Lipid Matters - Archive of Older Blogs - 2020
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 16th, 2020
Thanks
to a useful review of ether lipids, I have learned of a lipid class that had previously entirely escaped my attention
(Dorninger, F. et al. Plasmalogens, platelet-activating factor and beyond - Ether lipids in signaling and
neurodegeneration. Neurobiol. Disease, 145, 105061 (2020);
DOI).
Fecapentaenes are mono-alkyl-glycerols produced by colonic bacteria in animals and have five conjugated double bonds in the alkyl moiety
(12 or 14 carbons in total).
They are of particular interest in that they have genotoxic and mutagenic potential.
However, I hope my lack of awareness can be forgiven in that there appears to have been nothing written concerning them since 2012
according to the Web of Science.
In view of the increasing interest in the influence of the gut microflora on the metabolism of host tissues, they should not be forgotten.
Early in my career a paper appeared in a reputable journal claiming that lysophosphatidylcholine was a major components of the membranes in one particular tissue. I found this hard to believe, not least because of the strong detergent properties of this lipid, which can cause cell lysis, and sure enough a retraction eventually appeared; a flawed solvent extraction method had been used that activated phospholipases. This coloured my views when I first read of elevated levels of lysophosphatidic acid in ovarian tissues - again, I suspected that this was a result of flawed extraction/metabolism rather than a direct involvement. However, it soon became apparent that there was something special very about this simplest of all phospholipids in terms of signalling, and since then evidence has emerged that the lyso-forms of all the common phospholipids have distinctive function in signalling usually through specific receptors. Of course, we can add the sphingolipid analogue, sphingosine-1-phosphate, to this number. A new review provides a general overview of the nature and activities of these lipids (Tan, S.T. et al. Emerging roles of lysophospholipids in health and disease. Prog. Lipid Res., 80, 101068 (2020); DOI ).
I am pleased to acknowledge that Dr. Maria Fedorova of the Universität Leipzig has responded to my blog of two weeks ago in which I asked for a definition of "epilipidome". This has been defined as: "Epilipidome - a subset of the natural lipidome formed by lipid modifications via enzymatic and non-enzymatic reaction (e.g. oxidation, nitration, sulfation, halogenation) required to regulate complex biological functions" (Ni, Z.X. et al. Computational solutions in redox lipidomics - Current strategies and future perspectives. Free Rad. Biol. Med., 144, 110-123 (2019); DOI).
This will be my last blog for 2020. I wish all my readers a very happy Christmas and New Year - stay safe and healthy!
December 9th, 2020
Ceramide 1-phosphocholine, better known as sphingomyelin, is the most abundant sphingolipid in mammalian tissues, but the comparable lipid ceramide 1-phosphoethanolamine rarely gets a mention. It is produced in tissues by the action of sphingomyelin synthases, but in very small amounts, although there is also a distinctive and specific synthase, termed 'SMS related protein', which is a mono-functional enzyme and is active in brain especially. Why this minor lipid is produced at all in mammalian tissues is not known, although it has been suggested that the process may assist in the removal of any excess of potentially toxic ceramides. It would not surprise me if other more distinctive functions were discovered eventually.
In contrast, ceramide phosphoethanolamine is a major component of the cellular components that are the functional equivalent of myelin in the brain of Drosophila, where CDP-ethanolamine is the donor of the head group for ceramide phosphoethanolamine synthesis (akin to phospholipid biosynthesis by the Kennedy pathway). In this species and many other invertebrates, it replaces galactosylceramide (Murate, M. et al. Wrapping axons in mammals and Drosophila: Different lipids, same principle. Biochimie, 178, 39-48 (2020); DOI). It is apparently able to do this because the two lipids have similar physical properties. There are obvious differences in the charged state, but both lipids have a high phase transition temperature and tight packing, and neither is miscible with cholesterol.
December 2nd, 2020
Corynebacteria and Mycobacteria spp. are gram-positive bacteria with a complex cell envelope that contains many different classes of lipids of which many are unique to these species, not least the mycolic acids and trehalose lipids, and are factors in their virulence and resistance to antibiotics. However, when browsing through the abstract of a new publication on lipids from such species, I was delighted to see mention of one that occurs ubiquitously in prokaryotes and in plants and animals, i.e., cytidine diphosphate diacylglycerol (Wang, H.Y.J. et al. Unveiling the biodiversity of lipid species in Corynebacteria - characterization of the uncommon lipid families in C. glutamicum and pathogen C. striatum by mass spectrometry. Biochimie, 178, 158-169 (2020); DOI. Although this lipid is the precursor of many key complex glycerolipids, it is rarely mentioned in lipidomic studies, in part because it turns over rapidly and its steady state concentration is low and in part because it is relatively unstable. In this paper, it gets a full treatment including details of the ms fragmentation mechanisms, so hopefully we will learn more of its occurrence in future.
