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

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

November 14, 2018

Two substantial journal issues dealing with aspects of lipid biochemistry and analysis have now been published, although I have to confess that I have been enjoying the sunshine and beaches of Gran Canaria for the last week so I have not had time to do other than browse through them briefly, i.e. "Dietary fatty acids, lipid mediators, cell function and human health" - edited by Philip Calder (Molecular Aspects of Medicine, 64, Pages 1-182 (December 2018) ) - and "Lipidomics" - edited by James Ntambi and Sarah Spiegel (Biochem. Biophys. Res. Commun., 504, Issue 3, Pages 553-628 (7 October 2018)).

I did, however, note a number of interesting reviews dealing with bioactive amides, both endocannabinoids and others, and one especially dealing with N-docosahexaenoylethanolamine (synaptamide) (Kim, H.Y. and Spector, A.A. N-Docosahexaenoylethanolamine: A neurotrophic and neuroprotective metabolite of docosahexaenoic acid. Mol. Aspects Med., 64, 34-44 (2018);  DOI). This does not interact with the endocannabinoid receptors, but has its own target (GPR110 or ADGRF1), a G-protein coupled receptor that is highly expressed in the central nervous system and promotes neurogenesis in developing neurons at nanomolar concentrations. It invokes a signalling pathway that leads to the expression of neurogenic genes while suppressing the expression of proinflammatory genes. It hardly needs saying that this is yet another indication of the importance of omega-3 fatty acids for our health and well being.

A separate review elsewhere deals with the how various bioactive amides in the gut influence the microbial biome and vice versa, with eventual impacts on the brain (Russo, R. et al. Gut-brain axis: role of lipids in the regulation of inflammation, pain and CNS diseases. Curr. Med. Chem., 25, 3930-3952 (2018);  DOI). I need to spend more time with both of these.

October 31, 2018

Scottish thistle During embryonic development in many mammals, including the rat, the eyelids migrate over the cornea and fuse in order to protect the eyes during birth and early postnatal development. It has now been established that a key factor in this process is the lipid sphingosine-1-phosphate, which promotes the activation of proteins involved in cell migration and stimulates signalling by the epidermal growth factor receptor (EGFR) (Bian, G. et al. Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling. Sci. Signal., 11, eaat147023 (2018);  DOI). In the early part of my career, we looked on sphingolipids as interesting curiosities that simply had ill-defined roles in membranes, so the all-pervasive nature of their signalling properties has come as a surprise - see the latest review (Pulli, I. et al. Sphingolipid-mediated calcium signaling and its pathological effects. Biochim. Biophys. Acta, Mol. Cell Res., 1865, 1668-1677 (2018);  DOI).

I was stimulated myself in writing the above to check the spelling of 'signalling' (ll) or 'signaling' (l); apparently the former is British English and the second American English. "We have really everything in common with America nowadays except, of course, language" - Oscar Wilde (The Canterville Ghost, 1887), not George Bernard Shaw to whom it is often attributed.

A fascinating paper in JBC describes how the acyl-coA synthetase 1 can direct fatty acids to many different functions in different membranes in the liver (Young, P.A. et al. Long-chain acyl-CoA synthetase 1 interacts with key proteins that activate and direct fatty acids into niche hepatic pathways. J. Biol. Chem., 293, 16724-17740 (2018);  DOI). It is reported that the enzyme can interact with a number of different proteins at the outer mitochondrial membrane and the endoplasmic reticulum to determine whether the fatty acids are directed to oxidation or esterification or to other purposes. Incidentally, my former Institute can no longer afford a subscription to JBC, but the journal permits access to early versions of the paper even after formal publication and this is sufficient for my purposes. How I wish others were equally enlightened, especially ACS publications.

