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Lipid Matters - Archive of Older Blogs - 2015

This Blog is an occasional series of notes on publications or other items dealing with lipid science that seem to be of particular interest to the editor Bill Christie. Inevitably, the selection is highly personal and subjective. In this web page, the blogs for 2015 are archived, while those for other years can be accessed from the foot of the current blog page.

December 30th, 2015

Scottish thistlePhosphatidylthreonine (PtdThr) is a little known lipid first found at trace levels in brain and subsequently in a few other animal tissues and some bacterial species. It is now reported to be a major phospholipid of the protozoan parasite Toxoplasma gondii, which can infect animals and humans. As this is the holiday period, I trust readers will forgive me if I simply quote from the authors' summary - "PtdThr is made by a novel parasite-specific enzyme, PtdThr synthase, which has evolved from the widespread enzyme phosphatidylserine synthase. The study shows that PtdThr is required for asexual reproduction and virulence of the parasite in vivo, and a metabolically attenuated mutant strain of Toxoplasma lacking PtdThr can protect vaccinated mice against acute and currently incurable chronic infection. This discovery demonstrates adaptive "speciation" of PtdThr from an otherwise near-universal membrane lipid phosphatidylserine and reveals de novo PtdThr synthesis in T. gondii as a potential drug target." (Arroyo-Olarte, R.D. et al. Phosphatidylthreonine and lipid-mediated control of parasite virulence. PLoS Biol., 13, e1002288 2015; DOI). The paper is open access. I suspect that this fascinating lipid will now become more than an academic curiosity.

Formulae of phosphatidyl-L-threonine

There is an impression that the modern approach to lipid analysis is simply a matter of injecting a sample into a mass spectrometer together with appropriate standards and letting the instrument and a computer do the work - the "shotgun" technique. While this is obviously a very great over-simplification, there is increasingly an element of truth when it is applied to the analysis of the main lipid constituents of animal and plant tissues. Because of its relative simplicity, high sample throughput and cost-effectiveness, this approach has proved its value in innumerable applications. However, it fails when it comes to the analysis of minor lipids, which can be those with key biological functions. Often these are masked by major lipid components of the same molecular weight, e.g. phosphatidylglucoside by phosphatidylinositol. Combining mass spectrometry with HPLC can lead to major improvements in the number of lipid species detected, but the chromatography step can itself be challenging, especially with plant lipids where the analysis of glycosylinositolphosphoceramides presents real difficulties. A new lipidomics platform based on a single extraction step followed by a series of ultra-performance liquid chromatography separations directed to both a triple quadrupole analyzer for targeted profiling and a time-of-flight analyzer for accurate mass analysis yielded 393 molecular species within 23 different lipid classes from leaves. This is more than twice as many as the previous best. An application to drought affected plants has provided new insights into how the plant responds (Tarazona, P. et al. An enhanced plant lipidomics method based on multiplexed liquid chromatography-mass spectrometry reveals additional insights into cold- and drought-induced membrane remodelling. Plant J., 84, 621-633 (2015); DOI).

December 23rd, 2015

There has been a long search for a universal detector for HPLC of lipids, starting with the transport-flame ionization detector, which had its good points but ultimately was a commercial failure. Then came the evaporative light-scattering detector (ELSD), which I made good use of in my own research, though I always preferred to use it with a stream-splitter as a micro-preparative tool rather than for direct quantification. In recent years, two variants on this have become available - the condensation-nucleation light-scattering detector (CNLSD), commercially known as the nano-quantity analyte detector (NQAD) and the charged-aerosol detector (CAD). So far I have seen only a handful of applications to lipid analysis with these. A new review examines the general properties of each of the three critically (Magnusson, L.E. et al. Aerosol-based detectors for liquid chromatography. J. Chromatogr. A, 1421, 68-81 (2015); DOI). The general conclusion appears to be that the CNLSD/NQAD is much the most sensitive with a linear response of at least two orders of magnitude. However, it is also responsive to impurities in the solvents, which would preclude its use with mobile phases containing ionic species as is essential for many lipid applications. Incidentally, the same issue of the journal has a useful review on detectors for gas chromatography.

I have established search parameters that I use with the Web of Science to keep myself and the literature survey pages here up to date. This means that I scan rapidly through the titles of 400 or more papers every week to select the few that I can list in my data base and the even fewer that I can take the time to read. Of course, there are innumerable new publications that simply escape my attention. One such published last year, which I have just come across, deals with what appears to be an important new class of lipids, termed "branched fatty acid esters of hydroxy fatty acids (FAHFAs)" by the authors, although they should more simply be called 'estolides' perhaps (Yore, M.M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell, 159, 318-332 (2014); DOI). I illustrate the palmitoyl ester of 9-hydroxystearate as an example.

Estolide of palmitic and 9-hydroxystearic acids

These were found in the adipose tissue of mice and more recently in eggs, and they exert their biological effects via specific receptors. Although little is yet known of their biosynthesis, it has been demonstrated that they are produced endogenously. It is also significant that they are anti-inflammatory but are not derived from essential fatty acids in contrast to the eicosanoids and docosanoids.

I wish all who read these pages a very happy Christmas and all the best for the New Year!

December 16th, 2015

Bis(monoacylglycero)phosphate is a fascinating lipid, not least in that the stereochemistry of the glycerol moiety is the opposite of that in all other phospholipids. Much remains to be learned of the mechanism of biosynthesis, and even its structure in membranes is in doubt because of the ease with which acyl migration can occur. It is enriched in the endosomal membranes of cells in the liver and other tissues, where its stereochemistry ensures that it is not readily digested along with other lipids by the well-known phospholipases. On the other hand, there has to be a mechanism that enables turnover and a new study demonstrates that a hydrolase designated ABHD6, once thought to be mainly a monoacylglycerol lipase, is able to accomplish this with high specificity in liver (Pribasnig, M.A. et al. α/β Hydrolase domain-containing 6 (ABHD6) degrades the late endosomal/lysosomal lipid bis(monoacylglycero)phosphate. J. Biol. Chem., 290, 29869-29881 (2015); DOI).

