Lipid Matters - Archive of Older Blogs - 2021
This Blog is an occasional series of notes on publications or other items dealing with lipid science that seem to be of particular interest to the editor Bill Christie. Inevitably, the selection is highly personal and subjective. Older entries are archived in separate web pages by year (see the foot of this page).
December 15th, 2021
It has become a cliché to describe
sphingolipids as enigmatic, but this adjective could equally be applied to plasmalogens.
Their existence was first postulated in 1924, when they were found in myelin and termed ‘acetal phospholipids’, but it was the 1950s before
the structure was identified definitively (see - Rapport, M.M. The discovery of plasmalogen structure.
J. Lipid Res., 25, 1522-1527 (1984); DOI).
It has become evident only recently that they are synthesised by a quite different mechanism in aerobic bacteria (and eukaryotes) from
that in anaerobic bacteria.
As they appear to have evolved quite separately in the two groups of organisms, they must have important biological functions, but determining
what has proved to be a challenge.
For many years, they were discussed in vague terms as antioxidants or as simply adding some ill-defined but desirable physical properties to membranes. Now, we know much more, although I am sure there is still more to be learned. Physical properties are of course important, and plasmalogens tend to concentrate in raft regions of membranes, normally associated with more saturated lipids. There, they can affect signalling, and two phospholipases specific for plasmalogen as have been discovered that may be important for eicosanoid production. Also, plasmalogen levels are known to be reduced in several pathophysiological conditions involving chronic inflammatory processes, and plasmalogen replacement therapy appears to be a promising treatment option. Two recent reviews from the same laboratory shed some light and discuss these and other functions for these lipids (Bozelli, J.C. et al. Plasmalogens and chronic inflammatory diseases. Front. Physiol., 12, 730829 (2021); DOI: and Plasmalogen replacement therapy. Membranes, 11, 838 (2021); DOI).
This will be my last blog for 2021. I wish all my readers a very happy Christmas and New Year - please stay safe and healthy!
December 8th, 2021
Linoleic acid is an essential fatty acid, both as a source of arachidonic acid and other fatty acids of the omega-6 family and for eicosanoid biosynthesis. It is also essential in its own right, as it is required as a structural component of ceramides in healthy skin. Since the 1960s, every important national nutritional society, has advocated replacing some of the saturated fatty acids in the diet with linoleate, and only recently has a consensus appeared that this advice may have been too simplistic and that perhaps the linoleate to linolenate or omega-6 to omega-3 ratio might be more important. I recall a paper from early in my research career, which unfortunately I can’t locate now, that compared human milk fatty acids from mothers (‘post-natal people’ as some would term them) in the UK versus those in the Netherlands, where it was noted that the latter had double the linoleate content of the former, presumably because they had received the relevant nutritional advice. At the time, I was a little uneasy with this finding, simply because it seemed to be an unintended and un-monitored nutritional trial with human infants. However, the Dutch have the tallest population in Europe, so it doesn’t seem to have done them any harm – perhaps it could have increased my stature!
On the other hand, a new review suggests that there may indeed be problems with excess linoleate in the diet (Hamilton, J.S. and Klett, E.L. Linoleic acid and the regulation of glucose homeostasis: A review of the evidence. PLEFA, 175, 102366 (2021); DOI). Epidemiological studies in the USA have shown a massive decrease in deaths from cardiovascular disease as a result of this dietary change, but the incidence of diabetes and obesity has risen dramatically. The authors discuss how linoleate can "influence insulin sensitivity and peripheral glucose uptake as well as insulin secretion and pancreatic beta-cell function". I should add that I don’t pretend to be a nutritionist myself – merely someone who enjoys a good debate.
December 1st, 2021
It is good to read a review occasionally that challenges some preconceptions, and I have just enjoyed reading one on whether two fat-soluble vitamins are antioxidants and/or transcriptional regulators for specific genes (Blaner, W.S. et al. Vitamin A and vitamin E: will the real antioxidant please stand up? Annu. Rev. Nutr., 41, 105-131 (2021); DOI). The conclusion is that vitamin A, acting via its metabolite, all-trans-retinoic acid, is a potent transcriptional regulator, but it is only ‘an indirect antioxidant’ by regulating ‘a number of genes involved in mediating the body's canonical antioxidant responses’. In contrast, vitamin E (tocopherol) is a direct antioxidant, but it only indirectly affects gene expression by preventing an increase of peroxidized lipids that alters metabolic pathways. There is further useful discussion of vitamin E in another review from the same lab (Traber, M.G. and Head, B. Vitamin E: How much is enough, too much and why! Free Rad. Biol. Med., 177, 212-225 (2021); DOI).
In sections dealing with lipid compositions in this web site, I rarely if ever tabulate molecular species data and instead use positional distributions on the glycerol moiety, usually adapted from older publications. The latter enable comparisons between lipid classes, animal/plant species and tissues in relatively compact tables. On the other hand, molecular species data from more recent papers are simply too unwieldy, and my wish for the New Year is that more analysts would use their mass spectrometry/computer data to generate and tabulate positional information, when this is possible. Perhaps I am old-fashioned, but I like to see numbers rather than graphs to permit comparisons with other published work. Of course, graphical presentation may be the only convenient way with molecular species, and even if I can’t use the data here, I must commend a good example of how to deal with an analytical project that yielded 1,636 molecular species from one tissue (Lange, M. et al. AdipoAtlas: A reference lipidome for human white adipose tissue. Cell Rep. Med., 2, 100407 (2021); DOI).
November 24th, 2021
α-D-Galactosylceramides,
i.e., linked by an α-D- rather than by the ubiquitous β-D-bond to galactose,
are one of the more interesting of the newer lipids to have been discovered in recent years.
They were found to be potent stimulators of mammalian immune systems by binding to the protein CD1d on the surface of antigen-presenting cells
to activate invariant natural killer T cells.
First found in a sponge, their occurrence in the human gut microbiome and specifically in Bacteroides fragilis has
intriguing practical implications.
It had been assumed that this activity was due primarily to the change in anomeric configuration of the link to carbohydrate,
but a new study suggests that this organism utilizes branched-chain amino acids to introduce an iso-methyl branch into the sphinganine
and fatty acid components of the lipid, and that this is required to form the CD1d ligands (Oh, S.F. et al.
Host immunomodulatory lipids created by symbionts from dietary amino acids. Nature, in press (2021);
DOI).
Sphingolipids are intimately involved in many aspects of the development of cancers in humans, and several drugs that target sphingolipid metabolism have been developed and tested in animal models and in pre-clinical and phase-1 clinical studies. Of these, it appears that α-D-galactosylceramides, administered via pulsing antigen presenting cells, are the most promising. They have been found to be both safe and efficacious in a number of settings as recorded in a new review (Companioni, O. et al. Targeting sphingolipids for cancer therapy. Front. Oncol., 11, 745092 (2021); DOI).
November 17th, 2021
A headline in the Guardian newspaper caught my eye this week – “Fatty acid found in palm oil linked to spread of cancer: Study on mice found palmitic acid promoted metastasis in mouth and skin cancers.” I have no comment on the original research paper in Nature, and I hold no brief for palm oil, but I was aching to point out to someone that palmitic acid is a ubiquitous component of most foods, both animal and vegetable. For example, human milk contains appreciable amounts, and indeed it is added to infant formulae, with an excess in position sn-2 of the triacylglycerols to aid in digestion. As fatty acid synthesis de novo can increase substantially in cancer cells, they must produce much palmitic acid endogenously and some of this may be used to drive the development of cancer. In contrast, while I don’t want to go into all the important functions of palmitic acid for healthy life, I must mention that it is required for the biosynthesis of all sphingolipids, for S‑acylation of proteins to direct them to membranes, and even as I mentioned in my last blog for a lipid mediator involved in the relief of chronic pain (reviewed by Carta, G. et al. Palmitic acid: physiological role, metabolism and nutritional implications. Front. Physiol., 8, 902 (2017); DOI). Arguably, it is not palmitic acid per se that is the problem but a large excess.
This brings me back to palm oil. Some years ago, the soybean lobby in the USA financed a campaign against the use of ‘tropical oils’, by which they meant palm oil, that met with some success in the western world and led to substantial reductions in its use. Ironically, at the time, they were advocating its replacement by partially hydrogenated soybean oil enriched in harmful trans fatty acids (again see my last blog). This in turn gave rise to a campaign against dairy foods (‘palmitic acid - a poison produced by cows’). Palm oil has been a relatively inexpensive high-calorie food ingredient in Asia for more than 50 years now. Are there any epidemiological studies to suggest an increase in the prevalence of cancer in these populations?
November 10th, 2021
Like most people, I have occasional aches and pains, which go away with aspirin or paracetamol, and I can’t imagine how difficult it must be to deal with chronic pain. However, it looks as if lipids may be riding to the rescue. For example, the specialized pro-resolving lipid mediators, resolvins, maresins, protectins and lipoxins, have been tested in a number of painful conditions, including rheumatic diseases, migraine, and neuropathies, with promising results. Obviously, this research is at an early stage, and many practical difficulties lie ahead (Chavez-Castillo, M. et al. Specialized pro-resolving lipid mediators: the future of chronic pain therapy? Int. J. Mol. Sci., 22, 10370 (2021); DOI). Another promising therapy involves the use of palmitoylethanolamide, an agonist of the transcriptional regulator of cellular metabolism, peroxisome proliferator-activated receptor-α (PPAR-α). This lipid has long been known to alleviate pain, and indeed is available over the counter in some countries for this purpose. Now it seems that we have a better understanding of how it works, and the N-acylethanolamine acid amidase (NAAA) has been identified as a control point in the progression to chronic pain. Inhibition of this enzyme is now a target for drug development (Fotio, Y. et al. NAAA-regulated lipid signaling governs the transition from acute to chronic pain. Science Adv., 7, eabi8834 (2021); DOI). Incidentally, this is yet another example of the importance of the saturated palmitic acid for health.