There are many techniques to which I would have liked to have access during my research career, and one such is bench-top counter current chromatography, which would have been invaluable for my structural studies of minor fatty acid components of lipid extracts. The most recent example of this technique is to alkylresorcinols, which are bioactive phenolic lipids that are particularly abundant in cereal crops (Hammerschick, T. et al. Countercurrent chromatographic fractionation followed by gas chromatography/mass spectrometry identification of alkylresorcinols in rye. Anal. Bioanal. Chem., 412, 8417-8430 (2020); DOI - open access). The authors identified 74 different molecular forms, many of which were new to science.
My recent blog on the differences in the stereochemistry of glycerolipids in Bacteria and Archaea attracted some interest, and a further fascinating review has appeared on the topic (Fiore, M. and Buchet, R. Symmetry breaking of phospholipids. Symmetry-Basel, 12, 1488 (2020); DOI - open access).
November 25th, 2020
As I cautioned in one of my recent blogs, it is impossible to prove how evolution
has shaped lipid biochemistry and vice versa, but it is sometimes possible to make reasonable deductions from molecular studies
and it is fun to speculate.
I enjoy the thoughts of others on the topic, for example in a recent publication on prostaglandins (Fujino, H.
Why PGD2 has different functions from PGE2. Bioessays, e2000213 (2020);
DOI).
These are structural opposites in the location of the oxygen groups on the cyclopentane ring, and they are also functional opposites.
For example, PGD2 is largely anti-inflammatory, while PGE2 is pro-inflammatory; PGD2 decreases food intake,
while PGE2 increases it; PGD2 has anticancer effects and may ameliorate ischemic injury,
while again PGE2 has opposing effects.
The author suggests that PGD2 and its enzymes and receptors are relative newcomers that have evolved from the PGE2
equivalents following a process of gene duplication (their genes are both on the same chromosome).
The structural similarity means that these prostaglandins act as partial agonists of each other's cognate receptors,
and this may explain some of the functional differences.
The bargain of the week is undoubtedly a 32-page open-access publication on the biosynthesis of oxylipins (Hajeyah, A.A. et al. The biosynthesis of enzymatically oxidized lipids. Front. Endocrinol., 11, 591819 (2020); DOI). This is the first in a promised series on the topic of "Epilipidome as a New Level of Cellular Regulation". Perhaps I am behind the times, but "epilipidome" was a new word for me, and I gather that it refers to lipid species derived from enzymatic and non-enzymatic modifications of the lipidome (main-stream lipids?). Is there a formal definition anywhere?
November 18th, 2020
On a number
of occasions, I have discussed here the concept of membrane rafts or microdomains,
i.e., laterally segregated, liquid-ordered regions of membranes that are enriched in sphingomyelin and cholesterol and
to which specific proteins can associate to do what proteins do.
Usually, this has been because a new publication has appeared that has cast doubt on whether they were indeed formed,
what their lipid constituents are, and whether they have any true functions.
Of course, this has caused me some difficulties as an outsider trying to chronicle the topic in my web page here in a balanced
and proportionate manner.
A major problem, which seems to have been resolved to some extent, has always been the difficulty of observing raft domains in living cells
as opposed to model membranes.
They were first described in 1997, and after more than 20 years of research and argument, I have the impression that the general consensus
now seems to be that they do indeed exist and that they have great biological importance.
A new review, which in part is far too mathematical for me, seems to cement this view (Kinnun, J.J. et al. Lateral
heterogeneity and domain formation in cellular membranes. Chem. Phys. Lipids, 232, 104976 (2020);
DOI).
The remaining argument seems be what further mechanisms for raft formation and structure are possible.
In contrast, there seems to be no doubt at all about the nature and structure of the related membrane structures termed caveolae,
which can be observed and studied much more easily, including by electron microscopy (see - Filippini, A. and D'Alessio, A.
Caveolae and lipid rafts in endothelium: valuable organelles for multiple functions. Biomolecules,
10, 1218 (2020); DOI - open access).
A corollary of the existence of liquid-ordered membranes domains is that if some lipids are sequestered in this way, then the remaining lipids must exist in more disordered domains. Cholesterol appears to associate in a different manner with unsaturated as opposed to saturated components of lipids and this may “push” cholesterol from non-raft domains to augment the “pull” mechanism whereby cholesterol is incorporated into rafts and so increase raft size, a concept discussed in the first of the reviews cited above. Do these remaining liquid-disordered membrane domains associate also with specific proteins with distinct functions?