Protein palmitoylation is an essential mechanism in cells to translocate proteins from the cytosol to membranes in a reversible manner. For many years, there was a debate as to whether this was an autocatalytic or an enzymatic process, and this was eventually settled when it was recognized that a family of protein transacylases existed that carried out the reaction; however, these enzymes were themselves palmitoylated autocatalytically. The acyltransferases of which 23 are known in humans are membrane proteins with a number of subcellular locations that span the bilayer at least four times and with a characteristic DHHC motif in a cysteine-rich domain facing the cytosol. It has now been shown that in one of these enzymes at least, the cysteine in the DHHC motif is palmitoylated autocatalytically in the presence of palmitoyl-CoA, before the palmitoyl residue is transferred from this intermediate to a target protein (Gottlieb, C.D et al. The cysteine-rich domain of the DHHC3 palmitoyltransferase is palmitoylated and contains tightly bound zinc. J. Biol. Chem., 290, 29259-29269 (2015); DOI). I have updated the figure in my web page on this topic, which I trust illustrates the mechanism.

Following my comments last week, a new study has demonstrated that obtaining a PhD can be a useful career step - see Science Daily. However, please don't get stuck on the permanent post-doc path.

December 9th, 2015

I have commented on the lack of job opportunities for new PhDs many times in this blog, and the problem does not seem to lessen with the passing years. Too often young graduates are seen simply as a pair of inexpensive hands to progress the work of tenured scientists. However, others are aware of the problem, as a recent article in Nature testifies. The author points out that in 2013, 42% of life-science students graduated without a job commitment of any kind - a substantial increase on 10 years earlier. The author of the article suggests that one answer might be to have a new type of PhD with a greater vocational component. Perhaps! The lucky ones are those who get away from academia at the end of their PhD. Those I feel really sorry for are the scientists stuck in an unending series of short term post-doctoral positions. There needs to be a fundamental re-think, and there is encouraging evidence that some scientists looking for solutions see -

N-Palmitoylethanolamide was detected as a component of eggs more than 50 years ago and its analgesic properties were soon identified. However, interest appeared to wane for a long period until the discovery of the endocannabinoids such as anandamide resurrected interest in other amides of fatty acids. There is now a substantial body of evidence that this natural derivative of a saturated fatty acid can bring about pain relief in many circumstances, without the side effects associated with many synthetic drugs (Hesselink, J.M.K. and Kopsky, D.J. Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome. J. Pain Res., 8, 729-734 (2015); DOI). The paper is open access and as an interesting novelty there is a video abstract by the senior author. I am not aware of this fascinating lipid having been accepted officially by the FDA or any other representative body, although it is available as a non-prescription drug in the USA.

December 2nd, 2015

Tetrahymanol is a polycylic triterpenoid and sterol surrogate first found in ciliate protozoa but subsequently in many other types of eukaryote that live under anoxic conditions, where the relevant enzymes are believed to have been introduced via gene transfer. It was also known that it occurred in two species of bacteria, where it was seen as something of an anomaly. A new publication demonstrates that it is more widespread in bacteria than had been believed, and that it is produced via a very different biosynthetic mechanism from that in eukaryotes involving a hopanoid as an intermediate (Banta, A.B. et al. A distinct pathway for tetrahymanol synthesis in bacteria. Proc. Natl. Acad. Sci. USA, 112, 13478-13483 (2015); DOI).

There is a vast literature on the biochemistry of eicosanoids and increasingly these days on docosanoids, but the oxylipins derived from linoleate are relatively neglected, although they can be more abundant in plasma than the eicosanoids. A new metabolomics study demonstrates that linoleate-derived oxylipins can account for some of the variability in the response to aspirin in terms of platelet reactivity (Ellero-Simatos, S. et al. Oxylipid profile of low-dose aspirin exposure: a pharmacometabolomics study. J. Am. Heart Assoc., 4, e002203 (2015); DOI). They certainly merit further study. Incidentally, the authors use the term 'oxylipid' as opposed to 'oxylipin'. Which is correct? A quick search on Google Scholar gave 749 uses of 'oxylipin' in 2014 and only 50 of 'oxylipid'. Personally, I prefer to use 'oxylipin' for metabolites of fatty acids and 'oxylipid' for metabolites of intact lipids - another task for the international nomenclature bodies?

Continuing on the theme of oxidized lipids, a recent issue of the journal Antioxidants and Redox Signalling has a number of review articles that I would have found useful for updating my Lipid Essentials pages on this site. However, only one of these is open access (Spickett, C.M. and Pitt, A.R. Oxidative lipidomics coming of age: advances in analysis of oxidized phospholipids in physiology and pathology. Antiox. Redox Signal., 22, 1646-1666 (2015); DOI). As this journal does not allow further access after a fixed period, I will have to forgo reading and citing these publications here.

November 25th, 2015

Scottish thistleIn a recent blog, I mentioned a review discussing the merits of saturated fatty acids in human metabolism. There is an interesting popular account of the debate on saturated fat in the diet in New Scientist. It appears to suggest that the reports that saturated fatty acids are a causal factor in heart disease can no longer be sustained. What I fail to understand is how we could have been misled for so long!