Not all lipids are so benign, and trans fatty acids come into the harmful category, although the worst of these are not natural and are a by-product of industrial processing of vegetable oils, a practice that is rapidly being phased out. The underlying mechanism for these effects has been uncertain, but it has now been established that trans isomers have unique pro-apoptotic effects as described in a new review (Hirata, Y. trans-Fatty acids as an enhancer of inflammation and cell death: molecular basis for their pathological actions. Biol. Pharm. Bull, 44, 1349-1356 (2021); DOI).
November 4th, 2021
Sadly, I must report that
my former PhD supervisor, colleague, mentor, and friend Professor Frank D. Gunstone passed away at the weekend,
three days after his 98th birthday.
His wife Eleanor, who was a lively foil to Frank’s studious nature, died three years ago, but they are survived by their three children,
and numerous grandchildren and great-grandchildren.
For much of his early professional career, Frank was a lone voice in terms of the chemistry of lipids in the UK at the University of St Andrews, but his work was greatly appreciated here and internationally, and he attracted students to his laboratory from all over the world, but especially India, Pakistan, Sri Lanka, and Malaysia, not to mention those like me from Scotland. With his students, he isolated and characterized many novel fatty acids, including an isomer of ricinoleic acid, the first natural epoxy acid, and many new hydroxy- and acetylenic fatty acids. He was a pioneer in GC analysis and NMR spectroscopy of fatty acids and lipids, and he made great advances in studies of the synthesis of fatty acids and their chemical reactions. These endeavours were recognized by international awards by the American Oil Chemists’ Society (AOCS), i.e., the prestigious Lipid (Supelco) Award (1973), Alton E. Bailey Award (2005) and Stephen Chang Award (2006), while the German Society for Fat Science awarded him their Kaufmann medal (1976) and Normann Medal (1998), and the Association Francaise pour l’Etude des Corps Gras awarded him the Chevreul Medal (1990). His first book, An Introduction to the Chemistry of Fats and Fatty Acids (Chapman and Hall Pub., London 1958), was for many years the only one available on this topic.
His former student Marcel Lie Ken Jie has had a distinguished career as a Professor in the School of Biological Sciences at the University of Hong Kong, and he has published a substantial biography of Frank that tells of his achievements in much greater detail than is possible here (Frank D. Gunstone – Teacher, researcher, and writer. Eur. J. Lipid Sci. Technol., 117, 135-140 (2015); DOI - open access). This blog is my personal tribute.
I first encountered Frank in his lectures to undergraduates in 1957, when I was greatly impressed by the clarity and organization of his presentations, and the personal interest he took in his tutorials. When it came time to consider a PhD degree, it was the person rather than the topic that was the main factor in my decision. Three successful years later, I has happy to take his advice and apply to Ralph Holman at the Hormel Institute for a post-doctoral fellowship, and when that ended Frank made a temporary place available in his lab for me while I looked for a permanent position. While I was subsequently employed at the Hannah Research Institute in Ayr, Frank commissioned me to write my first independent review articles and encouraged my further literary ambitions. He was always available to discuss lipid science and act as a mentor.
When I moved to the James Hutton Institute (Invergowrie, Dundee), much closer to St Andrews, Frank was officially retired but he continued to write and lecture, and he maintained a small analytical service with one part-time technician, mainly for small companies who could not afford appropriate laboratory facilities. However, in 1995, he had to relinquish this when his lab was required by others after a bad fire in the department. He offered this analytical service to me, and after a brief discussion with the head of the commercial arm of the Institute (Mylnefield Research Services), we welcomed this with open arms and invited Frank to join us as a consultant. This was the start of the MRS Lipid Unit with one technician and an annual turnover of £40,000. By the time Covid struck, this had seven staff and a turnover of £500,000. Frank helped to train and encourage staff, liaised with chemical and pharmaceutical customers, and with myself and other colleagues, he inaugurated an annual three-day course on Lipid Chemistry, which attracted participants from all over Europe and further afield. He continued with these activities into his late 80s, although he could no longer drive and required a tedious two-bus journey to reach us.
Four years or so ago, Frank was struck down by a serious illness and had to go into residential care. Although he was frail physically, he remained mentally alert and enjoyed visits from friends and former colleagues. Sadly, these visits came to an end because of Covid, and now we miss his life, work and example.
November 1st, 2021
My arms are full of holes from all the vaccinations I have received, including the flu vaccine and my Covid booster in the last month, but so far my wife and I have kept clear of illness and I am able to continue with this blog. Like most of you, I am frustrated about how much of life is passing me by. While Skype and Zoom have been invaluable, they do not really make up for visits with family. Thousand of papers have appeared on the science of the infection, and of course only specialists can hope to keep up with it all (a search for "lipids and covid" for the current year listed 534 publications). As far as clinical studies are concerned, I am little more than a layman, so I hesitate to make pronouncements. That said, I have been intrigued by a number of publications suggesting that phospholipases may be to blame for the severity or prolongation of Covid symptoms. Secretory phospholipase A2 in particular has been heavily implicated, and highly elevated serum levels have been reported in several studies (e.g., DOI1 and DOI2). It is easy to imagine that this could have a direct impact by causing damage to cell membranes in addition to setting off eicosanoid cascades with physiological consequences. Other lipases such as a phosphatidylserine-specific phospholipase have also been implicated in this and other respiratory diseases such as COPD. Hopefully, this knowledge will lead to new therapeutic treatments for Covid.
The COP26 Conference is on in Glasgow this week, so out of interest (or for amusement) I carried out a search for "lipids and (climate change)" in the Web of Science; this gave a list of 368 publications for the current year.
October 27th, 2021
In the news this week,
a fossil triceratops was sold at auction for £5,500,000, while a fossilized crab caught in amber was a headliner
in many popular scientific web sites.
What are fossilized lipids worth? Probably not much in monetary terms other than as components of petroleum deposits,
but they are of great interest scientifically.
Proteins and DNA don’t last but the hydrocarbon cores of lipids can survive in sedimentary deposits for time-scales of billions of years, and
diagnostic structural features are often recognizable.
They can delineate the period when life in the oceans switched from bacteria mainly to algae, and they mark bio-extinction events or periods
of biotic stress such as elevated temperatures.
They can also help with the identification of fossils of higher organisms.
Some such molecules like the hopanoids were identified first in sedimentary deposits,
some as much as 2.7 billion years old, before they were found in living bacteria.
Highly unsaturated molecules such as carotene survive as fully saturated carotane, and this is a biomarker for the origins of photosynthetic
organisms.
Could we one day identify extra-terrestrial life in this way?
I can recommend a new review on the topic to all lipid lovers (Summons, R.E. et al. Lipid biomarkers:
molecular tools for illuminating the history of microbial life. Nature Rev. Microbiol., in press (2021);
DOI).
The biology of cholesterol oxides has been a major topic of interest in recent years, and I have done my best to keep up with the more important aspects at least. However, I have just been made aware of one issue that I had neglected, namely the biological fate and activity of cholesterol hydroperoxides. These are reduced much more slowly than fatty acyl hydroperoxides to the corresponding hydroxides, especially when they are located in membranes. They can be transferred between membranes and then impact negatively on tissue metabolism, for example by impairing cholesterol utilization in steroidogenic cells or anti-atherogenic reverse-cholesterol transport in vascular macrophages. See a new review (Girotti, A.W. and Korytowski, W. Pathophysiological potential of lipid hydroperoxide intermembrane translocation: Cholesterol hydroperoxide translocation as a special case. Redox Biol., 46, 1020962 (2021); DOI).
October 20th, 2021
It is a truism that improvements in analysis lead to increases in our knowledge of biochemistry and other scientific disciplines. In recent years, this is exemplified by the developments in mass spectrometry that have turned lipid analytical methodology from a fringe activity into the recognized science of lipidomics. However, not every analytical development need involve costly equipment. For many years, including much of the 1970s, the most highly cited publication in the scientific literature was the ‘Folch’ procedure using chloroform-methanol for the quantitative preparation of relatively pure extracts of lipids from tissues (DOI). Another in the top five was a method for preparing methyl esters of fatty acids for GC analysis (DOI). I have just been reading a fascinating review on the biochemistry of lipopolysaccharides (LPS) from Gram-negative bacteria, in which I learned that protocol for the isolation of these using hot phenol-water and published in 1952 by Westphal and Lüderitz (DOI) is still in use today. These molecules are of course responsible for the toxicity of many pathogenic bacteria, and for their resistance to antibiotics, so the ability to isolate and characterize them has vastly increased our understanding of the underlying science. This culminated in the award of a share in the 2011 Nobel Prize for Physiology or Medicine to Bruce A. Beutler for his discoveries in relation to the identification of Toll-like receptor 4 (TLR4) as the immune sensor that perceives and binds the LPS.
I can’t imagine a more thorough and readable review of the topic than that just published (Di Lorenzo, F. et al. A journey from structure to function of bacterial lipopolysaccharides. Chem. Rev., in press (2021); DOI). Only the specialist will want to delve into it deeply, but the introductory pages are well worth a read during your next lunch break (or you can view my web page here).
October 13th, 2021
I have to confess that until I began to compile the web pages in my Lipid Essentials section, I had not paid as much attention as I should to sterols and their metabolism. One aspect that I had largely overlooked is the reduction of cholesterol to coprostanol in the intestines, which I covered in one sentence in the relevant web page. In my defence, I have not seen much more than this in many reviews I have read. Now a new publication is devoted solely to this topic, and it appears that this may be a more important route to the elimination of cholesterol from the body than I had realized (Juste, C. and Gerard, P. Cholesterol-to-coprostanol conversion by the gut microbiota: what we know, suspect, and ignore. Microorganisms, 9, 1881 (2021); DOI). There are two mechanisms for this conversion in bacteria, one involving direct reduction and another via cholestenone and coprostanone as intermediates, and the relevant genes have only recently been identified. The authors suggest that this knowledge “could pave the way for the use of the cholesterol-to-coprostanol metabolism as a predictive biomarker of health status and may lead to microbiota-targeted therapeutic interventions, for example, in the context of cardiovascular disease”.
