The LipidWeb blank

Lipid Matters - A Personal Blog



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


May 27th, 2020

Leaf and other tissues in plants contain a range of sterol glycosides and sterol acyl-glycosides in which the hydroxyl group at C3 on the sterol is linked to the sugar by a β-glycosidic bond. Such lipids have only rarely been found in animal tissues, although cholesterol glucoside (1-O-cholesteryl-β-D-glucopyranoside) and less often cholesterol acyl-glucoside have been detected, and were found first in the skin of snakes and birds. Now both cholesterol glucoside and galactoside have been shown to be present throughout development in mouse brain from the start of myelination in embryos through to adults, with biosynthesis involving a transfer of glucose/galactose from cerebrosides to cholesterol catalysed by a lysosomal β-glucocerebrosidase (Akiyama, H. et al. Glucocerebrosidases catalyze a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol. J. Biol. Chem., 295, 5257-5277 (2020);  DOI). It will be interesting to know what their function is there.

In plants, sterol glycosides are synthesised by a very different mechanism, i.e. from free sterols with a glucose unit catalysed by a sterol glycosyltransferase, or by reaction of the sterol with uridine diphosphoglucose (UDP-glucose) and UDP-glucose:sterol glucosyltransferase on the cytosolic side of the plasma membrane. In this instance, they are believed to have a number of biological functions, for example in the adaptation of plant membranes to low temperatures and other stresses, in the response to fungal pathogens and in signal transmission. A new review discusses findings that through acting as immunoadjuvants, sterol glycosides are efficacious in protecting animals against lethal Cryptococcal infections (Normile, T.G. et al. Steryl glycosides in fungal pathogenesis: an understudied immunomodulatory adjuvant. J. Fungi, 6, 25 (2020);  DOI - open access). Does this give us a clue as to the function of the endogenously synthesised lipid in animals?

Last question - is the correct nomenclature "sterol glycosides" or "steryl glycosides"?

May 20th, 2020

Scottish thistleTwo publications dealing with analytical methodology have caught my eye this week, and happily both are open access. The first deals with a particularly taxing problem, i.e. the analysis of those acyl moieties attached to acyl-carrier proteins, which are of course not only intermediates but the products of fatty acid synthesis in plants (Nam, J.-W. et al. A general method for quantification and discovery of acyl groups attached to acyl carrier proteins in fatty acid metabolism using LC-MS/MS. Plant Cell, 32, 820-832 (2020);  DOI). The authors were able to identified acyl-ACP elongation intermediates (3-hydroxy-acyl-ACPs and 2,3-trans-enoyl-ACPs and medium-chain-ACPs, together with polyunsaturated long-chain acyl-ACPs (16:3) that might not have been anticipated. The methodology will of course be invaluable for the development of genetically modified seed oils, as the authors intend, but interesting questions regarding fatty acid metabolism in chloroplasts are also posed. Although the method is described for plants, it should be applicable to mammalian systems as it involves a preliminary step of hydrolysis at a highly conserved amino acid sequence in ACPs retaining the phosphopantetheinyl linker to which acyl groups attach.

The second publication is a review less of analysis per se but more of the results of analyses of carnitines and acyl-carnitines (Bene, J. et al. Mass spectrometric analysis of L-carnitine and its esters: potential biomarkers of disturbances in carnitine homeostasis. Curr. Mol. Med., 20, 336-354 (2020);  DOI). As is well known, carnitine plays a vital role in the mitochondrial oxidation of long-chain fatty acids by enabling them to cross the inner mitochondrial membrane, although it has wider functions in cells by controlling the acyl-CoA/CoA ratio thereby influencing innumerable enzyme systems. Screening of the carnitine ester profile of newborn infants is well established and can lead to the detection of more than 30 metabolic disorders, but this methodology is now proving useful in investigating diseases of adult patients, including diabetes and cardiovascular diseases.

The Journal of Lipid Research and the Journal of Biological Chemistry already have enlightened access policies, but I was delighted to learn that they will become fully open access soon. Now if only the major chemical societies would follow suit - over to you ACS and RSC!

May 13th, 2020

When I was starting to write my web pages on different lipid classes in the Lipid Essentials section of this website, I had most problems with that on cytidine diphosphate diacylglycerol (CDP-DAG), in spite of the fact that it is a key intermediate that occupies a branch point in the biosynthesis of certain complex glycerolipids, especially phosphatidylinositol and cardiolipin. For example, it was extremely difficult to find any compositional data, and I had to rely on a publication from 1976 (as an aside, I should not apologize for this, as the work is probably as sound as anything published more recently). Modern mass spectrometric methods do not appear to be sufficiently sensitive to detect this lipid in natural tissues - if anyone out there is interested, it might be a useful project for someone to find a means of concentrating this lipid so it can be analysed more easily in order to have compositional information for different tissues. There have been some valuable new findings in recent years, especially the characterization of three distinct CDP-DAG synthases with differing subcellular distributions and differing products. Now, two substantial reviews on the topic have come along at the same time (Blunsom, N.J. and Cockcroft, S. CDP-diacylglycerol synthases (CDS): gateway to phosphatidylinositol and cardiolipin synthesis. Front. Cell Dev. Biol., 8, 63 (2020);  DOI: and - Jennings, W. and Epand, R.M. CDP-diacylglycerol, a critical intermediate in lipid metabolism. Chem. Phys. Lipids, 230, 104914 (2020);  DOI).