I am always fascinating by new discoveries in relation to unusual lipids, such as cholesterol 6-O-acyl-β-D-galactopyranoside and its non-acylated form, which are significant components of membranes of the tick-borne spirochete Borrelia burgdorferi, the causative agent of Lyme disease. The cholesterol comes from the animal host and its glycoside can be transferred back to the membranes of the host animal, where it may facilitate the infective process. A new study demonstrates that these glycolipids, together with free cholesterol, form raft microdomains with proteolipids in the membranes of the organism, which may permit it to sense environmental changes and adapt to the host (Toledo, A. et al. The lipid raft proteome of Borrelia burgdorferi. Proteomics, 15, 3662-3675 (2015); DOI). This is probably the first demonstration of such microdomains in a prokaryote.

Jasmonates are key plant hormones with structural similarities to the prostaglandins but derived from α-linolenic acid; they have important signalling functions in algae and higher plants, but especially for plant stress responses, growth and development. I can recommend a substantial new review of their properties that is written from a historical perspective (Wasternack, C. How jasmonates earned their laurels: past and present. J. Plant Growth Reg., 34, 761-794 (2015); DOI).

November 18th, 2015

While I have been enjoying the sunshine of the Canary Islands over the last week, lipid science has been continuing to develop apace. Over the years, I have seen nutritional recommendations in relation to polyunsaturated fatty acids from several apparently august bodies being discredited, but rarely as thoroughly as in a new publication (Crawford, M.A. et al. The European Food Safety Authority recommendation for polyunsaturated fatty acid composition of infant formula overrules breast milk, puts infants at risk, and should be revised. PLEFA, 102-103, 1-3 (2015); DOI). It seems that the EFSA has concluded from a limited review of the literature that although docosahexaenoic acid (DHA) is required for infant formula, arachidonic acid is not "even in the presence of DHA". The authors of this rebuttal point out that arachidonic acid is not an optional drug but a ubiquitous component of the diets of newborn infants through breast milk with a myriad of essential functions. Removing it from infant formulae could have grave health implications.

Two new publications have appeared that deal with the biochemistry of cardiolipin. The first deals with the genetic disease Barth syndrome - I was deeply moved by meeting boys and young men suffering from this condition a few years ago, so any progress and increasing awareness of the condition is worthwhile (Gaspard, G.J. and McMaster, C.R. Cardiolipin metabolism and its causal role in the etiology of the inherited cardiomyopathy Barth syndrome. Chem. Phys. Lipids, 193, 1-10 (2015); DOI). The second publications deals with the ubiquitous nature of cardiolipin in Archaea, prokaryotes and eukaryotes, and its role in stress responses especially (Luevano-Martinez, L.A. and Kowaltowski, A.J. Phosphatidylglycerol-derived phospholipids have a universal, domain-crossing role in stress responses. Arch. Biochem. Biophys., 585, 90-97 (2015); DOI).

November 4th, 2015

It is dogma among many nutritionists that saturated fatty acids are bad for us, and that we must consume as little as possible. I recall seeing palmitic acid labelled a 'poison' in one popular nutrition article some years ago. Yet there are many essential functions for saturated fatty acids, in membrane lipids, as components of proteolipids, as activators of transcription factors, and as sources of monoenoic fatty acids. I can recommend a new review that attempts to redress the balance (Legrand, P. and Rioux, V. Specific roles of saturated fatty acids: Beyond epidemiological data. Eur. J. Lipid Sci. Technol., 117, 1489-1499 (2015); DOI).

I do not forget the requirements for unsaturated fatty acids, which are required to balance the saturated components in membrane lipids as well as having innumerable metabolic functions. The essential fatty acids of the (n-6) and (n-3) families and the balance between the two is a never-ending nutritional debate. A new element has been added with the discovery of the lipid mediators derived from these fatty acids, especially the relatively recent findings on the pro-resolving docosanoids and inflammation. A new brief review offers a useful perspective on the subject (Marion-Letellier, R. et al. Polyunsaturated fatty acids and inflammation. IUBMB Life, 67, 659-667 (2015); DOI).

I have belatedly come across a series of three reviews in the Journal of Biochemistry (February issue) on the theme of "Recent Progress in Lipid Mediators". The topics covered are leukotrienes, prostaglandins and lysophosphatidic acids, and all are open access.

October 28th, 2015

Scottish thistleThe techniques and science of lipidomics have legitimized analytical chemistry as a major tool in understanding not merely the composition of lipids, but also their metabolism and functions in tissues. Increasingly, information of this kind is being obtained in relation to structures within organs and even membranes within cells by these techniques. I have just been updating my web page on sulfoglycosphingolipids, where there is now a much greater understanding of their role in the different regions of kidney in maintaining a steady pH in plasma. Similarly, lipidomic studies of different organs of more primitive organisms is providing information on relatively obscure lipids. For example, ceramide aminoethylphosphonate is a common if poorly understood lipid in marine invertebrates. A new lipidomic study has demonstrated that it is concentrated in the tentacles containing the stinging cells of jellyfish, where presumably it is able to stabilize the membranes against attach by phospholipases (Zhu, S. et al. Lipid profile in different parts of edible jellyfish Rhopilema esculentum. J. Agric. Food Chem., 63, 8283-8291 (2015); DOI).

I am fortunate in having home access to very fast broadband, which enables me to download pdf files in seconds from the websites of most of the large academic publishers. My moan this week is with many of the smaller ones, who have insufficient bandwidth so that it takes an age to access the sites and to navigate through them.

