supplements the written procedures with online videos showing in detail how to go about each analysis. Happily, it is also largely open access. Nowadays, I am an armchair scientist, but I enjoy viewing these videos, if only to see how others go about procedures with which I have some familiarity. Often they use different types of glassware, or equipment for handling samples with which I am not acquainted. I sometimes bring them to the attention of my former colleagues, not so that they should change how they go about things but simply to give them a fresh viewpoint. Two recent publications from this journal are relevant to my past research interests (Ginies, C. et al. Identification of fatty acids in Bacillus cereus. J. Vis. Exp., 118, e54960 (2016);  DOI; and Quideau, S.A. et al. Extraction and analysis of microbial phospholipid fatty acids in soils. J. Vis. Exp., 114, e54360 (2016);  DOI). Although both topics may appear rather specialized at first glance, many aspects of the methodology have more general applications. For example, the first illustrates the preparation of dimethyloxazoline (DMOX) and 3-pyridylcarbinol esters of fatty acids for mass spectrometry, while the second shows how to prepare a phospholipid fraction by solid-phase extraction methodology. There are some parts of both publications that I might prefer to do differently, but they are very useful guides for the novice while the expert can always learn something new.

February 1st, 2017

Studies of the occurrence and biochemistry of nitro adducts of unsaturated fatty acids only started in a systematic way in 1999 with the discovery that were present in the membrane phospholipids of human tissues in vitro and in vivo, and at concentrations that had the potential to exert biological effects. Now, their biology is a highly dynamic subject, not least because it has been demonstrated that they afford protection from inflammatory injury in several experimental models and so have therapeutic potential. In addition, they are electrophiles with a propensity to undergo reversible Michael addition reactions with cellular nucleophiles such as cysteine and histidine-containing peptides and proteins with further effects upon metabolism. While many different fatty acids can act as precursors, it has become evident that conjugated linoleate (CLA) isomers are by far the most active. A new important paper on the topic is a mechanistic and kinetic study of the reaction of CLA with thiols in the Journal of Biological Chemistry; it is the editor's choice and is therefore open access (Turell, L. et al. The chemical basis of thiol addition to nitro-conjugated linoleic acid, a protective cell-signaling lipid. J. Biol. Chem., 292, 1145-1159 (2017); DOI). Amongst many interesting findings, CLA reacts rapidly with thiols occur form adducts both β and δ to the nitro group, especially the latter. Indeed, the cysteine-δ-adducts have been detected in human urine.

Another paper from the same group (also open access) describes how nitro-fatty acids are catabolized and eliminated from the body in the urine. The main metabolite is 4-nitro-octanedioic acid (NO2-8:0-diCOOH) (Salvatore, S.R. et al. Evaluation of 10-nitro oleic acid bio-elimination in rats and humans. Sci. Rep., 7, 39900 (2017);   DOI). Stop Press: the February issue of the Journal of Lipid Research will contain a paper on the metabolism of nitro fatty acids in adipose tissue.

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Author: William W. Christie Updated: June 28th, 2017 Credits/disclaimer LipidWeb logo