We need now to take note that CDP-DAG synthases, as a regulators of phospholipid metabolism and the rate-limiting enzyme in phosphatidylinositol biosynthesis, have a key role in the regulation of signal transduction processes dependent upon this lipid and thence indirectly in diseases related to faulty lipid metabolism. Similarly, it influences the availability of phosphatidic acid for biosynthesis both of triacylglycerols and of complex lipids and for its signalling activities.

May 6th, 2020

In some types of glycosylphosphatidylinositols (protein anchors), the first mannose unit is decorated by the addition of a short oligosaccharide sequence starting with N-acetylgalactosamine, before galactose is added. A new publication shows that this step involves the action of a GM1 ganglioside synthase and requires the presence of lactosylceramide (Wang, Y. et al. Cross-talks of glycosylphosphatidylinositol biosynthesis with glycosphingolipid biosynthesis and ER-associated degradation. Nature Commun., 11, 860 (2020);  DOI - open access). It is thus an interesting link between glycerolipid and sphingolipid metabolism.

Some years ago, in the question session after a presentation, I was asked if I knew of links of this kind. Only two sprang immediately to mind - the biosynthesis of sphingomyelin requiring phosphatidylcholine as precursor, while ethanolamine phosphate derived from the catabolism of sphingolipids via sphingosine 1-phosphate is recycled for the biosynthesis of phosphatidylethanolamine. I was sure there were more and of course, once I was on my way home, I thought of others. I began to make a list, and eventually, I decided that this should be shared so I added a short section to my web page Introduction to Sphingolipids. Although more items have been added from time to time, I am sure that this list is far from complete, so I would be grateful for suggestions of further examples.

We must all be rethinking our relationship with the world and our environment during the Covid crisis. A new review on the application of lipidomics adds food for thought (Koelmel, J.P. et al. Environmental lipidomics: understanding the response of organisms and ecosystems to a changing world. Metabolomics, 16, 56 (2020);  DOI). Incidentally, there are three further reviews of various aspects of lipidomics in the current reference list(May) in the Literature Survey section of this web site.

April 29th, 2020

Scottish thistleA paper in press suggests a novel potential application of a common simple lipid as an antibiotic in nasal, tracheal, and bronchial epithelial cells (Verhaegh, R. et al. Sphingosine kills bacteria by binding to cardiolipin. J. Biol. Chem., in press (2020);  DOI). The authors show that unesterified sphingosine in protonated form rapidly causes death in a number of important bacterial pathogens by binding to the negatively charged lipid cardiolipin in bacterial plasma membranes. The suggestion is that the mechanism involves rapid permeabilization of the plasma membrane by promoting clustering of cardiolipin molecules in the membrane to generate gel- or even crystal-like structures. Sphingosine administered for antibiotic purposes is unlikely to reach cardiolipin in mitochondria in animal tissues, but I wonder whether some of the biological properties assigned separately to sphingosine and cardiolipin present endogenously in cells might be due to the two lipids acting in concert.

On a number of occasions over the last 15 years in this blog, I have drawn attention to the poor career prospects of most post-doctoral researchers in British Universities (not that the UK is unique in this respect). They may not be regarded overtly as a source of cheap and disposable labour, but this is the often the result. Nothing seems to change. The problem is likely to be exacerbated by the current financial problems of universities, and may even have become a feminist issue, as an article in the Guardian newspaper suggests.

April 22nd, 2020

I can remember when lysophospholipids were regarded merely as nasty lipids that would disrupt cell membranes if they were not rapidly catabolized or re-esterified. Their occurrence in lipid extracts was viewed as an artefact of a faulty extraction procedure (still true if too abundant). Now they are listed among the more important of lipid mediators with key functions in signalling, especially if sphingosine-1-phosphate is included in their number. I highlighted their potential use to deliver polyunsaturated fatty acids to brain in my blog of two weeks ago. Now a new publication describes yet another important function. It is reported that the phospholipase iPLA2γ hydrolyses fatty acids from position sn-1 of phospholipids to generate polyunsaturated sn-2-acyl lysophospholipids. In murine myocardium and in isolated platelets, human platelet-type 12-lipoxygenase (12-LOX) can then directly catalyse the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine and 2-arachidonoyl-lysophosphatidylethanolamine to produce 2(S)-HETE products, which can initiate signalling pathways. As these increase in concentration with age, they "may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions" (Liu, X. et al. 12-LOX catalyzes the oxidation of 2-arachidonoyl-lysolipids in platelets generating eicosanoid-lysolipids that are attenuated by iPLA2γ knockout. J. Biol. Chem., 295, 5307-5320 (2020);  DOI). There is a growing list of oxidized phospholipids that have biological activity in intact form (on this website see - here.. and here..)