October 21st, 2015

Because of the increasing problem with drug resistant bacteria, there is a major search underway for new antibiotics. Among the important potential sources are the bacterial lipopeptides, which can also be powerful surfactants. Lipopeptides are amphiphilic molecules that consist of short linear chains or cyclic structures of amino acids, linked to a fatty acid via ester or amide bonds or both. They are able to form pores and destabilize the membranes of bacteria. A new review summarizes their properties and applications (Ines, M. and Dhouha, G. Lipopeptide surfactants: production, recovery and pore forming capacity. Peptides, 71, 100-112 (2015); DOI).

One group that has interested me especially are the fusaricidins, because they contain the unusual fatty acid 15-guanidino-3-hydroxypentadecanoic acid, which I discussed in my blog in January this year. A new analytical study has shown that these lipopeptides in fact constitute a complex family of molecular species consisting of more than 20 variants of the basic cyclopeptide structure (Vater, J. et al. Characterization of novel fusaricidins produced by Paenibacillus polymyxa-M1 using MALDI-TOF mass spectrometry. J. Am. Soc. Mass Spectrom., 26, 1548-1558 (2015); DOI). No doubt further work will show which structures are most active biologically.

An item on the BBC website this morning discusses how scientists are thwarting the copyright attached to scientific papers together with the moral and commercial implications. I am ambivalent on the subject. As an author of a book that has been pirated (and as a former publisher), I believe that copyright should be protected. On the other hand, as a retired scientist I would like more access to online journals. There is no way that I could consider paying commercial rates to access single papers as a retiree, and I have to confess that I accessed the second of the papers cited this week on the ResearchGate website (via Google Scholar) as a proof copy. I hope that at least I am helping by drawing attention to the publication and the journal. For those journals that allow free access after a year, I am usually content to wait. Perhaps the answer would be for more journals to adopt such a policy.

October 14th, 2015

A number of research groups operate altruistically in that they share their mass spectrometry software online. A new data base can now be added to these (Aimo, L. et al. The SwissLipids knowledgebase for lipid biology. Bioinformatics, 31, 2860-2866 (2015); DOI). I am no longer in a position to make use of this or study it in detail, so please forgive me if I simply quote from the abstract - "SwissLipids provides curated knowledge of lipid structures and metabolism which is used to generate an in silico library of feasible lipid structures. These are arranged in a hierarchical classification that links mass spectrometry analytical outputs to all possible lipid structures, metabolic reactions and enzymes. SwissLipids provides a reference namespace for lipidomic data publication, data exploration and hypothesis generation. The current version of SwissLipids includes over 244,000 known and theoretically possible lipid structures, over 800 proteins, and curated links to published knowledge from over 620 peer-reviewed publications." Thus, it appears to differ from the other databases of this type of which I am aware in that it deals with metabolic processes as well as mass spectrometry.

The shops in the UK have had their Christmas displays up for weeks. Similarly, now that we have so much publication online first, I have already started to pick up references for the Literature Survey pages here for papers dated to 2016!

October 7th, 2015

It was something of a surprise when the neutral lipid 1,2-diacyl-sn-glycerols first were shown to be important signalling molecules back in the 1970s, as well as being components of cellular membranes and building blocks for glycerophospholipids. This is no longer news, but a current and substantial review article looks at the topic from a rather different perspective and happily it is open access (Eichmann T.O. and Lass, A. DAG tales: the multiple faces of diacylglycerol-stereochemistry, metabolism, and signaling. Cell. Mol. Life Sci., 72, 3931-3952 (2015); DOI). Their approach is to consider the stereospecificity of all the enzymes involved in diacylglycerol metabolism from lipases to kinases to demonstrate how these affect their functions. Only the sn-1,2-stereoisomer has signalling activity.

The arsenic-containing lipids (arsenolipids) in fish have been attracting great interest over the last few years. Until recently, the assumption has been that these presented no toxicity problems, because they were thought to be broken down to water-soluble metabolites, which were rapidly eliminated from the body. Then it was noted that arsenic-containing hydrocarbons were cytotoxic to human cell preparations in vitro.

Formula of 1-Dimethylarsinoylpentadecane

Now it has been shown that both arsenic-containing hydrocarbons and fatty acids are taken up readily by an intestinal model in vitro, though the fatty acids are rapidly degraded in the intestines (Meyer, S. et al. Arsenic-containing hydrocarbons and arsenic-containing fatty acids: Transfer across and presystemic metabolism in the Caco-2 intestinal barrier model. Mol. Nutr. Food Res., 59, 2044-2056 (2015); DOI). What this means for consumers of fish is uncertain, but I suspect that it will prove to be trivial at the concentrations that occur naturally otherwise effects would have been noted long before now. I will continue to enjoy fresh fish in my diet.

September 30th, 2015

Scottish thistleGlycosyldiacylglycerols are best known as major lipids of the photosynthetic apparatus in plant. However, it appears to be less well known that mono- and digalactosyldiacylglycerols are minor lipid components of brain and nervous tissue in animals, or that glucosyldiacylglycerols with 1 to 8 glucose units are major components of the membranes of intestinal tissues. A major review on these compounds was published in 1992 in Progress in Lipid Research, yet when I undertook a citation search (ISI Web of Science) last week to see what had been published on this topic in the intervening period so that I could update the appropriate web page here, I found only 20 citations none of which appeared to advance the field. Similarly in 2001, a digalactosyldiacylglycerol was characterized from a human carcinoma and found to have distinctly different stereochemistry from the plant equivalent (see the link above for details). This paper does not appear to have been cited even once since then, so why the lack of interest? One explanation might be that a common procedure used in the preparation of glycosphingolipids for analysis involves base-catalysed methylation to remove any glycerophospholipids that might interfere; this would of course also eliminate any glycosyldiacylglycerols at the same time. Out of sight - out of mind.