Bis(monoacylglycero)phosphate ('BMP') is a unique phospholipid in many ways, but in particular that its stereochemical configuration differs from that of all other animal glycero-phospholipids in that the phosphodiester moiety is linked only to positions sn-1 and sn-1’ of glycerol, rather than to positions sn‑3 and sn‑3’. It is most abundant in the internal membranes of mature or ‘late’ endosomes. A new report shows that it may not be unique to animals as the plant bacterial pathogen Agrobacterium tumefaciens can take up lyso-phosphatidylglycerol and convert it to two distinct isoforms of BMP (Czolkoss, S. et al. Synthesis of the unusual lipid bis(monoacylglycero)phosphate in environmental bacteria. Environm. Microbiol., in press (2021); DOI). However, it does not appear to be known whether these forms have the distinctive stereochemistry of the animal lipids.
October 6th, 2021
The activation of C-H bonds in aliphatic and other compounds in order to introduce an oxygen atom is not a simple task in chemistry as such bonds are thermodynamically strong and rather inert. Of course, there are many enzymes that can accomplish this with the added advantage that they have high positional and stereo selectivity. The biotechnology industry has identified many enzymes from bacteria and fungi, including lipoxygenases and P450 monooxygenases, that have the required properties, although many of these require costly co-factors and regeneration systems. However, some fungi produce peroxygenases that introduce oxygen atoms into aliphatic (including alkanes) and aromatic compounds and they only require H2O2 for their catalysis. A new review terms them “dream biocatalysts” (Aranda, C. et al. Advances in enzymatic oxyfunctionalization of aliphatic compounds. Biotechn. Adv., 51, 107703 (2021); DOI).
For some years, it has been evident that the oxylipin 12S-HETE promotes cancer by various mechanisms, and that platelets have similar effects, although with the latter the mechanism was unknown. Now, an elegant series of experiments with co-cultures of platelets and colon cancer cells in vitro has demonstrated that extracellular vesicles derived from platelets deliver 12-lipoxygenase to cancer cells, where 12S‑HETE is generated as the free acid or linked to the plasmalogen form of phospholipids. As this enzyme was then detected in such vesicles in plasma of patients with adenomas or adenocarcinomas, it is apparent that these lipids have the potential to affect cancer cell biology in vivo also (Contursi, A. et al. Platelets induce free and phospholipid-esterified 12‑hydroxyeicosatetraenoic acid generation in colon cancer cells by delivering 12‑lipoxygenase. J. Lipid Res., 62, 100109 (2021); DOI). Hopefully, this information will one day lead to new anti-cancer therapies.
Continuing the topic of oxylipins, an editorial summarizes themed reviews published over the last year or two on "eicosanoids in cancer" (Front. Pharm. DOI).
September 29th, 2021
The Guinness Book of Records
has a lot to answer for.
We are continually seeking for the biggest, fasted and generally most extreme in every conceivable category.
Politicians are even worse – they must be “world leaders” at everything they do – it has become such a cliché.
Lipid scientists are not exempt from these traits, and I have discussed what may be the most abundant lipids on Earth, and those that are longest
lived in the environment, on several occasions in this blog.
I have just come across a report on a lipid-based material, which I have to confess that I had never encountered before and which may indeed be among
the most resilient organic materials on Earth (Grienenberger, E. and Quilichini, T.D. The toughest material in the plant kingdom:
an update on sporopollenin. Front. Plant Sci., 12, 703864 (2021);
DOI).
In flowering plants, sporopollenin is the structured outer pollen wall or exine surrounding pollen grains, and its resilience is evident from
its chemical preservation in fossil spores from 450 million years ago that provide the earliest record of plant life on land.
This chemical stability of sporopollenin has meant that analysis has proved to be technically very difficult, as there is no easy way to solubilize and break down such a complex biopolymer for analysis. Progress has been made, however, and while it appears that there is still much to be learned, it is now evident that it consists of hydroxylated aliphatic units linked to polyhydroxylated alpha-pyrone subunits with extensive cross-linking; phenylpropanoid units are incorporated also. Through a gene-targeted approach, it has been determined that polyketide and fatty acid synthases, together with cytochrome P450 oxygenases, produce much of the backbone of polyhydroxylated subunits, with remarkable conservation of biochemical pathways across the plant kingdom. Should we submit an entry to The Guinness Book of Records?
September 22nd, 2021
If judged by the numbers of publications on the topic in the last year or two, ferroptosis is currently one of the most active areas of lipid research. This is an often pathological form of cell death that is genetically, morphologically and biochemically distinct from apoptosis per se in that it is not activated by caspases, and pore-forming or functionally related proteins. Rather, it is dependent on iron and is characterized by the unrestricted accumulation of lipid peroxides derived from polyunsaturated fatty acids to such an extent that cellular membranes, including the plasma membrane, are disrupted.
Two important publications dealing with the effects of ether lipids in the process have appeared and these are now the subject of short commentaries (Lee et al. DOI; and Balgoma and Hedeland, DOI). It has become evident that the biosynthesis of ether-linked phospholipids influences ferroptosis. The picture is complicated, but if I understand it correctly, the new data explain why saturated fatty acids have been implicated in promoting ferroptosis, as they are reduced by the enzyme FAR1 to the alcohol precursor of ether lipids, plasmanyl forms, with subsequent addition of polyunsaturated fatty acids into position sn-2 of phospholipids (although these are not the important factor in this instance). Plasmanyl forms promote ferroptosis. However, another key factor is the action of the desaturase TMEM189 to generate the vinyl ether bond in plasmenyl phospholipids, which have different effects upon ferroptosis. The nature of the effects in different cell types varies and this may be dependent upon the concentrations of plasmalogens, especially plasmenylethanolamine, in the inner leaflet of the plasma membrane. One suggestion is that at high levels of this lipid, TMEM189 is down-regulated with protective effects against ferroptosis, while at lower levels, down-regulation of TMEM189 may not change the sensitivity to ferroptosis significantly. To further complicate matters, plasmalogens are reported to act as antioxidants in some circumstances.
September 15th, 2021
The biochemistry of the phosphoinositides has been a major topic for lipid research for more than 50 years, and this is likely to continue for the foreseeable future. From my standpoint as someone trying to provide a simplified guide to the topic, I often feel myself bogged down in a morass of seemingly unrelated facts. However, a new review has given me a new perspective, although at first glance I thought I was going to see more of the same (Overduin, M. and Kervin, T.A. The phosphoinositide code is read by a plethora of protein domains. Exp. Rev. Proteomics, 18, 483-502 (2021);). I was aware of the PH and a couple of other protein domains in the recognition of phosphoinositides, but it seems that there are at least 70 readers of this membrane code and this review suggests why. A key sentence for me that explained the role of phosphoinositides in about twenty words was - “As a master currency of organelle information, PtdIns and its network of PI isoforms organize cells into dynamic and responsive membrane-bound compartments”. Incidentally, I was introduced to a new word – ‘lipidon’, coined to describe the unique collection of co-located lipids that distinguish biological membrane nano-environments and which provide the context for PI recognition in vivo.
Following my comments on the miss-use of computerized identification of mass spectra, a correspondent has sent me a publication that supports my views (Whelton, H.L. et al. A call for caution in the analysis of lipids and other small biomolecules from archaeological contexts. J. Archaeol. Sci., 132, 105397 (2021); DOI). Although it is written for researchers for whom lipids are a secondary interest, it is worthy of a wider audience. Incidentally, the abstract of a recent publication in an ACS journal reported 15 sphingomyelin species in oil seeds, either a remarkable first or a failure of computer identification (I don’t have access to the journal to check). I should say that computer identification can be an extremely useful tool when combined with a knowledge of basic fragmentation principles in mass spectrometry and a wider understanding of lipid science. For example, I was once highly sceptical when our computer identified 9-hydroxy-nonanoic acid in a bacterial sample, before realizing that it was correct.
September 8th, 2021
As I mentioned in a recent blog, I tend to read only those analytical papers dealing with mass spectrometry of fatty acids with electron-impact ionization (GC-MS) nowadays as these were a large part of my own research interests years ago and are the subject of my mass spectrometry pages here, which I try to keep up to date. One of the commonest errors I see in papers dealing with mass spectrometry is over-reliance on the computer identification software supplied with instruments when it comes to analysis of methyl esters of monoenes and dienes. Most of these have identical mass spectra regardless of double bond position (other than when very close to the carboxyl group) or geometry. The computer will give 98-99% identification confidence for all of these, so users tend to pick whatever is the top of an arbitrary list if they have no understanding of the underlying chemistry. For example, I have seen more than one report of seed oils in which most of the double bonds in fatty acids were implausibly of the trans configuration or had strange cyclic structures or branch points. I even saw one published spectrum in which by far the most abundant ions were for air. The responses to my blog were that I should name and shame, so I will keep this in mind.
There are fewer papers in which GC-MS is used for fatty acid identification now and of course, I do not ignore those on newer methodology and LC-MS, which have great advantages for oxylipins, especially, though in my opinion less so for the common range of fatty acids where the old adage of "using a sledge hammer to crack a nut" comes to mind at times. My PhD supervisor and mentor Frank Gunstone identified the first natural epoxy fatty acid using nothing more than a balance, burette and his knowledge of chemistry. I do not at all advocate a return to those days, but you don’t always require equipment costing in the 7-figure range to do good work. Incidentally, Frank is nearing his 98th birthday and is well if frail.
From time to time, I like to have a rant about the scientific publishing industry, but in fairness, I must acknowledge how well many publishers are adapting to the open access movement. It is much easier for desk warriors such as myself now. There are still holdouts of course, but I suspect that it is only a matter of time before most bow to the inevitable. The other major improvement is in the area of early access to new publications. Of the three main publishers, Elsevier, Wiley and Springer, I prefer how the first of these tackles the problem in giving a volume number, article number and DOI address without waiting for a journal issue to be completed. If I could make one change, I would like to see an addition to the article number to show the number of pages, e.g., xxxxxx-yy, so we know whether it is a short note or something much more substantial. With the other two publishers, it is a chore to have to cite papers as simply “in press” without a volume number or even sometimes the year of final publication in my literature service pages and elsewhere, and then to have to fill in the details at a later date.