I am grateful to a correspondent who pointed out an error in my structural formulae for the furanoid fatty acids (via the link) highlighted in my last blog; corrections or suggestions for improvements are always welcome. Another correspondent has drawn my attention to a useful online data base of plant fatty acids. He also sent a copy of a new review on a related topic, which I will enjoy reading in self-isolation (Cahoon, E.B. and Li-Beisson, Y. Plant unusual fatty acids: learning from the less common. Curr. Opinion Plant Biol., 55, 66-73 (2020);  DOI).

April 15th, 2020

For many years, I was puzzled by the appearance of minor components in GC-MS traces of fish oil methyl esters, the mass spectra of which bore no resemblance to conventional fatty acids. Eventually, a colleague suggested that they were furanoid fatty acids, and this proved to be correct. Once I knew what to look for I found them in every fish oil sample that I looked at, and especially in fish oil concentrates prepared for nutraceutical purposes (analysed by Mylnefield Lipid Analysis to which I was a consultant until recently). I am sceptical of a recent claim that they can be formed artefactually from EPA and DHA in pharmaceutical preparations. However, their precise origin is uncertain, although it is believed to be somewhere in the marine food chain, probably algae. In fish, they tend to be concentrated in reproductive tissues, although their function is unknown.

When consumed by humans, furanoid fatty acids have generally been suggested to have benign functions as antioxidants with cardioprotective effects. However, short-chain metabolites or "urofuranic acids", beta-oxidation metabolites of the longer-chain components from fish in the diet, are found in plasma, and when kidney function is impaired one isomer in particular, i.e. 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), can accumulate and is reported to be a significant uremic toxin. Its concentration increases in plasma of patients who progress from prediabetes to type 2 diabetes also, and it may be a marker for this disease; it increases oxidative stress and impairs insulin secretion. Analysis has always been a technical challenge, but a new LC-MS/MS technique with charge-reversal derivatization appears to be the answer (Xu, L. et al. Development of a sensitive and quantitative method for the identification of two major furan fatty acids in human plasma. J. Lipid Res., 61, 560-569 (2020);  DOI). Hopefully, the availability of the method will enable a better understanding of the metabolic consequences.

April 8th, 2020

I don't believe that I am unique in being confused by nutritional science in relation to recommendations for the intake of specific fatty acids, especially for eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. As far as I can understand it, the evidence that supplementation in the early years of life is a good idea seems to be fairly solid. On the other hand, this may not continue to be true as children get older. Unfortunately for myself, increased intake of these fatty acids does not seem to help with cognitive decline in the elderly, and the jury seems to be out on whether it helps with neurological diseases. On the other hand, there is a school of thought that conventional supplementation of the diet with these fatty acids does not help because they cannot cross the blood-brain barrier with sufficient rapidity to enter the brain where they are needed. There have been a few publications recently suggesting that this problem can be circumvented if they are administered as esters of lysophosphatidylcholine. A new paper describes this work and especially a relatively stable analogue, i.e. 1-acetyl,2-docosahexaenoyl-glycerophosphocholine, which has the potential to be supplied orally (Hachem, M. et al. Brain targeting with docosahexaenoic acid as a prospective therapy for neurodegenerative diseases and its passage across blood brain barrier. Biochimie, 170, 203-211 (2020);  DOI).

The most recent paper I have seen on analysis of fatty acid esters of hydroxy fatty acids (FAHFA) nearly doubles the number of reported molecular species in rat adipose tissue to over 300 (Zhu, Q.F. et al. FAHFA footprint in the visceral fat of mice across their lifespan. Biochim. Biophys. Acta, 1865, 158639 (2020);  DOI). They are known to have anti-inflammatory and anti-diabetic effects. I suppose that we must classify them as oxylipins, although we tend to think of most such lipids as being produced under strict stereospecific and regiospecific control. It is not yet known whether FAHFA have a specific receptor, but if so does it really handle such a wide range of isomeric compounds?

April 4th, 2020

News of the untimely death of Michael Wakelam from Covid-19 came as a great shock. I first met him when he was a lecturer at Glasgow University in the 1980s, and I followed his career via his publications with great interest thereafter. It was he who invited me to add my blog and later this website to that of LipidMaps. Lipid science will be much the poorer for his passing.