The exception is seminolipid, i.e. a glycerolipid analogue of cerebroside sulfate that also has parallels with the plant sulfolipid. This is an important constituent of male reproductive tissues but is also found in many other tissues. Unusually for a lipid from sperm and testis, it is highly saturated and consists largely of the 17:0-alkyl-16:0-acyl species. This lipid does seem to get the attention it merits.

September 23rd, 2015

Gangliosides are fascinating lipids that are essential for the development of the brain and nervous tissues. They have always been a challenge to lipid analysts, however, partly because of their intrinsic complexity and partly because of their high polarity. A valuable new publication describes the analytical problems, and suggests a comprehensive route to detailed analysis (Masson, E.A.Y. et al. Apprehending ganglioside diversity: a comprehensive methodological approach. J. Lipid Res., 56, 1821-1835 (2015); DOI). One aspect I found especially interesting is that the favoured method for separating individual ganglioside types is still high-performance thin-layer chromatography, not ultra-high-performance liquid chromatography or shotgun mass spectrometry, which are now so widely used for other aspects of the analysis of complex lipids. Sometimes the "old-fashioned low-tech" methods are the best.

Incidentally, in revising and updating my web page on gangliosides here, I came across an excellent article on their structures and function by a well-known expert in the field that I had missed when it was first published (Kolter, T. Ganglioside biochemistry. ISRN Biochemistry, 2012, 506160 (36 pages) (2012); DOI). It has the additional virtue of being open access.

We are used to the merits and demerits of omega-3 fatty acids being discussed and argued over in relation to human health by everyone from serious scientists to media charlatans to the point where it is impossible for more objective observers to be sure of the true situation. One aspect I had never considered is the value of omega-3 fatty acids to the health of the oceans. It appears that copepods, minute creatures related to crabs, like all animals require a source of essential fatty acids and especially omega-3s, which they acquire by consuming marine algae. In turn, the copepods are a major source of food for fish larvae, so a healthy population leads to lots of fish who also require omega-3s. In addition, it is noted that the marine algae take up atmospheric carbon, a proportion of which is locked up permanently as dead organisms and their excreta fall to the ocean floor. You can find a longer version of the story together with a link to the original research in Science Daily.

September 16th, 2015

When I do my weekly literature search, it is a common occurrence to find a new lipid described, usually from some obscure organism. It is virtually unheard of to find a new important membrane lipid in an animal or higher plant context. Nonetheless, this happened two years ago when glucuronosyldiacylglycerol (a conjugate of diacylglycerol with glucuronic acid) was found in the model plant Arabidopsis thaliana during phosphate deprivation. It accompanied the plant sulfolipid sulfoquinovosyldiacylglycerol (SQDG) to replace the phospholipids. The likelihood was that the new lipid was produced by the SQDG synthase. In a new publication from the same laboratory, these findings have now been confirmed and extended (Okazaki, Y. et al. Induced accumulation of glucuronosyldiacylglycerol in tomato and soybean under phosphorus deprivation. Physiologia Plantarum, 155, 33-42 (2015); DOI). It is now evident that the new lipid occurs in a wide range of plant species under normal growth conditions, but it increases appreciably in concentration when phosphate is limiting, presumably to help to supply a need for anionic lipids in the chloroplast membranes.

Forgive me if I point out that it is easy to incorporate this new information quickly into a relevant webpage here, long before it appears in major review articles or text books - a major virtue of the WWW.

Biosynthesis of 4,7,10,13,16,19-docosahexaenoic acid (22:6(n‑3) has long been though to proceed by chain-elongation of 22:5(n‑3) to 24:5(n‑3), desaturation to 24:6(n‑3) by a Δ6 desaturase, followed by beta-oxidation to 22:6(n‑3), i.e. by the 'Sprecher pathway' named after Howard Sprecher, who was briefly a colleague of mine at the Hormel Institute in 1964. Now new research has shown that 22:5(n‑3) can be desaturated directly to 22:6(n‑3) by a Δ4 desaturase produced by the FADS2 gene in human cells (Park, H.G. et al. The fatty acid desaturase 2 (FADS2) gene product catalyzes Δ4 desaturation to yield n‑3 docosahexaenoic acid and n‑6 docosapentaenoic acid in human cells. FASEB J., 29, 3911-3919 (2015); DOI). Regretfully, I will have to wait for a year after the print version of the paper appears before I can read it.

This contrasts with the journal Free Radical Research (Volume 49, Issue 7, 2015), which has just published a special issue on "Recent progress in lipid peroxidation based on novel approaches" (H. Yin, E. Niki and K. Uchida), which looks interesting but which I will never be able to read directly as they don't have an enlightened policy in relation to access.

September 9th, 2015

What is the most abundant lipid on Earth? Over the years, I have seen suggestions of at least four different lipid classes that might hold this title. Amongst living organism, two different plant lipids have been suggested. The first lipid class is the galactosyldiacylglycerols, which are present in all chloroplasts of green leaves of higher plants as well as in lower photosynthetic organisms. The second is the layer of wax that covers the leaves and often the shoots of plants. How do we decide between these two? The third class to come into the reckoning is the ether lipids of the Archaea. It is claimed that these organisms make up 20% of the total biomass in the oceans, so that will add up to a lot of lipid, but what about the other 80%? If in addition to living organisms, we consider the lipids deposited in sediments then the total of archaeal lipids increases very substantially as their structures remain stable over geological time scales. Similarly, I have seen suggestions that hopanoids are also chemically stable and accumulate in sediments, and they are obviously favoured as world champions by experts in this particular field. On the other hand, if we are going to consider lipids in sediments, we might have to consider petroleum deposits, although in this instance it may be harder to determine the original lipid precursors. I will let others argue over the answer to the question I posed at the beginning.