September 1st, 2021
I have commented on developments in the production and properties of microbial lipopeptides many times over the years in this blog in the hope that novel antibiotics would emerge to engage with antibiotic resistant strains of bacteria. So far, the results have been disappointing, and for example, of the 3000 or so membrane-active antimicrobial peptides discovered, only two lipopeptides, have been approved with reservations by the U.S. Food and Drug Administration (FDA) for therapeutic applications, i.e., daptomycin and colistin (polymyxin E), although gramicidin could perhaps be added to the list. Applications against plant pathogens or in bioremediation do hold more promise perhaps. However, I have tended to overlook the fact that bacteria do not produce these molecules for our benefit, but for their own purposes, for example to aid motility, to gain a competitive advantage against other microorganisms and to de-toxify (or make use of) heavy metals in their environment. A new review has given me an important reminder of these aspects (Gutiérrez-Chávez, C. et al. The ecological roles of microbial lipopeptides: Where are we going? Comput. Struct. Biotechn. J., 19, 1400-1413 (2021); DOI).
You are unlikely to find a more comprehensive review on fatty acid synthases than one just published (Paiva, P. et al. Animal fatty acid synthase: a chemical nanofactory. Chem. Rev., 121, 9502-9553 (2021); DOI). I am working my way through it and am still on the easy readable part, though I doubt whether I will make it to the end when the going gets tougher.
August 25th, 2021
In many species of bacteria,
an oleate hydratase requiring FAD as a cofactor catalyses the addition of water to the double bond of oleic acid
to produce (R)‑10‑hydroxystearic acid with high stereospecificity.
One suggested explanation of this activity is that it is a mechanism to remove toxic (to bacteria) unsaturated fatty acids from a growth medium.
Many microbial enzymes of this type that produce saturated and unsaturated hydroxy and keto acids are being studied, as the products have potential
industrial value, as a new review describes (Hagedoorn, P.L. et al. Novel oleate hydratases and potential biotechnological
applications. Appl. Microbiol. Biotechnol., in press (2021); DOI).
An enzyme of this type together with a microbial acyltransferase has been utilized in an elegant method for synthesising fatty acid esters of hydroxy fatty acids
of the kind present in animal tissues
(FAHFA) (Zhang, Y. et al. A bi-enzymatic cascade pathway towards optically
pure FAHFAs. Chem. Eur. J., 22, 2146-2153 (2021); DOI).
We now must classify these with the oxylipins as they are oxygenated lipid mediators with anti-diabetic and anti-inflammatory properties.
My understanding is that we have very little knowledge yet of how these are produced in animal tissues, but I presume that someone has looked
for oleate hydratase activity.
I no longer agree to review papers, mainly because it is so long since I was involved in research and I am not up to date with the latest methodology, although in years gone by, I did indeed do my duty in this respect. Of course, I do read some analytical papers still, mainly in relation to my former research interests, and mass spectrometry of fatty acids in particular, as these are relevant to this website. Occasionally, I find some gross errors, often relating to misunderstandings of computerized identifications, which I then report to the journal editors. However, some editors do not respond. I have never discussed any of these in this blog or in any public forum, although it does concern me that such errors may be propagated. Am I being too kind to authors and editors?
August 18th, 2021
It is now well established that cholesterol and sphingolipids spontaneously form stable subdomains in the plasma membrane termed ‘rafts’, which act as signalling platforms by attracting specific proteins. The key to the phenomenon is that the two lipid classes form extensive intramolecular hydrogen bonds with each other leading to formation of a stable ordered phase and phase separation in the membrane. In particular, the packing of the relatively saturated acyl/alkyl chains of sphingolipids with cholesterol is thermodynamically favoured over that with unsaturated chains. I was intrigued to see that this phenomenon has been exploited in a chromatographic system in which cholesterol was bonded to an inert support to act as the stationary phase for separation of plant glucosylceramides according to the geometry of the double bond in position 8 of the sphingoid base component (Steshin, M. and Ishikawa, T. Liquid chromatography-tandem mass spectrometry with a new separation mode for rapid profiling of the Z/E isomers of plant glucosylceramides. J. Chromatogr. B, 1178, 122807 (2021); DOI). This separation is apparently much more difficult with conventional reversed-phase columns. I will look forward to seeing further applications of the technology.
August 11th, 2021
It was something of a surprise to learn that very little was known of the catabolism of phytol in plants, although this molecule is essential for photosynthesis and thence for all life on earth as a key component of chlorophyll. It is also vital for the biosynthesis of tocopherols (vitamin E) and phylloquinone (vitamin K). Now, it has been determined that phytenal is an intermediate in the degradation of phytol, although doubts appear to remain as to the enzymology of this process (Gutbrod, P. et al. Phytol derived from chlorophyll hydrolysis in plants is metabolized via phytenal. J. Biol. Chem., 296, 100530 (2021); DOI (see also a commentary on the paper at DOI - both open access). Subsequent steps are also uncertain although phytanoyl-CoA has been detected in stressed plants. As phytenal is a highly reactive unsaturated aldehyde and potentially toxic via its interaction with proteins, its concentration must be kept at a low level by competing pathways.
I have commented on two occasions in this blog in the past year on the difficulty of browsing through the Journal of Biological Chemistry. I still find this difficult, although I am happy to report that improvements have been made such that the Web of Science, which I use for much of literature updates, is now able to list papers in this journal, and this has enabled me to catch up – hence my entry above. Once I have this blog out of the way, I am sure that I am going to enjoy reading the autobiographical note by Professor George M. Carman (Lipid metabolism has been good to me. JBC, 296, 100786 (2021); DOI). I am sure many of us will echo the sentiments in the title, and perhaps the converse - "we have been good for lipids".
August 4th, 2021
When discussing the special physical properties of sphingolipids in relation to their functions in membranes, I have usually considered two regions of the molecule, i.e., first, the two hydrophobic alkyl chains, which are largely saturated (or trans unsaturated) and linear entities that pack relatively tightly and increase the thickness of membranes, and second, the polar headgroups which stick out from the membranes to interact with molecules in the aqueous phases. Now a new review has pointed out that we should also be considering what it terms the ‘sphingoid motif’, which is defined as the first five carbons of the sphingoid base as these “can undergo a relatively large number (compared to other lipid species) of molecular interactions with other membrane lipids, via hydrogen-bonding, charge-pairing, hydrophobic and van der Waals interactions”, for example with the cholesterol in the plasma membrane (Dingjan, T. and Futerman, A.H. The role of the ‘sphingoid motif’ in shaping the molecular interactions of sphingolipids in biomembranes. Biochim. Biophys. Acta, Biomembranes, 1863, 183701 (2021); DOI). This motif has atoms with both hydrogen donating and accepting properties in comparison to glycerolipids which may only have hydrogen accepting atoms in the corresponding region. In addition, the distinctive stereochemistry of this motif is important for interaction with proteins such as the ceramide transport protein CERT. My favourite quotation from the paper is that sphingolipids "display inordinate beauty" - please read it for an explanation.
The fatty acid esters of hydroxy fatty acids (FAHFA) are one of the most intriguing new classes of oxylipin to have been described in recent years, and they have been reported to have anti-diabetic, anti-inflammatory, anti-apoptotic, and antioxidant activities, with the last at concentrations comparable to those of the specialized pro-resolving mediators. A new report suggests that the antioxidant activity may be due to the effect of docosahexaenoic-containing estolides, as DHA-linked to 12-hydroxystearic acid is a potent stimulator of the nuclear factor erythroid 2-related factor 2 (NRF2), which is involved in upregulation of antioxidant enzymes and has a protective cellular function - another beneficial effect of omega-3 fatty acids (Gowda, S.G.B. et al. Docosahexaenoic acid esters of hydroxy fatty acid is a novel activator of NRF2. Int. J. Mol. Sci., 22, 7598 (2021); DOI - open access).
July 28th, 2021
We tend to discuss the
docosanoids (fatty acids of the omega-3 family) or specialized pro-resolving mediators (SPMs)
in terms of animal metabolism and especially as the generic term suggests as functioning at the later stages of inflammation to bring an end
to the acute inflammatory response.
However, it is now evident that SPMs are not only produced by animals but by marine diatoms (micro-algae).
For example, the diatom Cylindrotheca closterium is apparently a prolific producer of SPMs, and it forms appreciable amounts of
the resolvin RvE3 and novel structurally related eicosanoids derived from eicosapentaenoic acid with anti-inflammatory properties
(Jagusch, H. et al. 14,17,18-Trihydroxy-eicosatetraenoic acid: a novel pro-resolving lipid mediator from
marine microalgae. ACS Pharmacol. Transl. Sci., 4, 1188-1194 (2021);
DOI ).
What function these oxylipins have in this organism is a mystery, but I hope that they will one day prove to be a source for therapeutic
use in humans.
Now if only ACS had a more generous access policy so that I could actually read the paper.
July 21st, 2021
The Archaea represent one of the three primary kingdoms or domains of living organisms, and they include thermophiles, halophiles and acidophiles, collectively termed 'extremophiles'. They are single celled organisms with a low deoxyribonucleic acid content and lacking a nuclear membrane. The lipids of Archaea are different from those of Bacteria and Eukaryotes in many ways, and in particular, they contain isoprenoid moieties linked by ether bonds to glycerol with unique stereochemistry at the glycerol moieties. A further complication is the formation of internal cyclopentane and cyclohexane rings, produced by internal cyclization of the isoprene chains. These reduce the permeability of the cell membranes and permit growth at extreme pH, salinity, and temperatures.
As an example, crenarchaeol from hyper-thermophilic organisms of the Thaumarchaeota is a 66-membered macrocycle with four 1,3-trans-substituted cyclopentane moieties, one of which is connected by a single bond to a cyclohexane ring, a highly unusual and rare structural feature. There are 22 mainly remote stereocentres. The initial determination of the structure must have been a daunting task, but a revised structure has now been published involving total synthesis that demonstrates a correction in which one (only) of the 22 stereocentres is inverted from the original (Holzheimer, M. et al. Total synthesis of the alleged structure of crenarchaeol enables structure revision. Angew. Chem.-Int. Ed., in press (2021); DOI - open access). I am impressed – simply re-creating the structure in ChemWindowsTM was a sufficient challenge for me!