November 11th, 2020
Bacteria and Archaea are widely considered to be distinct kingdoms of life that have diverged early in evolution from an organism designated the 'Last Universal Common Ancestor' (LUCA). The two are substantially different in their lipid compositions in that bacteria and eukaryotes have membrane lipids in which fatty acids are linked to sn-glycerol-3-phosphate (G3P), while the main lipids in Archaea have membranes in which the lipids have isoprenoid alkyl chains that are ether linked to sn-glycerol-1-phosphate (G1P), i.e., of the opposite stereochemistry. One hypothesis is that the LUCA may have contained membranes in which the glycerol-phosphate precursor existed in both stereochemical forms, although no existing organism appeared to have such a composition, until now that is (Villanueva, L. et al. Bridging the membrane lipid divide: bacteria of the FCB group superphylum have the potential to synthesize archaeal ether lipids. ISME J., in press (2020); DOI - open access). The authors demonstrate that bacteria from the Fibrobacteres-Chlorobi-Bacteroidetes group, which are highly abundant in the deep anoxic waters of the Black Sea, encode a putative archaeal pathway for ether-bound isoprenoid membrane lipids in addition to the bacterial fatty acid membrane pathway, and that the glycerolipids can possess either a G1P or G3P stereochemistry. Of course, it is never possible to absolutely prove an event that occurred in evolution billions of years ago, but the authors suggest that their "results support the existence of 'mixed membranes' in natural environments and their stability over a long period in evolutionary history, thereby bridging a once-thought fundamental divide in biology."
November 4th, 2020
It is unlikely that lipids will ever feature in the Guiness Book of Records, but lipid scientists appear to do their best to provide entries. For example, I have read of two contenders for the most abundant lipid class on earth. Hopanoids may be first because of their abundance in bacteria together with their stability over geological time in sediments. For living tissues, waxes probably win as they cover every plant leaf. Now a claim has appeared for the most abundant sphingolipid on earth, i.e., the plant glycosylinositol phosphoceramides, which make up a high proportion of the total lipids in plants and fungi (Panzenboeck, L. et al. Chasing the major sphingolipids on earth: automated annotation of plant glycosyl inositol phospho ceramides by glycolipidomics. Metabolites, 10, 375 (2020); DOI - open access). I should add that the paper is worth reading for the novel methodology.
If you were to go back 10 years to read review articles on complex sphingolipids, it is probably that these particular lipids would not rate a mention, although they were first described 60 years ago by Herbert Carter and colleagues, before later a full structure was published in 1969. Then they were forgotten, presumably because analysis was very difficult because of their high polarity. I suspect that what brought about the renewal of interest was a publication from the laboratory of Ernst Heinz that demonstrated that the amounts and compositions of the total sphingoid bases in plant tissues were very different from those of the glycosylceramides, then though to be the main sphingolipid class. In the last 10 years or so, mass spectrometry coupled to liquid chomatography has made the task of analysis of complex polar lipids much easier, and it is now recognized that glycosylinositol phosphoceramides can comprise as much as 40% of the lipids in leaves, much more than of any other sphingolipid, and that they are key components of the outer leaflet of the plasma membrane especially. The next important issue is to reveal their functions in plants.
October 28th, 2020
For
much of my career, I have been preparing the methyl ester derivatives of fatty acids for analysis purposes,
and indeed I have a web page on this methodology here..
However, I have not paid much attention to the natural occurrence of such compounds,
although I know they are occasionally present in plants and insects as wax constituents or pheromones.
An exception of course is methyl jasmonate, which is a well characterized plant hormone, the relative volatility of which enables
it to act as an inter-plant defense messenger to warn of predation.
It was something of a surprise to find that the methyl stearate (18:0) is produced in mammalian tissues,
i.e., in the superior cervical ganglion (sympathetic ganglion) in brain (Chen, P.Y. et al. Stearic acid methyl ester
affords neuroprotection and improves functional outcomes after cardiac arrest. Prostaglandins Leukotrienes Essential Fatty Acids,
159, 102138 (2020); DOI).
It is here reported to have important protective effects against cerebral ischemia.
This lead me to an earlier publication from the same laboratory on the natural occurrence of methyl palmitate with similar properties.
After my 25 years in a dairy research institute, where I read constant comments concerning the nasty nutritional properties of saturated fats in dairy foods (even that "palmitic acid is a poison produced by cows"), I confess to unseemly glee when I find papers describing the health benefits of saturated fatty acids. Another paper in the same journal issue describes the use of octanoic acid (8:0 or caprylic) as a potential therapy for certain cancers, because of its ready conversion to ketone bodies.
I notice that a recent issue of Lipids is a tribute to the work of Randall J. Weselake, who is probably best known for his work on triacylglycerol biosynthesis in plants. I had the pleasure of working with Randy on the AOCS Lipid Library for several years, and I am please to offer him my tribute and a long and happy retirement.
October 21st, 2020
It is rather surprising to find that some red algae (seaweeds) such as Gracilaria species contain prostanoids (PGE2, leukotrienes and others) and are known to have a cyclooxygenase gene. In Gracilaria vermiculophylla, PGG2 is first synthesised from arachidonate by a cyclooxygenase, and this is converted to 15-hydroperoxy-PGE2, which can then react either enzymatically or non-enzymatically to generate PGE2 or 15-keto-PGE2; a similar but rather minor pathway has since been discovered in animals (reviewed by Jagusch, H. et al. Mammalian-like inflammatory and pro-resolving oxylipins in marine algae. ChemBioChem, 21, 2419-2424 (2020); DOI). Why these organisms produce such oxylipins is not known, but they may have a defensive function as they are believed to be causative toxins for lethal food poisonings that have occurred in Japan. Another important question is how the organism acquired this ability - was it gene transfer and from what? What is so special about a cyclopentane ring in a fatty acid for biological functions, considering that it occurs also in key plant hormones such as jasmonates?