September 2nd, 2015

It has been fairly evident from small studies over some years that dietary fish oil supplements do not improve cognitive ability in the elderly, and this has now been confirmed by a major new study that has been widely cited in the scientific press and in popular news media. Unfortunately, the message that this refers only to the elderly, while there is a body of evidence from other studies that there are significant improvements for the very young, has been lost in subsequent discussions. I watched a debate on the BBC News last week in which the participants had read the popular reports and were lamenting the fact that they had been made to take fish oil capsules by their parents in their youth. In fact they were lucky to get it in capsule form - my generation were given cod liver oil by the spoonful (as a source of vitamin D rather than of omega-3 fatty acids). Of course, there are many other good reasons to continue taking omega-3 fatty acid supplements in adulthood. If in doubt, check out the most recent PUFA Newsletter

Phosphatidylglucoside is a novel lipid in many ways, and for example its glycerolipid component more resembles a ceramide than a phospholipid in its fatty acid composition and physical properties. A new publication demonstrates that lysophosphatidylglucoside, i.e. with one fatty acid constituent, has distinctive biological activity in guiding the specific location of axons in the developing spinal cord, while mediating glia-neuron communication. The mechanism involves a G protein-coupled receptor GPR55, which was first identified as a receptor for lysophosphatidylinositol but is now determined to have a much higher affinity for lysophosphatidylglucoside (Guy, A.T. et al. Glycerophospholipid regulation of modality-specific sensory axon guidance in the spinal cord. Science, 349, 974-977 (2015); DOI).

August 26th, 2015

Scottish thistleTwo special journal issues devoted to lipids have come to my attention, one a little belatedly. Biochimica et Biophysica Acta (BBA) - Biomembranes (Volume 1848, Issue 9, Pages 1727-1954, September 2015) is devoted to the topic of "Lipid-protein interactions" (edited by Amitabha Chattopadhyay and Jean-Marie Ruysschaert). One article that interested me especially is devoted to cholesterol metabolism in cells and is open access.

Formula of 13-cysteinylglycinyl,14-hydroxy-docosahexaenoic acidThe second journal is Seminars in Immunology (Volume 27, Issue 3, 145-234, May 2015), which covers the topic of "Resolution of inflammation: New mechanisms in patho-physiology open opportunities for pharmacology" (edited by Mauro Perretti). This appears to be the most active and promising topic at present in relation to eicosanoid/docosanoid biochemistry, with the group lead by Professor Charles N. Serhan at the forefront. They do indeed contribute a substantial review to this journal issue, but only mention briefly a fascinating new range of metabolites. Last year the group published a paper describing novel sulfido-conjugates derived from epoxy-maresin (Dalli, J. et al. Identification of 14-series sulfido-conjugated mediators that promote resolution of infection and organ protection. PNAS, 111, E4753-E4761 (2014); DOI). These compounds, such as 13-cysteinylglycinyl,14-hydroxy-docosahexaenoic acid illustrated bear more than a passing resemblance to the pro-inflammatory cysteinyl-leukotrienes, although their biological effects are very different. At nanomolar concentrations, the new metabolites were shown to resolve E. coli infections, and in general they constitute a novel mechanism of chemical signalling that contains infections, stimulates resolution of inflammation, and promotes the restoration of function in human tissues and those of experimental animals. Similarly, in a paper published this year, the group show that protectins and resolvins produce related sulfido-conjugates that stimulated human macrophages and limited the effects of bacterial infections in a dose-dependent manner (Dalli, J. et al. Novel proresolving and tissue-regenerative resolvin and protectin sulfido-conjugated pathways. FASEB J., 29, 2120-2136 (2015); DOI). Unfortunately, I will have to wait a year until access to the latter paper is opened.

August 19th, 2015

Lipid droplets in tissues were once considered to be boring lumps of fat of little interest to anyone, but now it is recognized that they are dynamic organelles with numerous enzymes attached and a plethora of biological functions. Not only do they act as a reservoir of fatty acids for energy, protecting cells from lipotoxicity, but they also store a number of biologically active lipids to be sent to other tissues under appropriate stimulation. They regulate appetite and energy metabolism through release of adipokines, but they also are the source of hormones, secondary messengers and vitamins. Not surprisingly many proteins in the surrounding monolayer function in lipid metabolism, but others are involved in interorgan communication, development and immunity. A new review summarises the current state of play in relation to those in animal tissues (Hashemi, H.F. and Goodman, J.M. The life cycle of lipid droplets. Curr. Opinion Cell Biol., 33, 119-124 (2015); (DOI).

While lipid droplets in animal tissues have received most study for obvious reasons, those present in plants are equally important to life on earth and a further review discusses lipid droplets or plastoglobules in the photosynthetic apparatus of plants (Rottet, S., Besagni, C. and Kessler, F. The role of plastoglobules in thylakoid lipid remodeling during plant development. Biochim. Biophys. Acta, Bioenergetics, 1847, 889-899 (2015); (DOI). They appear to function in innumerable aspects of thylakoid function, and the attached proteins "act in metabolite synthesis, repair and disposal under changing environmental conditions and developmental stages".