April 1st, 2020

Two further brief autobiographies of lipid scientists have appeared this week - good reading matter at any time, but especially when in self-isolation. The first is by Howard Goldfine (Life without air. J. Biol. Chem., 295, 4124-4133 (2020);  DOI - open access). I first became aware of his work on cyclopropane fatty acids when I worked briefly on their chemical synthesis in my post-doc years. More recently, among a substantial body of work on microbial lipids, his work on plasmalogen biosynthesis in anerobic bacteria is ground-breaking, even if we don't have all the answers yet; unlike animal systems, the required enzymes do not need molecular oxygen.

The second of these autobiographies is by Robert C. Murphy (Lipid mass spectrometry: A path traveled for 50 years. J. Mass Spectrom., e4492 (2020);  DOI), who will be well known to users of the LipidMaps website, and whose name is synonymous with mass spectrometry of lipids. His book on this topic in the Handbooks in Lipid Research series was a well-used item on my book shelf, and now probably resides with one of my former colleagues. I had forgotten his early contribution to what was then known as the "slow reacting substance of anaphylaxis", which on sabbatical at the Karolinska Institute in Sweden he identified as the lipid mediator we now know as leukotriene C4. Since then, he has produced an enviable number of publications that are truly pioneering on the chemistry and biochemistry of eicosanoids, as well as on complex lipids. His studies based on the use of mass spectrometry have enabled us to look at the biochemistry of lipids in living systems at minute concentration that were unthinkable to earlier generations of scientists. He is one of the first I would list among those who have established "lipidomics" as a science.

A useful summary paper concludes a thematic series on the biological functions of phosphatidylserine (Calianese, D.C. and Birge, R.B. Biology of phosphatidylserine (PS): basic physiology and implications in immunology, infectious disease, and cancer. Cell Comm. Signal., 18, 41 (2020);  DOI). The various parts have been appearing over recent months.

March 25th, 2020

Scottish thistleIn the cell envelope of Gram-positive bacteria, there are usually two types of polyanionic polymers linked either to membrane diglycosyldiacylglycerols, i.e. lipoteichoic acids (LTA), or to peptidoglycans, i.e. wall teichoic acids (WTA), which together form a dense protective layer against the environment. The anionic polymer units in both appeared to be superficially the same in that they consisted of repeating glycerol-phosphate units decorated in various ways. However, it is evident that degradative enzymes discriminate between the two. It has now been demonstrated that in LTA, the repeating units consist of sn-glycerol-1-phosphate while in WTA they are sn-glycerol-3-phosphate. In other words, they are stereochemically distinct (Walter, A. et al. Phosphoglycerol-type wall and lipoteichoic acids are enantiomeric polymers differentiated by the stereospecific glycerophosphodiesterase GlpQ. J. Biol. Chem., 295, 4024-4034 (2020);  DOI - open access as author's choice). This adds weight to my recent blog in which I stressed the importance of the difference between regiospecific and stereospecific nomenclatures for glycerol derivatives.

I am appreciative of the policy of the Journal of Lipid Research in providing commentaries on articles, which the editors consider of special importance. Like most scientists, I scan the titles of innumerable new publications every week, and it is very easy to miss some that I ought to read. It is impossible to be an expert on everything, and I am grateful for any help that I can get. One such commentary appeared in press this week to discuss a paper also in press describing how unesterified fatty acids cross membranes (Pownall, H.J. J. Lipid Res.,  DOI - open access). The conclusion is that this occurs largely by a simple diffusion mechanism or 'flip-flop'. The process is not unregulated as sometimes suggested, nor is it controlled via the activity of specific transporters, but simply by the "balance between intracellular triacylglycerol synthesis versus hydrolysis, which transfer long-chain fatty acids into or liberate them from fat droplets, respectively".

March 18th, 2020

Some years ago, a colleague was contacted by a poultry company because the yolks of their eggs had a peculiar consistence. Not surprisingly, it turned out that they were using a less costly unrefined cotton seed oil in their feed, as it was well established that traces of cyclopropenoid fatty acids in this oil reacted with thiol groups and in particular inhibited stearoyl-CoA desaturase with dramatic effects upon the fatty acid composition and thence upon the properties of eggs. However, I was rather surprised to find in a new review that this activity now has clinical potential for use of this fatty acid as an adjuvant in diseases such as cancer, nonalcoholic steatohepatitis and skin disorders. It may also have a protective roles in retinal diseases such as age-related macular degeneration (Pelaez, R. et al. Sterculic acid: the mechanisms of action beyond stearoyl-CoA desaturase inhibition and therapeutic opportunities in human diseases. Cells, 9, 140 (2020);  DOI - open access).