Once upon a time, citing references was easy - all the numerical data needed was the volume number, page numbers and year. The age of digital publication has brought problems, however, although I can't fault the ease of early access we now have to the scientific literature. Of the major publishers, I prefer the Elsevier approach where they give a new publication a number as soon as it is in proof and this sticks with it throughout the publication process. The only disadvantage I can see is that the reader does not know whether it is a 50-page review or a two-page note. Could something be added to the publication number to provide this information? Other major publishers do not give any identifier other than the DOI address, when a publication is first accessible, and it can then be many months before it formally reaches the press, and meanwhile the preliminary details only are published in abstracting services. Full recording of bibliographic data as in my Literature Survey pages is then a tedious multi-step process.
I have seen a new paper on the analysis of milk lipids from the African elephant. Many years ago, I was asked by a friend to carry out stereospecific analysis of triacylglycerols from pig milk. Out of curiosity, I asked how he milked the pig. The answer was "very carefully!" Now an elephant?
October 14th, 2020
In plants, monogalactosyldiacylglycerols are the most abundant lipids in photosynthetic tissues especially of the membranes of the chloroplasts, and they are essential structural components of the photosystem complexes. As such, they indirectly support all higher life forms, including us. However, it is less well known that they are also present in animal tissues, especially the brain and spinal cord albeit in rather small amounts, and I had termed them the "forgotten lipids" in my web page on the topic here... I believe that they may have been neglected because they are often removed from lipid extracts by mild hydrolysis reactions in cleaning up glycosphingolipid concentrates for analysis. Happily, a new publication has confirmed the presence and composition of glycosyldiacylglycerols in brain and nervous tissue and has shown that they exist in diacyl-, alkyl,acyl- and alkenyl,acyl-forms (Wang, C.Y. et al. Analysis of monohexosyl alkyl (alkenyl)-acyl glycerol in brain samples by shotgun lipidomics. Anal. Chim. Acta, 1129, 143-149 (2002); DOI).
They exist in these tissues with one saturated alkyl/acyl constituent and one monoenoic, so their physical properties may resemble those of cerebrosides in membranes, and it would not be surprising if they are produced by the same galactosyltransferase system, perhaps promiscuously. On the other hand, it is just as likely that they have some highly specific function, and this new paper means that they may be easier to analyse and thence study in future. More than 30 years ago, a range of complex glycosyldiacylglycerols were identified in saliva, bronchial fluid and gastric secretions with possible functions in a defense mechanism against microbial attack. These too seem to have been forgotten.
October 7th, 2020
I am sure that I am not alone in being confused by nutritional advice in relation to dietary fatty acids. Saturated fatty acids are bad for you - except when they are not, while polyunsaturated fatty acids are good for you - except when they are not. Mono-unsaturated fatty acids are relatively benign, except when they are in the wrong molecular species of lipid. The only general consensus appears to be that fatty acids with trans-double bonds, especially those from industrially hydrogenated oils, are bad. On the other hand, there appears to be a body of work to suggest that natural trans fatty acids in dairy foods have no ill-effects, although the cynical side of me has wondered whether these findings were real or an attempt to appease the dairy industry.
Now, a new paper suggests a plausible explanation for the latter finding (Angers, P. et al. Cyclic fatty acid monomers or the potential wild card in trans fats. J. Am. Oil Chem. Soc., in press (2020); DOI). During industrial refining of vegetable oils (and during frying), the high temperatures cause unsaturated fatty acids to form internal cyclic structures, five and six membered rings, through a concerted cyclo-addition mechanism involving the double bonds. The paper argues that it is these rather than the trans fatty acids that responsible for the adverse nutritional properties of processed oils. If they are oxidized during refining or food preparation, they may form cyclopentene structures resembling some prostanoids. When I look back, it seems a life-time ago that I was involved with my colleagues at the James Hutton Institute and my friend Jean-Louis Sébédio of INRA in European projects to isolate and fully characterize these cyclic fatty acids in heated oils. I know how difficult it is to analyse them, and I am sure that they have been overlooked in nutritional studies.
September 30th, 2020
1-O-p-Coumaroyl-3-O-feruloylglycerol, i.e., a diacylglycerol with two different phenylpropanoid acids
esterified to positions 1 and 3, is novel plant lipid that has just been described (Rajagopalan, N. et al.
A phenylpropanoid diglyceride associates with the leaf rust resistance Lr34res gene in wheat. Phytochemistry,
178, 112456 (2020); DOI).
It is suggested that this is a storage form of the more potent anti-microbial hydroxycinnamic acids required for defense responses,
and in particular for leaf rust resistance in wheat.
The importance of squalene as a precursor of sterols was highlighted in a LipidMaps tweet in August. However, it has many other functions in animal tissues and these are described in a recent review (Micera, M. et al. Squalene: more than a step toward sterols. Antioxidants, 9, 688 (2020); DOI). I was unaware of one significant commercial use, that is in the manufacture of vaccines, and an article in the Daily Telegraph newspaper (unfortunately behind a pay wall) suggests that 500,000 sharks may be killed for their livers in the next year as this is the only accessible source.