October 24, 2018

I have a few open access review bargains for you this week of which my favourite and that most useful in updating my web pages in the Lipid Essentials section of the LipidWeb deals with sphingolipids (Harrison, P.J. et al. Sphingolipid biosynthesis in man and microbes. Nat. Prod. Rep., 35, 921-954 (2018);  DOI). In fact the title is something of a misnomer in that it does not treat sphingolipids as a whole but with the first steps in the biosynthesis of sphingoid bases, i.e. before the involvement of ceramide synthesis, and then with their catabolism via sphingosine-1-phosphate.

An even more substantial review deals with glycolipids from marine organisms (Cheng-Sanchez, I. and Sarabia, F. Chemistry and biology of bioactive glycolipids of marine origin. Marine Drugs, 16, 294 (2018);  DOI). This is perhaps one for the specialist, but it encompasses an astonishing array of glycosphingolipids, together with glycosyldiacylglycerols and others that seem to defy simple classifications. Marine organisms can produce polyunsaturated fatty acids in many different ways, and for example marine bacteria can synthesise such fatty acids both by aerobic and anaerobic mechanisms. In particular, marine invertebrates contain many diverse enzymes involved in the introduction of double bonds into fatty acids including both "front-end" and "omega" desaturases, and they are even able to produce what for most other animals are essential fatty acids. This is the subject of my third review of the week (Monroig, O. and Kabeya, N. Desaturases and elongases involved in polyunsaturated fatty acid biosynthesis in aquatic invertebrates: a comprehensive review. Fisheries Sci., 84, 911-928 (2018);  DOI). This is not simply an esoteric exercise as such enzymes may have appreciable biotechnological potential.

A month ago, I discussed the discovery of a cholesterol metabolite in a 600 million year old fossil, confirming that it was of an animal. Now the molecular fossil record for animals has been pushed back another 35 million years with the discovery in pre-Cambrian rocks of sterane structures that are made exclusively by demosponges (see the report in Science Daily).

October 17, 2018

The journal Biochimie has a special issue devoted to "Current trends in oxysterols and related sterols", edited by Gérard Lizard, Giulio Muccioli and Luigi Iuliano (Volume 153, Pages 1-238 (October 2018)). So far I have only had time for a brief overview, but I was especially interested in a multi-author inter-laboratory comparison of methods of oxysterol analysis (Lutjohann, D. et al. International descriptive and interventional survey for oxycholesterol determination by gas- and liquid-chromatographic methods. Biochimie, 153, 26-32 (2018);  DOI). Some surprising discrepancies among the various laboratories were noted, highlighting a need for standardized methods, and especially for the use of appropriate deuterated standards. Also, as I suggested some weeks ago to deafening silence, it would also be useful to have ready access to standard mass spectra of sterol derivatives for those new to the subject or with limited access to mass spectral libraries, ideally in a dedicated website - the next task for this multi-author panel? Those working with plant oxysterols have the same or perhaps greater problems because of the wide range of different sterols and triterpenoid alcohols in plant species. Similar aims to standardize methodologies are discussed in a multi-author study of plasma lipidomics (Burla, B. et al. MS‑based lipidomics of human blood plasma: a community-initiated position paper to develop accepted guidelines. J. Lipid Res., 59, 2001-2017 (2018);  DOI).

Oxidized lipids were the theme of a number of papers in this week's literature search, headed by a rather substantial review in an ACS journal for those of you who have access (I don't) (Parvez, S. et al. Redox signaling by reactive electrophiles and oxidants. Chem. Rev., 118, 8798-8888 (2018);  DOI). On the other hand, I have been able to read and can recommend an open access review on the signalling properties of oxidized phospholipids as opposed to the unesterified oxylipins (Tyurina, Y.Y. et al. "Only a life lived for others is worth living": redox signaling by oxygenated phospholipids in cell fate decisions. Antiox. Redox Signal., 29, 1333-1358 (2018);  DOI). Both enzymic and non-enzymic routes to such species are known, and oxidized cardiolipin is crucial to apoptosis and phagocytosis of mitochondria. This has been recognized for some time, but the role of oxygenated phosphatidylethanolamines as pro-ferroptotic signals has emerged relatively recently.