Gangliosides are another class of lipids involved in human disease states. Meat eaters and milk drinkers, including the human neonate, consume small amounts of these, but I had not realized that they had an influence upon human metabolism as dietary constituents. After all they are catabolized in intestinal tissues with release of their lipid and carbohydrate constituents. However, it appears that the sialic acid residues are re-utilized for ganglioside synthesis within tissues, and in particular that N-glycolylneuraminic acid (Neu5Gc), not normally found in human tissues, is used for ganglioside synthesis in some cancers. Now there is evidence that dietary control can regulate the expression levels of gangliosides in tissues, and it is hoped that this may helpful in treating ganglioside-related diseases (Okuda, T. Dietary control of ganglioside expression in mammalian tissues. Int. J. Mol. Sci., 21, 177 (2020);  DOI - open access).

If you are stuck at home in isolation because of Covid-19, why not spend a little time browsing through the Lipid Essentials pages (and other web pages) on this site. I am always grateful for feedback - suggestions for improvements, correction of errors, etc - as these pages are not peer reviewed, and like all humankind I am fallible.

March 11th, 2020

I can heartily recommend the personal reflections of Professor Sarah Spiegel (My journey with sphingosine-1-phosphate) that have just been published (Spiegel, S. Sphingosine-1-phosphate: From insipid lipid to a key regulator. J. Biol. Chem., 295, 3371-3384 (2020);  DOI - open access). Aside from being a remarkable account of the discovery of the manifold functions of this key lipid, which has inspired countless new research efforts, it is an enlightening story of how physical and personal difficulties were overcome to accomplish so much seminal work. Reading it caused me to reflect on how women in science have fared during my own research career. At high school in the 1950s, I only encountered two female teachers, who were both unmarried (then the norm), while girls were subtly directed away from the sciences. At University, I was never taught any course by a female lecturer/professor, and in my subsequent post-doctoral research at the Hormel Institute in Minnesota there were no female staff in tenured positions. This was also true for senior positions in my first permanent post at the Hannah Research Institute until the late 1970s. I am not in a position to judge now whether we have a truly level playing field in employment, and I don't suppose that we will be able to make such a judgment until we can discuss someone's research career without making an important issue of their gender.

Incidentally, I also encountered a new review from Spiegel's laboratory on sphingosine-1-phosphate and cancer (Singh, S.K. and Spiegel, S. Sphingosine-1-phosphate signaling: A novel target for simultaneous adjuvant treatment of triple negative breast cancer and chemotherapy-induced neuropathic pain. Adv. Biol. Regul., 75, 100670 (2020); DOI - open access).

Improved analytical methodology invariably leads to novel biological findings, and a new mass spectrometric technique applied to the much-studied gangliosides of human brain has revealed many novel molecular species, including those with up to seven sialylations, and with O-fucosylations and O-acetylations (Ica, R. et al. Orbitrap mass spectrometry for monitoring the ganglioside pattern in human cerebellum development and aging. J. Mass Spectrom., e4502 in press (2020);  DOI.

Two books on lipid biochemical topics have been published by Springer for those with access (not me) - Bioactive Ceramides In Health And Disease: Intertwined Roles Of Enigmatic Lipids. (Ed.: Stiban, J.), Adv. Exp. Med. Biol., Vol. 1159 (2019); and Role Of Bioactive Lipids In Cancer, Inflammation And Related Diseases (Eds.: Honn, K.V. and Zeldin, D.C.), Adv. Exp. Med. Biol., Vol. 1161 (2019).

March 4th, 2020

One of the key unknowns regarding plasmalogen biosynthesis has been identification of the enzyme responsible for introducing the double bond into position 1 of the alkyl chain. This has at last been identified as the orphan human protein designated TMEM189, following the identification of an analogous enzyme in bacteria (Gallego-Garcia, A. et al. A bacterial light response reveals an orphan desaturase for human plasmalogen synthesis. Science, 366, 128-132 (2019);  DOI). Now this opens the way to learning much more of the functions of plasmalogens in tissues. While they may have roles in membrane organization, signalling, and as antioxidants, my impression in that the data in some areas are not as solid as they could be.

I was also greatly interested in a lipidomics paper dealing with ether lipids that show appreciable differences in the nature and concentrations of specific alkyl and alkenyl ethers between centenarians and other age groups (Pradas, I. et al. Exceptional human longevity is associated with a specific plasma phenotype of ether lipids. Redox Biology, 21, 101127 (2019);  DOI). Unfortunately, there does not appear to be any way that I can use this information to my advantage to guarantee another 20 years of this blog.

My apologies if some of the external links from the Lipid Library have not been working correctly in recent weeks, especially DOI addresses. The problem should now have been corrected.