I can recommend the latest issue of Essays in Biochemistry devoted to the topic of "Lipid Mediators" (edited by John Harwood and Emyr Lloyd-Evans) and just formally published. It is headed by an appreciation of Michael Wakelam. Other articles deal with oxylipins, endocannabinoids, and bioactive phospholipids and glycosphingolipids.
September 23rd, 2020
I have to confess to a profound ignorance as to the occurrence and function of cilia in animal cells - I knew only of their presence and motile function in protozoa. Now, I have learned there are two types - primary and motile in animals, with most animal cells have at least one primary cilium, and I should have been aware that sperm tails are motile cilia, and some cells have multiple cilia. For example those in the Fallopian tubes move the ovum from the ovary to the uterus. It seems that I can be forgiven in part, since as recently as the mid-1990s primary cilia were described in the scientific literature as vestigial organelles with no known function. Their sensory functions should at least have been recognized, as the outer segment of the rod photoreceptor cell in the human eye is connected to its cell body by a specialized primary cilium and olfactory sensory neurons are also linked to primary cilia.
Now it has been amply demonstrated that primary cilia have important signalling functions and that lipids are essential to this, as described in two recent reviews (Nechipurenko, I.V. The enigmatic role of lipids in cilia signaling. Front. Cell Developm. Biol., 8, 777 (2020); DOI. And Kaiser, F. et al. Sphingolipids controlling ciliary and microvillar function. FEBS Letts, in press (2020); DOI - both are open access). For example, there is a sharp boundary in phosphoinositide composition with phosphatidylinositol-4,5-bisphosphate located in distinct membrane domains at the base of cilia, while the ciliary membrane contains high levels of phosphatidylinositol-4-phosphate relative to the adjacent plasma membrane and this is required to bind and activate specific proteins.
September 16th, 2020
Some nomenclature errors annoy me, chief of which is the use of the hybrid "triacylglyceride", as opposed to "triacylglycerol" or even "triglyceride". There are other naming issues where I wish we could start again. For example, I would prefer to see the term "lipoprotein" reserved for the loosely bound lipid-protein complexes in plasma, while covalently bound protein-lipid conjugates such as S-acyl or N-acyl proteins were named "proteolipids". However, the latter are just as often given the former generic term in the literature, and this is so embedded that it would be difficult to change. Whatever we choose to call them, proteolipids are fascinating molecules, and my favourites are the Hedgehog proteins, which contain covalently bound cholesterol, further confirmation of the vital importance of this molecule.
Another intriguing group of proteolipids are the Wnt proteins, which have a specific requirement for covalently bound but O-acylated palmitoleic acid (9-16:1) for their function as central mediators of embryonic development and tissue renewal in animals. Wnt proteins are relatively hydrophobic, and a new publication demonstrates that they are stabilized in the aqueous environment of the cell by binding in a hydrophobic space created by specific glypicans, i.e., heparan sulfate proteoglycans that are bound to the outer surface of the plasma membrane by a glycosyl-phosphatidylinositol anchor (McGough, I.J. et al. Glypicans shield the Wnt lipid moiety to enable signalling at a distance. Nature, 585, 85-90 (2020); DOI). It is proposed that these serve as a reservoir from which Wnt proteins can be handed over to signalling receptors.
A second new review on proteolipids describes the mechanism of action of the acyltransferases responsible for synthesis of S-acyl (palmitoyl) proteolipids, the most abundant of the post-translationally modified proteins (Stix, R. et al. Structure and mechanism of DHHC protein acyltransferases. J. Mol. Biol., 432, 4983-4998 (2020); DOI). High-resolution structures of two of these enzymes have recently been elucidated. This is part of a themed issue - "Molecular Mechanisms in Integral Membrane Enzymology" - dealing with a number of important lipids, including cardiolipin, eicosanoids, lipid A and the bacterial cell wall carrier lipid, together with relevant enzymes.
September 9th, 2020
I have to confess that I have not spent much of my time reading up on carotenoids. These are a class of highly unsaturated terpenoids that occur in innumerable molecular forms in plants, fungi, and bacteria, of vital importance to photosynthesis and also add ornament to the world. To a generalist such as myself, the study of the 1000 or so forms would be too arduous and I am happy to leave the task to specialists. One important gap in my knowledge relates to their function in plants where they originate, and I must address this in this site soon. A new special themed issue of Biochim. Biophys. Acta, Lipids (edited by Johannes von Lintig and Loredana Quadro) should help.
Rather I have been concerned more in these pages with the function of the carotenoid metabolites, the retinoids, which are so important for vitamin A activity and especially for vision. I am reminded of a story that in WWII, British intelligence released a fake study to the effect that eating raw carrots substantially improved night vision, with the result that German fighter pilots were force fed large quantities. The story may be apocryphal, but I would like to believe it.