August 12th, 2015

Sulfoquinovosyl diacylglycerol, the plant sulfolipid, is a glycolipid characteristic of photosynthetic organisms, including higher plants, algae, chloromonads and cyanobacteria. It is a key component of the photosynthetic apparatus and as such is essential to the continuance of life on earth. It does not occur in animal tissues, although there is a lipid with some structural similarities - seminolipid found in reproductive and some nervous tissues. I was therefore intrigued by a report (open access) that it selectively inhibits acute lymphoblastic leukemia cells in vivo in a mouse model. The authors suggest that it may partly replace some of the drugs used in chemotherapy to minimize side effects (Jain, C.K. et al. Sulfonoquinovosyl diacylglyceride selectively targets acute lymphoblastic leukemia cells and exerts potent anti-leukemic effects in vivo. Scientific Reports, 5, 12082 (2015); DOI). Note that the authors and journal cannot spell the name of the active compound (sulfoquinovosyl diacylglycerol NOT sulfonoquinovosyl diacylglyceride).

A correspondent has brought to my attention an interesting news item in the journal Chemistry and Industry (August issue, page 13). The pharmaceutical company Thetis is producing amide derivatives of omega-3 fatty acids to transform the latter into free flowing powders that are claimed to increase the bioavailability of the fatty acids. From the company standpoint, these new formulations are patentable and less likely to be copied by competitors. One new drug under test is an ionic compound derived from docosapentaenoic acid (22:5(n-3)), which shows promise to boost the LDL-cholesterol lowering ability of statins, while reducing any side effects. Of course, fatty acid amides can have biological effects in their own right (c.f. the endocannabinoids), and these will have to be checked if the new drugs are to receive regulatory approval.

August 5th, 2015

Of all the lipids that might be named as a signalling molecule, the last I would have expected might be the C18 saturated fatty acid - stearic acid. Yet this has just happened in a new publication in Nature in which stearic acid and human transferrin receptor 1 are shown to be regulators of mitochondrial function (Senyilmaz, D. et al. Regulation of mitochondrial morphology and function by stearoylation of TFR1. Nature, Online; DOI). A novel signalling pathway has been demonstrated whereby C18:0 stearoylates TFR1, i.e. it adds covalently to the protein by a mechanism analogous to palmitoylation. This inhibits its signalling actions, leading eventually to the promotion of mitochondrial fusion and function. According to the authors "This work identifies the metabolite C18:0 as a signalling molecule regulating mitochondrial function in response to diet".

Two weeks ago, I discussed the importance of gangliosides and recommended a review that discussed their importance in brain development. By coincidence, a second review has just been published on the same topic (Schengrund, C.L. Gangliosides: glycosphingolipids essential for normal neural development and function. Trends Biochem. Sci., 40, 397-406 (2015); DOI). I have always found it fascinating that ganglioside biosynthesis in the human brain differs in a significant way from that of all other animals including the great apes. Indeed, as far as I am aware, this is the only major metabolic distinction from apes. The same issue of the journal carries a second review on aspects of ganglioside biochemistry and function (Ledeen, R.W. and Wu, G.S. The multi-tasked life of GM1 ganglioside, a true factotum of nature. Trends Biochem. Sci., 40, 407-418 (2015); DOI). GM1 is one of the simplest of the gangliosides in structure, yet it has a wide range of functions through binding via specific proteins with glycolipid-binding domains, which are located in raft domains of membranes. To quote from the abstract, it modulates "mechanisms such as ion transport, neuronal differentiation, G protein-coupled receptors (GPCRs), immune system reactivities, and neuroprotective signalling".

July 29th, 2015

Scottish thistleA few years ago, I had to have surgery to for cataracts in my eyes. This involved removing the natural lens of the eye and replacing it with one of plastic. The procedure was quick and relatively safe, but any operation is a cause for concern. I was expecting only damage limitation, but the effects were wonderful - after 60 years I no longer needed to wear glasses other than for reading, and colours were brighter and 3D vision was sharper. Three cheers for our free National Health Service. A new publication now suggests that there is hope that surgery may not be required in future thanks to a lipid - lanosterol (Zhao, L. et al. Lanosterol reverses protein aggregation in cataracts. Letter to Nature published online; DOI). The lens of the human eye is comprised largely of crystalline proteins assembled into a highly ordered state, which is disrupted during cataract formation with formation of protein aggregates. Treatment with lanosterol, an important intermediate in cholesterol biosynthesis, reduced cataract severity appreciably both in vitro and in vivo in experimental animals. The authors state "Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

On the other hand, not all the news on the sterol front is good. There is a school of thought that considers oxidized cholesterol formed as a consequence of oxidative stress in the brain to be an important factor in inflammation. This in turn may be highly relevant to the development of Alzheimer's disease. A new review (open access) summarises the evidence (Gamba, P. et al. Oxidized cholesterol as the driving force behind the development of Alzheimer's disease. Front. Aging Neurosci., 7, 119 (2015); DOI).

Continuing the theme of sterols, two issues of journals have recently been devoted to sterol topics. Thus, Steroids (Vol. 99, Part B, Pages 117-298, July 2015) is devoted to the topic of "Oxysterols and related sterols: chemical, biochemical and biological aspects" (edited by Iuliano, L. and others). Similarly, the Journal of AOAC International (Volume 98, May/June) contains a number of articles under the theme of "Safety, health, and methodological aspects of plant sterols and stanols". Judging from the list of papers in press, the journal Lipids is also planning a special issue on sterols.

July 22nd, 2015

Gangliosides are crucial lipid components of animal systems, although their study has become a separate subject from the mainstream as they are most unlipid-like in most of their physical properties. For example, in the Folch extraction procedure, they partition into the aqueous phase with the non-lipids rather than into the organic phase. In my nearly 50 years of research, I have always discarded the aqueous layer and thrown them away! They are especially important in neuronal cell membranes and it is acknowledged that they play a critical role in neuronal and brain development. According to a new review article, "they are functionally involved in neurotransmission and are thought to support the formation and stabilization of functional synapses and neural circuits required as the structural basis of memory and learning. Available evidence suggests that dietary gangliosides may impact positively on cognitive functions, particularly in the early postnatal period when the brain is still growing" (Palmano, K. et al. The role of gangliosides in neurodevelopment. Nutrients, 7, 3891-3913 (2015); DOI). The review is open access.