February 26th, 2020

Scottish thistle Cardiolipin is a unique lipid in many ways, and in a new review it is described as a functional "glue" that binds components of the mitochondrial respiratory chain into an integrated system to provide efficient transfer of electrons and protons (Shilovsky, G.A. et al. Biological diversity and remodeling of cardiolipin in oxidative stress and age-related pathologies. Biochemistry (Moscow), 84, 1469-1483 (2019);  DOI). The oxidation of cardiolipin is a part of much studied route to apoptosis in mitochondria, but this review provides a new slant (to me at least) to the topic by describing what happens during aging, a subject close to my heart both literally and metaphorically. Oxidation triggers apoptosis and this review suggests that this is in part due to the loss of symmetry in the molecule that inevitably occurs. Also, during aging, there is a gradual loss of cardiolipin in mitochondria, and this is accompanied by changes in the fatty acid composition with higher polyunsaturated fatty acids replacing some of the linoleate. This also implies a loss of symmetry in the molecule and leads to a reduction in the efficiency of the respiratory chain. If this goes too far, it can result in mitochondrial dysfunction and the age-related pathologies of the title.

Incidentally, I wanted to check a point from a 1991 reference cited in this publication, but found that our Institute license did not cover this. It seems unlikely that publishers generate significant revenue from their back catalogue and it must deter proper bibliographic research. Young scientists probably think that anything published in the last century is the scientific equivalent of the stone age. Don't believe it!

I once had my own a Facebook page, and although I never added anything to it, it enabled me to keep abreast of the activities of my grandchildren. Now, they have reached an age where they don't want me to know what they are doing! Until recently, I had never bothered with Twitter, but I must admit that I find the Twitter feed to LipidMaps rather useful in making me aware of important references that I might otherwise miss.

February 19th, 2020

Bacterial lipopeptides from the genera/families Paenibacillaceae, Bacillus, Streptomyces and Pseudomonas are fascinating molecules in many ways, not least because of their potential to produce new antibiotics. However, it is easy to forget that the main reasons for the synthesis of these product is not to aid humans, they often have the opposite effects, but to aid the interaction with other bacteria and the environment and to create and sustain symbiotic relationships in mixed bacterial communities. The non-ribosomal synthetases responsible for their production are also distinctive and are organized into mega-enzyme complexes with molecular weights greater than 1.0 MDa in some instances. These are arranged in a systematic modular manner in assembly lines that permit the structural alteration of lipopeptide products by swapping domains or modules to create novel molecular structures. In general, the order of these modules is co-linear with the peptide sequence of the product, and each module contains multiple domains that are responsible for catalysing different enzymatic activities. For example, conversion of an L-amino acid to the D-isomer is carried out by an epimerization domain on the module that activates this and incorporates it into the growing peptide. It is the modular nature of these enzyme complexes that has lead to the hope that they can be manipulated to our benefit. As I have been reading in a new review, the biochemical mechanism in Pseudomonads has much in common with that for Bacillus and other species, but the two are evolutionarily distinct and there are some important differences (Götze, S. and Stallforth, P. Structure, properties, and biological functions of nonribosomal lipopeptides from pseudomonads. Nat. Prod. Rep., 37, 29-54 (2020);  DOI - free access to non-subscibers on registration).

Oleoylethanolamide is another lipid with the potential to benefit humans by its effects upon food consumption and weight management (Tutunchi, H. et al. A systematic review of the effects of oleoylethanolamide, a high-affinity endogenous ligand of PPAR-α, on the management and prevention of obesity. Clin. Exp. Pharmacol. Physiol., in press (2020);  DOI - open access). Perhaps I am cynical, but I suspect that whether this can be realized may depend on whether it can be patented to justify the expenditure on clinical trials.

February 12th, 2020

It is not often that I see Shakespeare quoted in a scientific paper, but this occurs both in the preamble and text of a review of oxidized phospholipids (Kagan, V.E et al. Redox phospholipidomics of enzymatically generated oxygenated phospholipids as specific signals of programmed cell death. Free Rad. Biol. Med., 147, 231-241 (2020);  DOI - open access). In relation to apoptosis - the "sweetness" of death that liberates from suffering, pain and loathed life. However, the review is not confined to literary appreciation but is a sometimes sobering account of vital biological processes. It appears that, in spite of all that has been learned of oxidation/anti-oxidative processes, not a single clinical trial of potential therapeutic antioxidants against inflammatory diseases has seen a positive outcome. It seems that biological systems are too complex to permit easy solutions.

Just when you think that all the important lipids have been characterized in a well-studied organism such as Escherichia coli, along comes a fascinating new lipopolysaccharide, the structure of which has now been confirmed. This was originally designated as "MPIase", as it appeared to have the biological activity of an enzyme, before its true nature was revealed. In fact, it has a long glycan chain composed of repeating trisaccharide units (GlcNAc, ManNAcA, Fuc4NAc) attached to an anchor composed of pyrophosphate linked in turn to a diacylglycerol. It is believed to alter the physicochemical properties of membranes to drive translocation and integration of proteins in membranes (Fujikawa, K. et al. Novel glycolipid involved in membrane protein integration: structure and mode of action. J. Synth. Org. Chem. Japan, 77, 1096-1105 (2019);  DOI - open access).