On the other hand, the themed journal has updated my knowledge of the function of non-provitamin A carotenoids in animal tissues. In particular, xanthophylls are plant C40 tetraterpenes that differ from the carotenoids in having oxygen atoms in the ring structures (hydroxyl, oxo or epoxyl). Lutein, zeaxanthin and meso-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, i.e., the functional center of the retina in a small central pit known as the macula lutea, where they protect the eye from high-intensity, short-wavelength visible light. It is interesting that this central region is only present in humans and other primates, not in animals in general. These carotenoids are also powerful antioxidants in a region vulnerable to light-induced oxidative stress. Other carotenoids are important constituents of skin, while in the brain, they may stimulate and maintain cognitive function in the elderly, and assist with brain development in infants, among many functions that are slowly being revealed.
September 2nd, 2020
A new publication has re-evaluated the functions and specificities of the components of the enzyme complex with serine palmitoyltransferase activity, i.e., that synthesises sphinganine as the first step in the biosynthesis of the wide range of sphingoid bases found in nature (Lone, M.A. et al. Subunit composition of the mammalian serine-palmitoyltransferase defines the spectrum of straight and methyl-branched long-chain bases. Proc. Natl. Acad. Sci. USA, 117, 15591-15598 (2020); DOI). There are three main subunits, designated SPTLC1 to 3, of which SPTLC1 is essential for activity, and it is ubiquitously expressed as is SPTLC2, while SPTLC3 is present in a relatively limited range of tissues and is most abundant in skin. In mammals, it is shown that the SPTLC1-SPTLC2 complex forms C18, C19, and C20 sphingoid bases specifically, while the combination of SPTLC1 and SPTLC3 gives a broader product spectrum, including an anteiso-methylbranched-C18 isomer (from anteiso-methyl-palmitate as the precursor). Branched bases are here shown to be synthesised to a limited extent in human skin, especially, and they are incorporated into ceramides and complex sphingolipids and are constituents of human low- and high-density lipoproteins. It is well known that they are major forms in lower invertebrates such as the nematode Caenorhabditis elegans.
In addition to the common range of C16 and C18 fatty acid components, many plant species produce novel fatty acids with unusual structural features. A new review discusses that can be learned from the biosynthesis of these (Cahoon, E.B. and Li-Beisson, Y. Plant unusual fatty acids: learning from the less common. Curr. Opinion Plant Biol., 55, 66-73 (2020); DOI). Some of these occur as polyesters in plant cutins, a barrier for water loss and pathogen protection, while others are found in seed oils, such as castor oil with ricinoleic acid - known for over 100 years. Study of the enzymes involved in biosynthesis has produced some fascinating findings. For example, mutations in fatty acid desaturases can effect hydroxylation, epoxygenation, triple-bond formation, or conjugated double bond biosynthesis.
I notice a tweet on the LipidMaps website on the life and achievements of Michel Eugène Chevreul. The excellent French website Cyberlipid is dedicated to him and contains a brief biography. My PhD supervisor Frank Gunstone used to keep a picture in his office of the great man at work in his laboratory in his 100th year, which I reproduce below. I don't promise to keep this blog going for that long, but I will do my best.
August 26th, 2020
Once upon a time,
lysophospholipids were regarded simply as nasty lipids that disrupted membranes and screwed up enzyme systems.
Those days are long gone, and now we know that most lysophospholipids have many essential functions, which I have highlighted in a number of posts
in recent months.
Two further interesting papers on such lipids have now been published.
The first suggests that lysophosphatidylinositol, which has a high content of arachidonic acid and is known to have important functions
via a specific receptor in its own right, can serve as the precursor for a quite different lipid 2-arachidonoylglycerol in cells.
The latter is a key lipid mediator with many different roles as an endocannabinoid,
so the process converts one set of vital biological activities to a quite different second set (Tsutsumi, T. et al.
Identification of human glycerophosphodiesterase 3 as an ecto phospholipase C that converts the G protein-coupled receptor
55 agonist lysophosphatidylinositol to bioactive monoacylglycerols in cultured mammalian cells. Biochim. Biophys. Acta,
1865, 158761 (2020); DOI).
The second publication also deals with arachidonic acid-containing lysophospholipids, which are substrates for lipoxygenases
to generate esterified oxylipins, e.g. 12(S)-HETE.
It is demonstrated that these react very specifically with certain human monocytes to generate tumor necrosis factor α (TNFα)
and thence initiate a key signalling pathway (Liu, G.-Y. et al. A functional role for eicosanoid-lysophospholipids
in activating monocyte signaling. J. Biol. Chem., 295, 12167-12180 (2020);
DOI).
August 12th, 2020
In this blog, I have often highlighted the potential of bacterial lipopeptides for use as novel antibiotics. It seems that any such hopes are unlikely to be realized soon, and I quote from a new review "Over 3000 membrane-active antimicrobial peptides (AMPs) have been discovered, but only three of them have been approved by the U.S. Food and Drug Administration (FDA) for therapeutic applications, i.e., gramicidin, daptomycin and colistin." In fact only two of these are lipopeptides, and of these daptomycin is only approved as a last line of defense for treating Gram-positive infections and even then resistant strains are emerging. It seems that we need to have better information on how these lipopeptides exert their biocidal effects if we are to make more substantial progress (Huang, H.W. Daptomycin, its membrane-active mechanism vs. that of other antimicrobial peptides. Biochim. Biophys. Acta, Biomembranes, 1862, 183395 (2020); DOI).