July 7th, 2021
I have dismissed definitions of lipids based on their solubility in organic solvents on numerous occasions over the years. For example, I would never consider trimethyl arsine to be a lipid, although some do because of its solubility properties, while gangliosides are undoubtedly lipids, although they are more soluble in aqueous systems. The latter are fascinating sphingolipids that are located on the outer leaflet of the plasma membrane, often in local subdomains or rafts, with the polar carbohydrate moieties sticking out into the extracellular space where they can function to receive molecular signals of various kinds that are vital to health. On the other hand, there is a great deal of evidence that synthesis of specific gangliosides, e.g., GD2, GD3 and fucosyl-GM1, is upregulated in certain cancers. For many years, it was not certain whether these were merely a symptom or else a cause, but it is now clear that they are responsible for many of the ill effects of the disease, sometimes simply by enabling escape from immune surveillance, but often by promoting the malignant properties of gliomas by mediating cell proliferation, migration, invasion, adhesion and angiogenesis.
The phrase “light at the end of the tunnel” has been over used in the last year in relation to covid, but it seems appropriate now in the context of gangliosides as antibodies have been developed that have been tested alone or in synergy with drugs in successful clinical trials against various cancers. A new review is an admirable introduction to the topic and is open access (Groux-Degroote, S. and Delannoy, P. Cancer-associated glycosphingolipids as tumor markers and targets for cancer immunotherapy. Int. J. Mol. Sci, 22, 6145 (2021); DOI).
As a young researcher, I had recourse to IR and UV spectroscopy on many occasions, as affordable mass spectrometry and NMR spectroscopy were just on the horizon and the top of our wish list. It was somehow satisfying to learn that UV spectroscopy still has its uses, especially for identification of products in the docosanoid field, and specifically for configurations of double bond and hydroxy versus hydroperoxide functionality (Jin, J. et al. Analysis of 12/15-lipoxygenase metabolism of EPA and DHA with special attention to authentication of docosatrienes. J. Lipid Res., 62, 100088 (2021); DOI).
June 30th, 2021
I do not claim
to be an expert on nutritional aspects of fatty acid biochemistry, but my understanding is that dietary supplements
of fish oils and especially of docosahexaenoic acid (DHA) aid cognitive development in young children,
but they have no effect upon cognitive decline in the elderly.
One explanation for the latter may be that the DHA is not used efficiently in the aging brain.
A new publication reports that there is a loss of acyl-CoA synthetase 6, which is specific for DHA, in the brains of aging mice
and that this depletes brain membrane phospholipid DHA levels, independently of diet (Fernandez, R.F. et al.
Acyl-CoA synthetase 6 is required for brain docosahexaenoic acid retention and neuroprotection during aging.
JCI Insight, 6, e144351 (2021); DOI).
It also appears that astrocytes express a non-DHA-preferring ACSL6 variant.
Another important factor for the uptake of DHA by the brain is a requirement for this to be preferentially esterified to lysophosphatidylcholine for transport across the blood-brain barrier requiring a specific receptor/transporter known as the sodium-dependent LPC symporter 1 (MFSD2A). The structure of this molecule has now been determined and shows that it functions through conformational changes that allow for the release of substrates into the membrane through a lateral gate (Cater, R.J. et al. Structural basis of omega-3 fatty acid transport across the blood-brain barrier. Nature, in press (2021); DOI)
Back in April, I complained that I found it difficult to browse through the new-look Journal of Biological Chemistry. I am not alone, as the Web of Science has still not listed any papers from the current volume although we are half way through the year.
June 16th, 2021
In a blog of a few weeks ago, I suggested that many of the minor fatty acids in animal tissues were not there simply to make up the numbers but had distinct biological functions. A new review suggests that odd-chain fatty acids are important dietary components (Dorna, K. et al. Odd chain fatty acids and odd chain phenolic lipids (alkylresorcinols) are essential for diet. J. Am. Oil Chem. Soc., in press (2021); DOI). As I understand it, the evidence comes mainly from nutritional and epidemiology studies, and some of the conclusions seem speculative but are nonetheless interesting. The main source of odd-chain fatty acids in the human diet is dairy products, but some synthesis de novo is possible.
Oxo fatty acids are also present in dairy products, and with my colleague Elizabeth Brechany, I identified 51 different fatty acids of this type in cheese many years ago (saturated – DOI, unsaturated - DOI); their mass spectrometric characteristics are described on this web site for methyl and 3‑pyridylcarbinol esters. Now, isomeric fatty acids of this type have been detected in human plasma; it is reported that they have biological activity and may be protective of human health (Batsika, C.S. et al. Saturated oxo fatty acids (SOFAs): a previously unrecognized class of endogenous bioactive lipids exhibiting a cell growth inhibitory activity. J. Med. Chem., 64, 5654-5666 (2021); DOI).
Another group of minor fatty acid components that perhaps should receive more attention are the branched-chain fatty acids. Humans produce such fatty acids in meibomian gland secretions, and 18-methyl-eicosanoic acid makes up a high proportion of the covalently bound fatty acids in mammalian hair (40% in humans). There must be good biochemical reasons for this, as yet unknown although speculation can be fun. Indeed, our primitive ancestor, the nematode Caenorhabditis elegans, is absolutely dependent on synthesis of branched-chain fatty acids de novo for growth and development.
June 9th, 2021
The process of autoxidation is of critical important to innumerable aspects of lipid biochemistry, and I have dealt with it in web pages here in relation to fatty acid hydroperoxide and aldehyde formation, isoprostanes, oxidized phospholipids and oxy-sterols (and others), and of course the actions of antioxidants are equally important, including my web pages here on tocopherols and coenzyme Q. Ferroptosis, a process of apoptosis induced by iron and hydroperoxides, is currently a hot topic. Aside from the biochemical effects, autoxidation and food spoilage are of vital economic importance. Two new reviews have just appeared on autoxidation (Juan, C.A. et al. The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies. Int. J. Mol. Sci., 22, 4642 (2021); DOI, and Helberg, J. and Pratt, D.A. Autoxidation vs. antioxidants - the fight for forever. Chem. Soc. Rev., in press (2021); DOI). One of these is open access and the other will cost me £42 to read. Guess which one I have to ignore! I don’t understand how journals can justify such high prices for pdf files.
Prostanoid-like lipids, the phytoprostanes are produced in plants in vivo, where they influence to response of plants to stress situations, and I presume that they must also be formed in plant foods during storage. As such, they are bio-active components of the human diet, and a new study demonstrates that they can protect against inflammatory events caused by the prostaglandin synthase COX-2 (Campillo, M. et al. Phytoprostanes and phytofurans modulate COX-2-linked inflammation markers in LPS-stimulated THP-1 monocytes by lipidomics workflow. Free Rad. Biol. Med., 167, 335-347 (2021); DOI).
June 2nd, 2021
Sulfoquinovosyldiacylglycerol the plant sulfolipid, is the single glycolipid most characteristic of photosynthetic organisms, including higher plants, algae, chloromonads and cyanobacteria, and it is unusual in many ways, not least in that it is a sulfono-lipid not a sulfate. If we exclude betaine lipids, ether lipids are rarely detected in plants and sometimes any such reports have been controversial. Now these two oddities are combined in a single lipid and organism, i.e., sulfoquinovosylchimyl alcohol from an algal species (Oku. N. et al. Sulfoquinovosylglyceryl ether, a new group of ether lipids from lake ball-forming green alga Aegagropilopsis moravica (family Pithophoraceae). Chemistry-Asian J., in press (2021); DOI). In effect, this new lipid is an ether analogue of lysosulfoquinovosyldiacylglycerol. Apparently, the organism has a distinctive life-style, and perhaps this new lipid assists this in some way.
A new report suggests that conjugated linoleic acid in the diet may be beneficial towards Alzheimer's disease (Fujita, Y. et al. Dietary cis-9,trans-11-conjugated linoleic acid reduces amyloid beta-protein accumulation and upregulates anti-inflammatory cytokines in an Alzheimer's disease mouse model. Sci. Rep., 11, 9749 (2021); DOI). Although the authors don't appear to mention the possibility, I wonder whether the effects might be mediated via the nitro adducts, which have well-established anti-inflammatory properties. I trust that I don’t need to dose myself with CLA yet, but you never know! Perhaps I should volunteer to replace a mouse in future trials. Incidentally, a review of another aspect of lipid metabolism and Alzheimer's disease has just been published (Gamba, P. et al. The controversial role of 24-S-hydroxycholesterol in Alzheimer's disease. Antioxidants, 10, 740 (2021); DOI).
May 26th, 2021
Lipid
signalling by lysophospholipids has become a major topic for lipid research in the last 20 years or so, but who would have expected
lysophosphatidylglucoside to be of particular interest?
After all, the parent phosphatidylglucoside is a very minor component of brain tissue
especially, though first found in human cord red cells, and rarely menioned in lipidomics studies;
it has been shown to exist in the form of a single saturated molecular species with 18:0 at position sn-1 and 20:0 at position sn-2
of the glycerol backbone, a highly un-mammalian-like structure for a phospholipid!
In addition, it has been shown more recently to exist in enantiomeric forms, i.e., a small proportion has the phosphoglucose moiety attached
to position sn-1 of an sn-2,3-diacylglycerol backbone. Again, this feature appears to be unique to this lipid.
The lipid backbone may have similar physical properties to those of a ceramide and I suspect that this may explain some of its functions in membranes.
But back to the lyso form. That in brain was reported to have distinctive biological activity in guiding the specific location of axons
in the developing spinal cord, while mediating glia-neuron communication.
The mechanism involves a G protein-coupled receptor GPR55, which was first identified as a receptor for lysophosphatidylinositol,
but about 5 years ago this was determined to have a much higher affinity for lysophosphatidylglucoside.
Now a new review places this activity in the context of those of other lysophospholipids (Guy, A.T. and Kamiguchi, H.
Lipids as new players in axon guidance and circuit development. Curr. Opinion Neurobiol., 66, 22-29
(2021); DOI).