Before completing my an update on my web page on phosphoglycolipids/glycophospholipids to include a brief note on this lipid, I did a quick literature search with these key words for the last five years in the Web of Science. This turned up 100 references, nearly all to new identifications of bacterial species containing such lipids mostly as "unidentified phosphoglycolipid", etc. Clearly, there is a lot of work to be done, although I suspect that part of the problem is that no standards are available commercially to aid in analysis.

February 5th, 2020

The structural identification of platelet-activating factor (PAF) in 1979 was an exciting milestone in lipid science for those of us who were around then, as it was the first time that an intact phospholipid was found to have biological activity in its own right, and not simply to have a structural function in membranes, or to act via hydrolysis products. Indeed, the activity was remarkable at 10-11M! I dumped my 1977 copy of Lehninger some years ago, but it had only 3 pages on lipid functions - mainly as structural components of membranes and as a source of energy, with a short note on prostaglandins in a side box. There was no mention of the phosphoinositides, which were just beginning to make an impression. Since then it has emerged that virtually every lipid has some distinctive biological activity in its own right, but in my opinion PAF was the real start of a change in how lipids were perceived by the scientific community in general. A new review celebrates the anniversary of the discovery with a historical note - three groups were in competition to identify the molecule - and a lengthy discussion of the potential health benefits of targeting PAF metabolism (Lordan, R. et al. Forty years since the structural elucidation of platelet-activating factor (PAF): historical, current, and future research perspectives. Molecules, 24, 4414 (2019);  DOI - open access).

From time to time, I put on my "grumpy old man" hat to complain about some current scientific use of language. Perhaps this is pedantry, but someone has to take a stand if only to educate the new generation. What has caused my ire this week is the use of mass spectrometry to determine "sn-position isomer" compositions. "sn" stands for stereospecific numbering, and mass spectrometry is not stereospecific in this context but "regiospecific", and this is the correct term to use. Of course, when you are dealing with a single glycerolipid enantiomer as with most (but not all) natural phospholipids, the end result is the same, but the term is frequently used also for triacylglycerol positional distributions, where it is entirely inappropriate. If a racemic synthetic phospholipid were to be analysed by mass spectrometry, the primary (mixed sn-1/3) and secondary fatty acids would be determined with the same accuracy as for natural phospholipids. Incidentally, in this blog, I have occasionally challenged analysts to compare the results of determining positional distributions in phospholipids by mass spectrometry with older techniques, such as hydrolysis with the phospholipase A2 of snake venom, against natural samples as opposed to model compounds. So far no takers, but it might be a useful short project for a student.

January 29th, 2020

Binding of ceramide to the corneocyte proteins via a reactive epoxyenone Skin ceramides are highly distinctive lipids with an essential function in maintaining the protective barrier to the environment, and a key feature is that they contain very-long-chain fatty acids with an ω-hydroxyl group that is esterified very specifically to linoleic acid. The ultimate fate of the ceramides is attachment covalently via the terminal tend of the molecule to the proteins of the corneocyte envelope. Until now, it was believed that enzymic oxidation of the linoleate molecule facilitated its hydrolysis and attachment of the ceramide to a protein by esterification of the ω-hydroxyl to a glutamic acid residue by an ester bond. This may indeed occur to some extent, but a new publication suggests an alternative with a more intimate role for linoleate in the attachment process (Takeichi, T. and 18 others. SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation. J. Clin. Invest., 130, in press (2020);  DOI - open access). The suggestion is that the linoleate residue attached to the ω-O-acylceramide is oxidized by 12R-LOX and eLOX3 and an NAD+-dependent dehydrogenation to a highly reactive 9,10-trans-epoxy,11E-ene,13-keto intermediate (see our web page on hepoxilins), which rather than being hydrolysed is able to link non-enzymatically by the Michael addition reaction to cysteine or histidine residues in proteins of the corneocyte envelope, or by formation of a Schiff base and eventually a pyrrole derivative with a lysine residue. Incidentally, this adds to the argument that linoleic acid is an essential fatty acid in its own right and is not simply a precursor of arachidonic acid and eicosanoids.

I hate to use a phrase such as - "Nothing is known of the ...." when writing the web pages in my Lipid Essentials section. Happily, I was able to remove these words in updating my web page on Archaeal lipids to introduce new information on how the cyclopentane rings are formed in the isoprenoid chains of the glycerol dibiphytanyl glycerol tetraethers thanks to the identification of two key enzymes (Zeng, Z. et al. GDGT cyclization proteins identify the dominant archaeal sources of tetraether lipids in the ocean. Proc. Natl. Acad. Sci. USA, 116, 22505-22511 (2019); DOI).