October 10, 2018

I was intrigued by the title of a recent paper (Zaidi, A. et al. Forgotten fatty acids - Surface properties supply conclusive evidence for including carotenoic acids. Chem. Phys. Lipids, 216, 48-53 (2018);  DOI), and I read through it rapidly to see whether I should add anything on these lipids to my Lipid Essential pages on the LipidWeb. I decided against, but was prompted to consider more deeply by a correspondent. I did not change my mind. Yes they are fatty and yes they are acids, but they do not occur naturally with the exception of retinoic acid, which I discuss appropriately in my web page on retinoids. LIPID MAPS® appear to agree with me as they list it in their isoprenoid group. Similarly, the acidic (carboxy) derivatives of tocopherols, which I mentioned in my blog of two weeks ago (September 26th), are technically fatty acids but to my mind are best discussed with the tocopherols. What about triterpenoids such as oleanolic and betulinic acids? They are fatty and acidic, but do we really need to call them fatty acids? I suppose another question raised by the publication might be whether surface active properties are of sufficient value in determining whether a lipid should be classified as a fatty acid. Retinoic acid, for example, is bound in tissues to specific transporter-carrier proteins, so I doubt whether it ever reaches an effective concentration in vivo where its surface active properties are relevant. If it does, my guess is that this would be a signal for oxidation, glucuronidation and elimination. Should any isoprenoids be classified primarily as fatty acids? In my personal view, phytanic acid should be because of its occurrence in esterified form in main-stream lipids in animals. Of course, all classification systems are simply academic exercises and they all boil down to personal opinions, so the authors of the paper are just as entitled to their view as I am to mine.

The journal Cancer and Metastasis Reviews has published a special issue (Volume 37, Issue 2-3, pp. 199-572 September 2018) that deals with the topic of "Bioactive Lipids" (Issue Editors: Dipak Panigrahy and Allison Gartung).

October 3rd 2018

Two reviews dealing with mass spectrometry of lipids have caught my eye this week, both by eminent practitioners of the subject. The first by Robert Murphy deals with mass spectrometry of neutral lipids, especially triacylglycerols and cholesterol esters, both by shotgun techniques and as part of chromatographic separations (Murphy, R.C. Challenges in mass spectrometry-based lipidomics of neutral lipids. Trends Anal. Chem., 107, 91-98 (2018);  DOI). The large number of molecular species present in triacylglycerols of natural origin, even those with relatively simple compositions, will always cause problems, especially when positional distributions are taken into account, and the author stresses the need for careful calibrations in quantitative analyses with internal standards labelled with stable isotopes. The second review by Fong-Fu Hsu deals with shotgun lipidomics (Hsu, F.F. Mass spectrometry-based shotgun lipidomics - a critical review from the technical point of view. Anal. Bioanal. Chem., 410, 6387-6409 (2018);  DOI). As an armchair scientist these days, I often get the impression that life is so much easier for the current generation with such powerful instrumentation at their disposal. This and the previous review clearly demonstrate that there is just as much need for care and attention to detail in experimentation as there ever was. As an example of what can be achieved by such methodologies, a new multi-author paper describes the lipidomics and proteomics of every cell type in the human lung (Kyle, J.E. et al. Cell type-resolved human lung lipidome reveals cellular cooperation in lung function. Sci. Rep., 8, 13455 (2018);  DOI - open access). The authors claim that this is the first such lipidome map of any organ.