One of the surprising new classes of oxylipin to have been discovered in recent years is the branched fatty acid esters of hydroxy fatty acids (FAHFAs), which are the subject of a substantial new review (Brejchova, K. et al. Understanding FAHFAs: From structure to metabolic regulation. Prog. Lipid Res., 79, 101053 (2020); DOI). Such estolide linked fatty acids have long been known in plants and fungi, especially, but the findings of biological activity in animals are novel.
I first encountered one such in plants when I did post-doc research with Ralph Holman at the Hormel Institute, who had just demonstrated the presence of a highly unusual estolide in triacylglycerols from the Chinese tallow tree, i.e., trans-2,cis-4-decadienoic acid linked to 8-hydroxy-5,6-octadienoic acid (Sprecher, H.W. et al. Structure of an optically active allene-containing tetraester triglyceride isolated from the seed oil of Sapium sebiferum. Biochemistry, 4, 1856-18631 (1965); DOI). At the time, this triacylglycerol was claimed to be the largest molecule to have its structure elucidated by mass spectrometry. A few years later, it was the subject of one of my first independent publications, when I demonstrated that the novel fatty acid components were entirely in position sn-3 of the triacylglycerols (Christie, W.W. The glyceride structure of Sapium sebiferum seed oil. Biochim. Biophys. Acta, 187, 1-5 (1969); DOI). Looking back now with 50 years of hind-sight, I wonder if it is a true estolide at all, but rather an oxylipin produced by oxidation and rearrangement of an unsaturated C18 fatty acid, as opposed to via esterification of the two components. Either way, its biosynthesis would be a fascination PhD project for someone.
August 5th, 2020
Life would be so much easier for those of us with an interest
in lipid science if we could simply classify lipids according to whether
they were good or bad for us (see last week's blog), but it is rarely that simple.
The biological activity of lysophosphatidylcholine is a case in point.
For example, it is usually considered to have pro-inflammatory properties, and it is known to be a pathological component of oxidized
lipoproteins (LDL) in plasma and of atherosclerotic lesions.
It is a major component of platelet-derived microvesicles and activates a specific receptor in platelets that ultimately leads
to vascular inflammation, increasing the instability of atherosclerotic plaques.
On the other hand, reduced concentrations are observed in some malignant cancers, and it has protective effects in patients undergoing chemotherapy.
Stearoyl lysophosphatidylcholine has an anti-inflammatory role in that it is protective against lethal sepsis in experimental animals
by various mechanisms, including stimulation of neutrophils to eliminate invading pathogens through a peroxide-dependent reaction.
There is also a suggestion that lysophosphatidylcholine per se is not the bad guy, but that lysophosphatidic acid formed by
the action of autotaxin in plasma may be the true source of some of the unpleasant effects that have been described.
A new review has changed my perspective on this lipid somewhat (Knuplez, E. and Marsche, G. An updated review of
pro- and anti-inflammatory properties of plasma lysophosphatidylcholines in the vascular system. Int. J. Mol. Sci.,
21, 4501 (2020); DOI).
The LipidWeb is now fully integrated into the LIPID MAPS® Lipidomics Gateway. Please bookmark the LipidWeb here, as you will be redirected from the old URL.
July 29th, 2020
This week
- the good, the bad and the ugly. From time to time,
I highlight publications here that deal with health-giving properties of lipids, and especially those that have value as antibiotics,
either directly or synergistically, as the rise of antibiotic resistant bacteria has the potential to do much more long-term damage than covid.
A new review is my bargain of the week (Alves, E. et al. Antimicrobial lipids from plants and marine organisms:
an overview of the current state-of-the-art and future prospects. Antibiotics, 9, 441 (2020);
DOI - open access and 88 pages).
In contrast, one lipid class that is definitely one of the bad guys is the bacterial triacyl-lipoproteins, although the lesser known diacyl-lipoproteins (lyso-form or N-acyl S-monoacylglycerol lipoproteins) are even worse in that they enable evasion of immune recognition by the Toll-like receptor 2 family complex. It has now been demonstrated that Enterococcus faecalis, a Gram-positive Firmicute, synthesises the diacylated proteolipid by transfer of the fatty acid from position sn-2 of the diacylglycerol moiety to the N-terminal cysteine residue of the protein by means of an integral membrane protein designated Lit (lipoprotein intramolecular transacylase) (Armbruster, K.M. et al. Bacterial lyso-form lipoproteins are synthesized via an intramolecular acyl chain migration. J. Biol. Chem., 295, 10195-10211 (2020); DOI).