May 19th, 2021
Two weeks ago, I expressed an interest in some of the idiosyncrasies of lipid metabolism in insects, and they continue to fascinate. The fruit fly Drosophila melanogaster, widely used as a model species, is a vegetarian and derives much of its unsaturated fatty acids from its diet; these do not include arachidonic, which can be lethal in some of the insect's developmental stages. It has now been determined that this species utilizes 2‑linoleoyl-glycerol as a signalling molecule in an endocannabinoid-like way in much the same manner as 2‑arachidonoyl-glycerol in higher animals (Tortoriello, G. et al. Genetic manipulation of sn-1-diacylglycerol lipase and CB1 cannabinoid receptor gain-of-function uncover neuronal 2‑linoleoyl glycerol signaling in Drosophila melanogaster. Cannabis Cannabinoid Res., 6, 119-136 (2021); DOI – open access). The suggestion is that this may be a signalling system from which endocannabinoids developed during evolution.
One of the most basic aspects of the plasma membrane is its lipid composition and how the various lipid components are distributed between the two leaflets of the bilayer. There appears to be little dubiety of how the phospholipids are distributed, but perhaps surprisingly the trans-bilayer distribution of cholesterol in the plasma membrane of mammalian cells has remained controversial. A new study using cholesterol sensors appears to confirm that the concentration of cholesterol in the inner leaflet is much lower than that in the outer leaflet in a range of mammalian cells (Buwaneka, P. et al. Evaluation of the available cholesterol concentration in the inner leaflet of the plasma membrane of mammalian cells. J. Lipid Res., in press (2021); DOI).
May 12th, 2021
Some interesting analytical papers crossed by desk this week. We tend to think of lipids as relatively small molecules (MW <1000), but the lipid A constituents of the cell walls of Gram-negative bacteria are much larger. They are heterogeneous mixtures that can contain up to six fatty acids of variable chain-lengths, some with hydroxyl groups or methyl branches, in addition to carbohydrate moieties and various ‘decorations’ including phosphate groups. Analysis is not a challenge likely to be accepted by the faint-hearted, so I was pleased to see some remarkable separations in a new publication. One secret was the use of ammonia-based elution schemes to prevent adsorption on stainless steel tubing (Okahashi, N. et al. Analyses of lipid A diversity in Gram-negative intestinal bacteria using liquid chromatography-quadrupole time-of-flight mass spectrometry. Metabolites, 11, 197 (2021); DOI). The main technical difficulty in the analysis of arsenolipids, on the other hand, arises from the low levels of their natural occurrence in marine samples not from inherent difficulties with their chemistry. A new approach to mass spectrometry has enabled the discovery of 23 new lipids of this type (Liu, Q.Q. et al. Discovery and identification of arsenolipids using a precursor-finder strategy and data-independent mass spectrometry. Environ. Sci. Techn., 55, 3836-3844 (2021); DOI). Both of these papers are open access.
It is a long time since I was actively involved in research, and I know that my knowledge of the newer analytical methodologies is waning. Regretfully, I must confess that I did not understand a word of the methodology description in the abstract of one new publication (and I don’t have access to ACS journals), but the claims to be able to locate double bonds with their geometry and the regiospecific distributions of the acyl groups is impressive (Bouza, M. et al. Triboelectric nanogenerator ion mobility-mass spectrometry for in-depth lipid annotation. Anal. Chem., 93, 5468-5475 (2021); DOI).
May 5th, 2021
Insects are crucial for many aspects of life on earth. They recycle nutrients, pollinate plants, control populations of other organisms, and provide a major food source for birds and animals. It is impossible to love the Scottish midge, but I find it surprising that we appear to know relatively little of insect biochemistry, especially in relation to lipids. One problem appears to be that there are so many different genera and species of insects and even within a genus, it is my impression is that the biochemistry can be very varied. I have just been reading a review of the lipid metabolism in the fruit fly Drosophila melanogaster, in which it appears that as in humans, triacylglycerol homeostasis is dependent on the interaction of organ systems involved in lipid uptake, synthesis and processing that are regulated by a network of hormones and messengers (Heier, C. et al. The Drosophila model to interrogate triacylglycerol biology. Biochim. Biophys. Acta, Lipids, 1866, 1163-1184 (2021); DOI). Lipid transport in the circulation of insects is very different from that in higher animals in that hemolymph, the circulatory fluid in insects, contains a single multifunctional lipoprotein termed lipophorin that transports lipids largely in the form of 1,2-diacyl-sn-glycerols.
Apart from this, I have garnered a number of disparate facts concerning insects over the years and not a consistent picture. It is always the oddities that stick in the mind, and I should really look for a more comprehensive review on the topic - hence the disconnected list that follows. I understand that some insects can synthesise linoleate de novo, but others cannot. Some can synthesise polyunsaturated fatty acids and even prostaglandins, while other appear to obtain them by feeding on animal hosts. Shellac is a polymer of unusual hydroxy fatty acids secreted by the female lac bug, Laccifer lacca (and the topic of my PhD thesis of too many years ago). Aphids synthesise triacylglycerols containing sorbic (2,4-hexadienoic) acid in their surface coating of wax, while others have acetate-containing triacylglycerols in their fat depots, which remain liquid and permit them to withstand low temperatures during hibernation. Ceramide-1-phosphate was first discovered as an important component of the venom from the spider Loxosceles reclusus.
April 28th, 2021
It is evident
that arachidonic acid is special in many ways, not least because it is an essential fatty acid and the precursor of innumerable
oxylipins, in that the four double bonds permit the formation of relatively stable resonance structures.
However, we tend to think of oleic acid as a fatty acid that simply makes up the numbers and is otherwise not particularly exciting as it is not
a precursor of oxylipins that might be lipid mediators in animal tissues.
However, it can indeed be special when in ester or amide form, for example as N-oleoylethanolamide or oleamide.
The former is an endogenous regulator of food intake, and it may have some potential as an anti-obesity drug.
It is believed to act as a local satiety signal rather than as a blood-borne hormone, and food intake is inhibited in rats following intraperitoneal
injection and even after oral administration.
The effects are mediated in the intestinal brush border of enterocytes by binding with high affinity to PPARα.
2-Oleoylglycerol has similar properties and is even more abundant in intestinal tissues.
Oleamide was first isolated from the cerebrospinal fluid of sleep-deprived cats, and it has been characterized and identified as the signalling molecule responsible for causing sleep. For example, it induced physiological sleep when injected directly into the brain of rats. Although it bears little structural relationship to other endocannabinoids, it is an agonist for the CB1 receptor. Among other unique roles for this fatty acid in esterified form, distinct oleic acid-containing species of phosphatidylserine are required for some of the biological properties of the latter.
Palmitoleic acid (9-16:1) is another monoene with special properties, and indeed the term ‘lipokine’ was introduced to characterize its biological functions, i.e., it is an adipose tissue-derived molecule, which amongst other effects stimulates the action of insulin in muscle. It is also an essential post-translational modifier of Wnt proteins. I tend to believe that most if not all fatty acids are present in lipids for some reason other than to simply provide appropriate bulk properties.
April 21st, 2021
There has been a deal of bad news regarding lipids in relation to health in some of my recent blogs, so I am happy to report on something more encouraging. It seems that 4-oxo-docosahexaenoic acid (4-oxo-DHA), a lipoxygenase metabolite of DHA, is a potent anti-tumour agent (Chen, K.M. et al. Lipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer. Sci. Rep., 11, 410 (2021); DOI - open access). The structure has not been fully elucidated, but it is presumed to have a trans-5 double bond, as it is an electrophilic molecule and can undergo Michael addition with cysteinyl residues of proteins, including the nuclear factor NF-κB. Nor is the biosynthetic route to this metabolite established, although it is present in plasma of rats fed DHA. The authors suggest that it has the potential to be an important therapeutic agent.
A further class of oxylipin that has therapeutic possibilities towards any number of metabolic ailments is the epoxy-eicosanoids, formed by the action of cytochrome P450 (CYP) epoxygenases on arachidonic acid. As a new review discusses, it is now established that these have beneficial effects against cardiovascular diseases, and drugs are under development to make use of their properties (Lai, J.S. and Chen, C. The role of epoxyeicosatrienoic acids in cardiac remodeling. Front. Physiol., 12, 642470 (2021); DOI - also open access).
April 14th, 2021
As I have commented before, it is only possible to accomplish regiospecific analysis of triacyl-sn-glycerols by mass spectrometry, and not full stereospecific analysis. I fear the use of methods for the latter is becoming something of a lost art, although such information is still of as much value to biochemists as it has ever been. To keep details of the methodology alive, I prepared a web page on the topic here earlier this year. However, the flame is still being kept burning in some laboratories and I can recommend a new paper from Finland (Kalpio, M. et al. Strategy for stereospecific characterization of natural triacylglycerols using multidimensional chromatography and mass spectrometry. J. Chromatogr. A, 1641, 461992 (2021); DOI). A different kind of flame caught my eye in the title of a second publication (Smit, N.T. et al. Novel hydrocarbon-utilizing soil mycobacteria synthesize unique mycocerosic acids at a Sicilian everlasting fire. Biogeosciences, 18, 1463-1479 (2021); DOI). I enjoyed reading the paper for the authors’ use of mass spectrometric methodology to locate multiple methyl branches in novel fatty acid structures. Both publications are open access.
I am grateful to the Journal of Biological Chemistry and the Journal of Lipid Research for allowing open access to all their publications. It therefore seems a bit churlish to complain about their new web sites, which appear to have been designed with a corporate image in mind as opposed to the convenience of their readers. I used to enjoy a regular browse through both to see what was new in each issue, but this is no longer straight forward. It appears that I am not the only one to find it less convenient, as the Web of Science has not listed any publications from these journals for this year yet.