While strongly supporting the open access movement for science publication, I have expressed concern in past contributions to this blog that some of the new journals may not operate to the same standards as the older pay-for-view journals. A correspondent has drawn to my attention a report in about the open access journal Nutrients. The Editor-in-Chief and all of his senior editors have resigned "alleging that the publisher, the Multidisciplinary Digital Publishing Institute (MDPI), pressured them to accept manuscripts of mediocre quality and importance." The presumed intention of the publisher is to increase the profitability of the journal, but the editors believe that this will harm the journal's impact factor and lead to a drop in submissions in the long term. I have been assured by my correspondent that this journal has had a good reputation until now.

The journal Biological Chemistry (Volume 399, Issue 10, October 2018) is devoted to the topic of "Sphingolipids in Infectious Biology and Immunology".

September 26, 2018

Scottish thistleI have to confess that I was entirely unaware of the importance of the nature and function of extracellular vesicles (exosomes and microvesicles) in lipid metabolism until the thematic series on this topic was announced in the Journal of Lipid Research (now reaching formal publication in the August issue). It seems that I was not alone in this regard as the subject is barely mentioned in two recent text books on lipid biochemistry, which I consulted. Although extracellular vesicles were first described as a means of selective elimination of proteins, lipids and RNA from cells, they are now considered to be a new mode of intercellular communication. I have a lot of catching up to do via the continuing JLR series, together with two recent reviews in other journals (DOI-1 and DOI-2).

The mechanism behind the biological effects of tocopherols other than their role as antioxidants has proved elusive, although evidence has been accumulating that the 13'-carboxy metabolites may be of importance. It has now been established that the 13'-carboxy metabolite of α-tocopherol (α-T-13'-COOH) is a potent inhibitor of 5-lipoxygenase, a key enzyme in the biosynthesis of the inflammatory leukotrienes (Pein, H. et al. Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. Nature Commun., 9, 3834 (2018);  DOI - open access). α-T-13'-COOH accumulates in immune cells and inflamed exudates both in vitro and in vivo in mice, and the authors suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on this endogenous metabolite.

This week's lipid oddity is an N-acylhomoserine lactone produced by bacteria in the human gut (Landman, C. et al. Inter-kingdom effect on epithelial cells of the N-acyl homoserine lactone 3-oxo-C12:2, a major quorum-sensing molecule from gut microbiota. PLOS One, 13, e0202587 (2018);  DOI - open access). The full structure of this particular molecule has still to be established, but it has been determined that it has a C12 acyl chain with a 3-oxo group and two double bonds (positions and geometry unknown). Such lipids function normally in a form of intercellular signalling termed 'quorum sensing', which controls gene expression in response to the population density of the species, resulting in coordinated regulation of a range of group-level behaviours, including production of secondary metabolites and virulence factors, bioluminescence and biofilm formation, i.e. when these signal molecules reach a threshold concentration in a particular environment, they bind to their intracellular receptor/activator proteins to induce the expression of relevant genes. The importance of these new molecules is that they also interact with the host intestinal epithelial cells as anti-inflammatory agents with the potential to affect human metabolism including diseases of the gut.

N-acylhomoserine lactone

When we are all dead and gone, it appears that our cholesterol lingers on as in the fossil of a 600 million year old animal (pre-Cambrian) (Bobrovskiy, I. et al. Ancient steroids establish the Ediacaran fossil Dickinsonia as one of the earliest animals. Science, 361, 1246-1249 (2018);  DOI).

September 19, 2018

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

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

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

September 12, 2018

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

Tetrahydrofuranoid fatty acid from sea lampreys

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

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

September 5th 2018

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

Formula of nebraskanic acid

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

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

August 29nd 2018

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

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

August 22nd 2018

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

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

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

August 15th 2018

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

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

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

August 8th, 2018

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

Resolvin D4

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

August 1st, 2018

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

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

July 25th, 2018

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

Formulae of two representative ascarosides

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

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

July 18th, 2018

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

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

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

July 11th, 2018

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

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

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

July 4th, 2018

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

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

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

June 27th, 2018

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

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

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

June 20th, 2018

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

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

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

June 13th, 2018

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

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

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

June 6th, 2018

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

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

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