January 22nd, 2020

The term 'lipokine' was coined in 2008 at first to define the biological activity of palmitoleic acid and then more generally as lipid molecules derived from adipose tissue that can act as hormonal regulators and coordinate a wide array of cellular processes. Research on such lipids has continued apace, and it is now described in a substantial new review (Hernández-Saavedra, D. and Stanford, K.I. The regulation of lipokines by environmental factors. Nutrients, 11, 2422 (2019); DOI - open access). While I was used to reading about polyunsaturated fatty acids and their oxygenated metabolites as vital molecules in biochemistry and physiology, it came as something of a surprise to me at least to find that a simple monoenoic fatty acid could stimulate muscle insulin action and suppress hepatic lipogenesis (steatosis or 'fatty liver') and triacylglycerol synthesis in the liver in such profound ways. Among many other effects, palmitoleate generation in macrophages is reported to alleviate lipotoxicity-induced stress in the endoplasmic reticulum with beneficial effects on the progression of atherosclerosis while reducing apoptosis. It should not be forgotten that palmitoleic acid has a further essential property in that it is linked very specifically to a conserved serine residue in the Wnt family of proteins involved in tissue development, and it is essential for their function.

A further lipid molecule considered to be a lipokine is 12,13-dihydroxy-9Z-octadecenoate (12,13-diHOME), derived from linoleic acid, synthesis of which is activated by cold exposure and exercise and results in improved whole-body metabolic homeostasis. Similarly, fatty acid hydroxy fatty acids (FAHFAs) constitute a novel lipid class that act as lipokines to improve glucose tolerance and insulin sensitivity, among innumerable other effects. I have always been a little puzzled by the last, as so many isomeric forms are known, between 160 and 300, and we usually expect lipid mediators to have high structural specificity.

It is vitally important that we get the correct fatty acid composition (and other nutrients) in infant formulae, and I have found it strange that there has been no specific recommendation for arachidonic acid levels when eicosanoids are so important in human metabolism. A new publication by an expert panel recommends that arachidonic acid should be added at least at the same levels as DHA (Koletzko, B. and 26 others. Should formula for infants provide arachidonic acid along with DHA? A position paper of the European Academy of Paediatrics and the Child Health Foundation. Am. J. Clin. Nutr., 111, 10-16 (2020); DOI - not immediately available to non-subscribers, unfortunately).

January 15th, 2020

The Lipid Essentials pages on this site are based on essays on individual lipid classes, rather than on chemical, biochemical or physiological processes. In consequence, I have tended to spread general subjects such as lipid autoxidation over several web pages, rather than treating them in a more coherent fashion. One aspect that I have just discovered that I have ignored is photo-oxidation, so I am grateful for a reminder as to its importance (Bacellar, I.O.L. and Baptista, M.S. Mechanisms of photosensitized lipid oxidation and membrane permeabilization. ACS Omega, 4, 21636-21646 (2019); DOI - open access). In animals, photo-oxidation is of course relevant to skin metabolism, but it is now of increasing importance in clinical practice because of the development of photodynamic therapies to treat such diseases as cancer and bacterial infections. The presence of photosensitizers, both natural or added therapeutically, is a key factor. Of course, many of the end results are the same as with other aspects of autoxidation including membrane disruption and cytotoxic effects. This process must be of great importance in photosynthetic tissue and in food spoilage, but this is not discussed here.

Lipid metabolism at membrane contact sites is an important part of the theme of the special January issue of Biochimica Biophysica Acta. However, a separate new review article discusses this topic in relation to the phosphoinositides (Pemberton, J.G. et al. Integrated regulation of the phosphatidylinositol cycle and phosphoinositide-driven lipid transport at ER-PM contact sites. Traffic, 21, 200-2019 (2020); DOI). This is a topic with which I have struggled because of the complexity of the innumerable metabolites and pathways involved, and at first glance I am sure this review will enlighten me - helped by excellent illustrations.

January 8th, 2020

One of the many things I like about the journal "Lipids" is its short but descriptive title, and there are a few more out there like it, such as "Blood", "Bone", "Cells" and "Cancers" that are equally pithy. I turn up my nose at anything that begins with "The International Journal of etc" - what journal of any note is not international? It will be hard to find a journal title that is more succinct than "Gut", and we can be thankful that it is not the "Journal of the British Society of Gastroenterology". At least, with an unwieldy title such as "Proceedings of the National Academy of Sciences of the United States of America", we can abbreviate it to "PNAS", while "Prostaglandins, Leukotrienes and Essential Fatty Acids" is "PLEFA". Not that I am a great fan of acronyms and especially abbreviations in general, and for example I have just come across "DIM lipids" in the title of a publication. This conjured up some interesting mental pictures but when I read the abstract, this turned out to refer to phthiocerol dimycocerosates, the use of the abbreviation only a minor flaw in my opinion at least in an otherwise fascinating study (DOI).


Earlier entries in this blog (older than 4 months) are archived by year as follows -

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Author: William W. Christie Updated: May 27th, 2020 Contact/credits/disclaimer LipidWeb logo