New functions for minor lipid components are now reported every week, so that it much be difficult for newcomers to the subject to realize how surprising it was for most of us when it was first revealed that a lipid we had never heard of previously, lysophosphatidic acid, had essential messenger functions. I first came across it when a correspondent wrote to ask how best to analyse it, since it had just been shown to be implicated in ovarian cancer. I had no idea how to help. Two new studies highlighted in Science Daily illustrate the importance of this lipid to neurotransmission and to myelin formation.

July 15th, 2015

The website Science Daily provides a link to an interesting new development in the science of brown fat that has the potential to lead to highly significant improvements in the treatment of type 1 diabetes. It is reported that a transplant of embryonic brown fat reversed the disease and restored glucose tolerance to normal in non-obese diabetic mice (in 53 percent of the study sample) without the use of insulin, and that such transplantation before onset could delay or prevent the disease altogether.

As I mention in my last blog, I keep an eye out for anything that might alleviate the symptoms of cognitive decline with aging. Unfortunately, a new meta-analysis seems to demonstrate that omega-3 fatty acids are not the answer except in rare circumstances (Cooper, R.E. et al. Omega-3 polyunsaturated fatty acid supplementation and cognition: A systematic review and meta-analysis. J. Psychopharm., 29, 753-763 (2015); DOI). I'll keep taking my fish oil tablets, in the expectation that they have other beneficial functions.

I try to keep clear of the thorny subject of fatty acids in nutrition, as I have the impression that the topic is subject to constant re-assessment. This view is confirmed by a fascinating report of a debate by recognized experts, who appear to cast doubt on the dogma on whether reducing the intake of saturated fatty acid lowers the risk of coronary heart disease (Nettleton, J.A. et al. ISSFAL 2014 Debate: it is time to update saturated fat recommendations. Annals Nutr. Metab., 66, 104-108 (2015); DOI). One problem seems to be what the replacement for saturated fat should be.

The journal Analytical and Bioanalytical Chemistry (Volume 407, Issue 17, pp. 4971-5239, July 2015) is largely devoted to the topic of 'Lipidomics' (guest editor - Michal Holčapek). As might be expected most of the substantial number of articles deal with mass spectrometry of lipids, and I note that many of the important scientists in this area have provided contributions. Most of these reviews will be listed in my next monthly literature survey.

July 8th, 2015

Heinrich Otto Wieland (1877-1957) is one of the great lipid scientists, who was awarded the 1927 Nobel Prize in Chemistry for his research into the bile acids. His achievements were extraordinary considering that he did not have access to any of the chromatographic and spectroscopic techniques we take for granted nowadays. He is back in the news after his Nobel medal was recently auctioned, and it is evident that he was also a great humanitarian. I have been entranced by a newspaper account - not of his science but of his life, as he was a dedicated and active anti-Nazi, who did not shirk assisting Jewish students or attempting to protect co-workers, even during the war years. The account in The Guardian is well worth reading. If you are interested in a relatively accessible account of the history of bile acid research, I can recommend a recent article in the Journal of Lipid Research.

I have reached an age when I read anything that might be relevant to delaying the onset of dementia or Alzheimer's disease with great interest. There is a popular account, with a link to the original paper, of work suggesting that omega-3 supplements and antioxidants may help with preclinical Alzheimer's disease in Science Daily. It is suggested that clinical trials should be undertaken for people with mild impairment.

I have no intention of commenting on political matters here, but innumerable holidays in Greece over the years have left me with nothing but happy memories of the country and its people. Everyone is apparently suffering real hardship and to add to the tribulations of scientists there, it seems they have been unable to continue their subscription to online journals as well as losing research funding.

July 1st, 2015

I have just been revising my web page on phosphatidylinositol mainly in the light of two recent papers from the same laboratory (where I have to make do with the abstracts as I don't have access to the full publications). A distinctive feature of the mammalian lipid is that it consists largely of a single molecular species with stearic acid in position 1 and arachidonic in position 2. This is important for a number of reasons, not least because this is the primary source of arachidonic acid for eicosanoid production and also of specific diacylglycerols with messenger functions. It has long been assumed that the final composition is attained by the 'Land's cycle', the process of partial hydrolysis and re-acylation that leads to remodelling of the fatty acids compositions in each position. While this process probably does occur, it seems that a more important pathway and the key to the specificity is the use of a specific cytidine diphosphate diacylglycerol synthase (CDS2), which generates preferentially the precursor cytidine diphosphate diacylglycerol as the 1-stearoyl-2-arachidonoyl species (D'Souza, K. et al. Distinct properties of the two isoforms of CDP-diacylglycerol synthase. Biochemistry, 53, 7358-7367 (2014); DOI). In contrast, the next step in which a phosphatidylinositol synthase catalyses the reaction of CDP-diacylglycerol with inositol exhibits no specificity for particular molecular species (D'Souza, K. and Epand, R.M. The phosphatidylinositol synthase-catalyzed formation of phosphatidylinositol does not exhibit acyl chain specificity. Biochemistry, 54, 1151-1153 (2015); DOI).

Incidentally, I have found it very difficult to find information on the amount and composition of cytidine diphosphate diacylglycerol as it occurs naturally in tissues. It seems that the natural levels must be too low to by detected in modern lipidomic studies. In my web page on this lipid, I had to cite data from a paper published in 1976.

Author: William W. Christie Updated: April 4th, 2018 Credits/disclaimer LipidWeb logo