April 7th, 2021
In my blog of March 10th, I discussed the inconsistencies in the definition of what constituted an 'endocannabinoid', together with the unsatisfactory nature of this as a collective term. We can’t simply call them all bioactive amides because 2-arachidonoylglycerol does not fall into this category, but this does have one common feature with other lipids that might come under this umbrella term, i.e., the presence of an arachidonoyl moiety. The fact that anandamide, 2-arachidonoylglycerol and some other lipids function in part via two receptors CB1/2 that happen also to be activated by phytochemicals from cannabis is simply an interesting coincidence. Should we simply consider these as part of the eicosanoid super-family of lipid mediators, including lipids such as N-arachidonoylglycine, which is an agonist for GPR55 but not CB1/2? The name 'anandamide' is derived from the Sanskrit for ‘bliss’. If we need a new collective term, we could call them ‘anandalipids’. One remaining anomaly is the position of oleamide, which is an agonist for the CB1 receptor, but this could simply be grouped with the bioactive amides such as most ethanolamides other than anandamide, and simple lipoaminoacids. Incidentally, a new review of anandamide biochemistry has just been published (Biringer, R.G. The rise and fall of anandamide: processes that control synthesis, degradation, and storage. Mol. Cell. Biochem., in press (2021); DOI).
I am itching to tell you of a lipid that does not induce bliss. Chronic itch is a distressing feature of pathologies like atopic dermatitis and allergic contact dermatitis. It has now been demonstrated that cysteinyl leukotrienes are potent itch inducers and that this effect depends on the specific coupling of LTC4 with its receptor CysLT2R in peripheral sensory neurons in the mouse and in human (Voisin, T. et al. The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch. Proc. Natl. Acad. Sci. USA, 118, e2022087118 (2021); DOI). The search is presumably now on for drugs that target this receptor.
March 31st, 2021
When I
was a student, the only spectroscopic technique to which I had access was infrared spectroscopy – NMR spectrometry was
too valuable to be wasted on undergraduates.
Later, during my research career, I continued to use IR spectroscopy from time to time but only for analyses of the trans
content of fats, for which it is still useful.
However, I have seen two interesting papers on the use of cryogenic IR spectroscopy recently which look impressive.
I have no idea what the equipment looks like (or costs, though it is obviously not for the faint hearted), but the technique
involves generating ions by electrospray ionization then trapping the ions in in superfluid helium nanodroplets,
which function as IR-transparent cryostats with an internal temperature of 0.4 K.
Following the IR measurements, the ions are transferred to a mass spectrometer.
The most recent paper deals with glycosphingolipids and demonstrates that isomeric glycan head groups, anomeric configurations
and different lipid moieties can be resolved unambiguously (Kirschbaum, C. et al. Unravelling the structural
complexity of glycolipids with cryogenic infrared spectroscopy. Nature Commun., 12, 1201 (2021);
DOI. - open access).
This follows an earlier open-access paper from the same group on applications to structural analysis of sphingoid bases
(DOI).
I was intrigued by a story in the popular science site Science Alert that certain deep-sea bacteria are so alien to humans that our immune cells do not even register that they exist, making them completely invisible to our immune systems. This contradicts the assumption of near-universal bacterial detection by pattern recognition receptors that is apparently a foundation of immunology. I don't have access to the original publication, but it appears that the reason for this is that the fatty acid components of the lipopolysaccharide of the gram-negative bacteria are much longer-chain than those to which our systems are accustomed. Those darn lipids are at it again!
March 24th, 2021
In preparation for my first attempt at a podcast for LipidMaps, I had to give some thought to the definition of what constitutes a lipid – something that has taxed me for much of my research career, not least because with the honorable exception of LipidMaps most international bodies have avoided the task. I discuss this at greater length in my webpage on Lipid Nomenclature, but in brief there are three main proposals, i.e., based on solubility in organic solvents (please avoid), lipid structure/function and biosynthetic mechanisms (LipidMaps). I set myself the task of producing a new definition based solely on structural criteria and avoiding the words, ‘solubility’, ‘function’ and ‘biosynthesis’, and I came up with -
Lipids comprise a heterogeneous class of predominantly hydrophobic organic molecules of relatively low molecular weight (commonly <1000) that are defined by the presence either of linear alkyl chains, usually with even-numbers of carbon atoms and saturated or unsaturated with double bonds in characteristic positions, or of isoprene units in linear or cyclic structures. These can contain variable numbers of oxygenated substituents such as carboxylic acid or hydroxyl groups, and/or other heteroatoms, but especially nitrogen in amines, for example. Often, these are linked covalently to glycerol, carbohydrates, phosphate and other small polar entities, which can render the molecules more amphiphilic.
In effect, I am suggesting that there are two main categories of lipid, which I might term 'acyl or main-stream lipids' and isoprenoids (terpenoids), such as sterols, carotenoids and most fat-soluble vitamins. This excludes polyketides, which to me at least seem to have been included among the lipids because no none knows where else to put them. If you have a better definition or have suggestions for improvement, please let me know.
March 10th, 2021
I am sure that I am not alone in having difficulties with the definition of what constitutes an "endocannabinoid". I don't like the term itself, as it seems to put the cart before the horse, i.e., it is based on the limited response of animal tissues to the constituents of a plant product as opposed to a complex metabolic system that has taken millions of years to evolve. Until a few years ago, few would have argued when endocannabinoids were characterized as those lipids that interacted with the two known receptors for the phytocannabinoids and designated CB1 and CB2, i.e., N-arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol. These might simply have been considered to be eicosanoid metabolites, but then it was determined that the sleep signalling molecule oleamide interacted with the same receptors. Now it is known that the two main "endocannabinoids" interact with a number of other receptors, including PPARα, TRPV1, GPR55, GPR119 and TLR4, activities shared with many other lipid mediators, but mainly N-acylethanolamides, the specificities of which are determined by the nature of the acyl moiety. Some of these share the synthetic and degradative pathways of anandamide and thus may indirectly affect its function ('entourage effects').
For example, N-palmitoylethanolamide functions mainly via GPR55 and PPARα, but in certain analgesic reactions it may activate CB2 also, while N-oleoylethanolamide is an endogenous regulator of food intake and is a ligand for GPR119. I can recommend a recent review (Im, D.S. GPR119 and GPR55 as receptors for fatty acid ethanolamides, oleoylethanolamide and palmitoylethanolamide. Int. J. Mol. Sci., 22, 1034 (2021); DOI). In addition, the amine moiety can vary and include amino acids, e.g. N-acylamino acids ('elmiric acids') such as N-arachidonoylglycine, which activates GPR55. To add to the mix, the most potent endogenous lipid ligand for GPR55 known to date is 2-arachidonoyl-lysophosphatidylinositol, which is also a precursor for 2-arachidonoylglycerol. Although I have treated them separately on this website, the distinction between endocannabinoids and other bioactive amides now looks tenuous. No prizes offered, but can anyone suggest a better collective term that encompasses all of these lipids, or do we simply have to accept "endocannabinoid" in a wider sense.
March 3rd, 2021
Retinoids and vitamin A are crucial for vision and innumerable other functions in human development and metabolism, but I confess that I have never taken much interest in their precursor carotenoids. The latter are too much of a niche subject with around a thousand structural forms. Of course, they add colour to the world, but when I see carrots on my plate, they do nothing for my appetite and I eat them only from a sense of duty. However, some intact carotenoids do have a vital role in humans in relation to vision. Lutein and zeaxanthin from dietary sources such as green leafy vegetables and yellow and orange fruits and vegetables are found specifically in the macula of the eye in humans and other primates, i.e., the functional center of the retina in a small central pit known as the macula lutea, where they enhance visual acuity and protect the eye from high-intensity, short-wavelength visible light. They are currently in use to ameliorate the effects of age-related macular degeneration. A new review, part of a thematic review series ("Seeing 2020:Lipids and Lipid-Soluble Molecules in the Eye"), discusses their occurrence and function (Bernstein, P.S. and Arunkumar, R. The emerging roles of the macular pigment carotenoids throughout the lifespan and in prenatal supplementation. J. Lipid Res., 62, 100038 (2021); DOI). The authors speculate on how we primates have repurposed these photoprotective pigments from plants during evolution to protect our sight.
February 24th, 2021
It is not really
surprising that a C17 oxylipin, i.e., 12-hydroxyheptadecatrienoic acid (12-HHT) produced by the action of the
thromboxane synthase on prostaglandin PGH2,
was first though to be an artefact or a by-product of the experimental system in vitro.
It is synthesised by a rather unusual rearrangement of the endoperoxide-cyclopentane structure with expulsion of a malondialdehyde molecule.
However, it is now known to be an important metabolite that is of special relevance to leukotriene function, rather than that of thromboxanes,
in that it is an endogenous ligand for the leukotriene receptor BLT2.
It is known to induce mast cell migration, and like leukotrienes it is a factor that contributes to allergic inflammation.
In skin, it contributes to the epithelial barrier functions while promoting wound healing.
Intriguingly, its 12‑keto metabolite (12‑KHT) has some functions that oppose those of thromboxane A2.
A new publication gives a useful overview (Okuno, T. and Yokomizo, T. Metabolism and biological functions of
12(S)‑hydroxyheptadeca-5Z,8E,10E-trienoic acid. Prostaglandins Other Lipid Mediators,
152, 106502 (2021); DOI).
During my career, I have had the good fortune to meet many of the greats in lipid science, although there are of course many who I have only known through their publications. One of the latter is Dr Lina M. Obeid who passed away at the end of 2019. Her former colleagues have just published a paper reviewing her many accomplishments in relation to ceramides, O-acyl-ceramides and sphingosine-1-phosphate especially - a worthy tribute (Velazquez, F.N. et al. Bioactive sphingolipids: Advancements and contributions from the laboratory of Dr. Lina M. Obeid. Cell. Signal., 79, 109875 (2021); DOI - open access).
February 17th, 2021
A multi-laboratory effort, with involvement from Lipid Maps, has lead to the discovery of a new pathway for the biosynthesis of bile acids in humans (Abdel-Khalik, J. and 18 others. Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates. J. Steroid Biochem. Mol. Biol., 206, 105794 (2021); DOI). In patients with the genetic disorder Smith-Lemli-Opitz syndrome, a defect in cholesterol biosynthesis leads to elevated levels of 7-dehydrocholesterol in plasma, and thence to this new pathway, which proceeds through 7-oxo and 7β-hydroxy intermediates so avoiding cholesterol, and results in the formation of unusual Δ5-unsaturated bile acids. There is concern for pregnant patients with this condition, in whom some of these intermediates have been detected in amniotic fluid, as they have the potential to interfere with the function of hedgehog proteins, which are critical to developmental processes in the infant. This pathway was detected also in healthy humans but to a minor extent.
One of the side-effects of the covid pandemic has been that we have had to rely on digital meetings with family and friends, and Skype has enabled my wife and I to keep in touch with our family at least, although we miss the personal contacts. One-to-one phone calls are a poor substitute. I have also enjoyed webinars both in relation to lipid science and to my hobbies. I am sure that Zoom will be part of our lives for the foreseeable future, and it will ensure that young scientists continue to learn from the luminaries in our field; it always helps to be able to put a face and voice to a name from the literature. Time will tell if this will result in fewer conferences and less travel, although this may be of benefit if it enables wider participation in more smaller events. However, one of the great advantages of being a scientist has been the ease of making international friends and collaborators, so it will be a pity if face-to-face contacts are lessened too much when travel restrictions ease. I should add that I am making no comment on digital learning as applied to undergraduates - I truly feel for them.
February 10th, 2021
A new and very substantial kind of lipid economy in the oceans has just been described that is part of a dynamic and complex hydrocarbon cycle of biological alkanes (Love, C.R. et al. Microbial production and consumption of hydrocarbons in the global ocean. Nature Microbiol., in press (2021); DOI). It is reported that hydrocarbon-producing cyanobacteria of the Prochlorococcus and Synechococcus genera produce the hydrocarbon pentadecane (C15) by decarboxylation of palmitic acid in amounts such that two million metric tonnes are present in nutrient-poor regions of the oceans at any given time. This total dwarfs the amount of hydrocarbons from petroleum products due to spillages or seepages (by 100- to 500-fold) in the oceans, and is similar in magnitude to the atmospheric release of two other important hydrocarbons, methane and isoprene. In turn, this pentadecane production sustains the growth of a population of pentadecane-degrading bacteria, and possibly archaea, which were found to be especially prevalent in regions of the oceans that had been exposed to oil spills. We can only speculate on how pentadecane production benefits the species that synthesise it. There is an interesting popular account of this work in the online journal Science Alert.
I am getting used to and can cope with the minor physical ailments that come with getting older, but worry that one day I will be faced with a slow and inexorable loss of memory. Ironically, it appears that this may be because of my lipids. It has been reported that in mice PGE2 signalling through its EP2 receptor promotes an energy-deficient state in the brain that drives pro-inflammatory responses, effects that can be reversed by inhibition of myeloid EP2 signalling (Minhas, P.S. et al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature, 590, 122-128 (2021); DOI). The last sentence of the abstract provides hope - "Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions". But will it be possible in time for me?
February 3rd, 2021
When I am updating my web pages in the Lipid Essentials section of this web site, it gives me some pleasure to replace a phrase such as "Nothing is known of …" by "It has now been established that …" . I was therefore grateful to a correspondent who drew my attention to a new publication, which describes the likely mechanism for plasmalogen biosynthesis in anaerobic bacteria (Jackson, D.R. et al. Plasmalogen biosynthesis by anaerobic bacteria: identification of a two-gene operon responsible for plasmalogen production in Clostridium perfringens. ACS Chem. Biol., 16, 6-13 (2021); DOI). It was determined a few years ago that a diacyl-phospholipid, as opposed to an alkyl,acyl-phospholipid was the probable precursor in these organisms but now an enzyme complex containing reductase and dehydratase enzymes has been identified that is responsible for plasmalogen biosynthesis by reduction of an ester bond to a vinyl ether. It may be a universal mechanism in such species as the relevant genes have been detected in many different obligate and facultative anaerobic bacteria, including a number from the human gut.
Incidentally, it is only in the last two years that the desaturase enzymes responsible for introducing the double bond into position 1 of alkyl ether precursors of plasmalogens in aerobic bacteria and humans have been characterized.
January 27th, 2021
Papers dealing
with interactions between covid and lipids are now appearing in numbers, but the one I have found most interesting and readable is a two-page
freebie in Science (Theken, K.N. and FitzGerald, G.A. Bioactive lipids in antiviral immunity. Science,
371, 237-238 (2021); DOI).
The paper comes under the heading 'Viewpoint: covid-19' and has the subheading 'Lipids may influence viral entry, replication, and clearance
and modulate immune responses'.
It summarizes how oxidized phospholipids, sphingosine-1-phosphate and eicosanoids especially interact with viruses in general.
Oxidized phospholipids (see my account on this website) were one of the 'hot topics' last year, and ferroptosis, a type of cell death that is genetically and biochemically distinct from apoptosis per se, and is dependent on iron and characterized by the accumulation of lipid peroxides, has been the subject of several reviews listed in my literature survey pages. However, two review articles dealing with oxidized lipids in their function as lipid mediators have caught my eye this week (Oskolkova, O.V. and Bochkov, V.N. Gain of function mechanisms triggering biological effects of oxidized phospholipids. Curr. Opinion Toxicol., 20-21, 85-94 (2020); DOI: Spickett, C.M. Formation of oxidatively modified lipids as the basis for a cellular epilipidome. Front. Endocrin., 11, 602771 (2020); DOI). These deal with signalling and regulatory effects acting via specific receptors as opposed to physical effects of hydroperoxide accummulation. It is fortunate that I asked for a definition of the term 'epilipidome' a few weeks ago, as it looks as if we are going to see it used much more often.
January 20th, 2021
From time-to-time, I have a minor rant in this blog as to the accuracy of positional distributions of fatty acids in glycerolipids as determined by mass spectrometry. Of course as a retiree, I have no evidence that this methodology is not perfectly satisfactory, but then I have never seen a comparison with data obtained with older methods such as the use of phospholipase A2 from snake venom as applied to natural phospholipid samples. A recent letter to the editor suggests potential problems in calibrations for triacylglycerol regiospecific distributions by mass spectrometry (Ramaley, L. et al. Determination of regioisomers in triacylglycerols. Rapid Commun. Mass Spectrom., 35, e8961 (2021); DOI). As a generality, triacylglycerols have relatively simple fatty acid compositions. Does this mean that the scope for errors in regiospecific analysis of glycerophospholipids with more highly unsaturated fatty acid components is much greater? Can anyone put my mind at rest - ideally by reporting appropriate experiments?
For the last year, I feel that I have been hiding under my duvet thanks to covid, while others have been working to study the disease - not least in Lipid Maps. The journal Biochimie has published a special issue section on 'Involvement of lipids in the occurrence of COVID-19', guest edited by Professor Vincent Rioux and Dr Michel Record. No miracle cure is described, but all new data are welcome. I expect to receive my first vaccination this month, but it may be a while before I can emerge from my cocoon.
Another special journal issue of interest is 'Lipids in disease pathology, diagnosis & therapy', edited by Heidi Noels and Twan Lammers (Advanced Drug Delivery Reviews, 159, Pages 1-390 (2020)).
January 13th, 2021
Over the years, there have been any number of papers describing reagents that add to double bonds as an aid to determining their position and geometry in alkyl chains by means of mass spectrometry. My own favourite has been the use of dimethyldisulfide, although this is only of used for monoenoic acids except in special circumstances. I have also employed deuteration, although this does not give information on the geometry of double bonds. You can find a page on my website that discusses this methodology here.. I was intrigued by the title of a paper that suggested that addition of water might be used for the purpose (Zhang, X. et al. Mass spectrometry distinguishing C=C location and cis/trans isomers: A strategy initiated by water radical cations. Anal. Chim. Acta, 1139, 146-154 (2020); DOI). The water radical cations are generated by corona discharge, the reaction is rapid and organic solvents are not required. However, the paper at this stage is merely a proof of concept and the method is applied only to hexenol isomers, so I will await further developments to see if, for example, it is a challenge to the Paternò-Büchi approach.
Sometimes it is the simple things that frustrate us during analysis - you spend a six/seven figure sum on instrumentation, and then you are set back by problems with inexpensive consumables. When I first started in mass spectrometry, it was peaks due to phthalates that were a nuisance. On one occasion, it took weeks before this was traced to the distilled water supply, caused by someone having replaced a piece of tubing with the wrong type in the lab still. Then came hydrocarbons from rubber bungs and silicone polymers from septa producing spurious peaks in GC-MS traces. It appears that the last is still a problem, now by causing ion suppression (Benke, P.I. et al. Impact of ion suppression by sample cap liners in lipidomics. Anal. Chim. Acta, 1137, 136-142 (2020); DOI).
January 6th, 2021
I keep a log of changes to the web pages in the Lipid Essentials section of the LipidWeb, and at this time of year it is an interesting exercise to browse through it to see which topics have occasioned most activity on my part. Over the last few years, I have spend more time on my web pages dealing with phosphoinositides and sphingosine-1-phosphate than on any others, and this is still true but only just. This year, I have been surprisingly busy with the page on triacylglycerol biosynthesis, and I suspect this is because of increasing interest in the metabolism of lipid droplets, especially in organs or organelles other than adipose tissue. Phosphatidic acid and its lyso-form have been the focus of much interest as usual, as have all classes of oxylipins. Perhaps surprisingly with the latter, it is the mono-oxygenated lipids, lipoxygenase and CYP450 products, that appear to have been a major focus. Finally, oxidized phospholipids and their biological functions are achieving some prominence, such that I have had to use the holiday break to pull together information from across this web site to create a new web page on the topic here.. This is still a work in progress, and I expect to do more with it during the coming year.
In addition to providing the unique resource of this website, members of the LIPID MAPS group along with several of their expert colleagues have set new standards in terms of the quality of their work and publications in relation to lipidomics, as most of you will surely be aware. They have been at the fore in attempting to standardize lipid nomenclature and the reporting of data across platforms. Now, they have turned their attention to offering some early stage recommendations on how the practical details and results of lipidomics should be reported in publications (O'Donnell, V.B. et al. Steps toward minimal reporting standards for lipidomics mass spectrometry in biomedical research publications. Circulation: Gen. Precision Med., 13, e003019 (2020); DOI). I should add the disclaimer that I am an independent observer and not a participant in research activities.
Blogs for the previous year (2020) can be located here..
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