In preparing my literature survey pages, I scan rapidly through the titles of 500-600 papers each week in my computerized search, then make a final selection after reading the abstracts from a short list. Sometimes, these are so detailed and intense that they defeat me, but occasionally, I find an abstract that is so brief as to be useless. To spare the blushes of the authors, journal and editors and avoid giving offense, I have removed a few words, but I recently found this as an abstract - "A *** fatty acid has been isolated as an antimicrobial principle from ***. Its structure was determined on the basis of spectral data." I know that authors are urged to be concise, but it is ridiculous that the systematic name of the compound is not given at the very least. Needless to say this paper is not included in my lists.
July 22nd, 2020
The mechanism for the biosynthesis of furanoid fatty acids in two species of α-proteobacteria has now been fully elucidated (Lemke, R.A.S. et al. A bacterial biosynthetic pathway for methylated furan fatty acids. J. Biol. Chem., 295, 9786-9801 (2020); DOI - Editors' pick - open access). 11-cis-Octadecenoic acid is the precursor and this is methylated on carbon 11 with S-adenosylmethionine (SAM) as the methyl donor. This is accompanied by migration of the double bond with a change in conformation to produce 11-methyl-12t-18:1, and it is followed by a desaturation step to produce 11‑methyl-10t,12t-18:2, and then by cyclization to form the furan ring. Molecular oxygen (O2) is the source of the oxygen atom and the product is 10,13-epoxy-11-methyl-octadecadienoate. A further methylation reaction can introduce a second methyl group into the ring. It seems likely that biosynthesis of furanoid fatty acids proceeds via analogous steps and related enzymes in other organisms such as higher plants and algae.
They are known to be scavengers of hydroxyl and hydroperoxyl radicals and this may be the function of natural furanoid fatty acids in membranes, i.e., as antioxidants. For this reason, it has been suggested that they may play a part in the cardio-protective effects of dietary fish oils. However, I would not be surprised if such distinctive oxylipins were found eventually to have other functions in vivo, such as in signalling.
Incidentally, the mass spectrometry pages of my website are cited in the Experimental section of the paper. I am always pleased to see my efforts recognized in this way.
July 15th, 2020
Much of my former research interests were in analytical methodology, and I always felt flattered when I saw a method that I had developed being applied by others. On the other hand, I recall the eminent plant lipid biochemist Paul Stumpf documenting an instance of an author deliberately omitting a step in a published method so he could keep ahead of the opposition (Stumpf, P.K. A retrospective view of plant lipid research. Prog. Lipid Res., 33, 1-8 (1994); DOI). Thankfully, I do not believe that this is a frequent occurrence.
Many times over the years, I have had arguments with journal editors about how much practical information should go into the 'Experimental' section of papers. When others try to repeat a published method, it is often minor details that are important. The primary concern of editors is often to save space, and this may not coincide with the interests of readers - hence the perennial cry -"why does your method not work when I try it?" On occasion, errors arise because of imprecision on the part of authors. For example, a procedure carried out at "room temperature" in Dundee may be several degrees C different from that in Arizona. In summer, the latter may even be cooler because they have air-conditioning - a facility not often required in Scotland! Suppliers can make changes to their products as "improvements". For example, my former colleagues had great difficulties with the work-horse GC columns they used, because the manufacturer had changes the chemistry of the stationary phase slightly - sufficient to render one key separation no longer possible, even if other aspects were arguably better. The more honest of us will confess that we may occasionally have difficulties in repeating some of our own published methods after a key worker has left, so it is hardly surprising that others have this difficulty also. Every lab needs someone with "green fingers" for the difficult tasks.
July 8th, 2020
While our eyes are focussed on Covid, it does not do to forget that there are many other nasty organisms out there, not least M. tuberculosis, which is reported to kill over 1,000,000 people every year. This is one where we really do have to blame the lipids. A key factor in the persistence of M. tuberculosis infections is its distinctive cell wall, a high proportion of which consists of complex and often unique lipids, which confer extreme hydrophobicity to the outer surface, resist degradation by host enzymes, including those of the immune system, and by antibiotics, and so are associated with its pathogenicity. It has a distinctive dual membrane structure that is neither fully Gram-negative nor Gram-positive. The outermost layer consists of free waxy lipids, while the inner membrane structure is enriched in phosphatidylinositol mannosides. In between, the complex mycolic acids link to both membranes and provide structural support to the cell wall. Another unusual feature is that biosynthesis of the aliphatic constituents requires an interplay between fatty acid synthases I and II and polyketide synthases. A new review provides a clear and accessible account (Batt, S.M. et al. The thick waxy coat of mycobacteria, a protective layer against antibiotics and the host's immune system. Biochem. J., 477, 1983-2006 (2020); DOI).
It was not too difficult for John Harwood to pull me out of retirement from more formal publication to act as a coauthor on his overview of lipoxins as part of a series of articles for Essays in Biochemistry, published by the Biochemical Society. It is accessible ahead of print here... Many more relevant reviews in this series are now freely available from the journal ahead of publication.
July 1st, 2020
I recall in the days when I worked in a dairy research institute that I wrote that anyone who wanted to stretch their methodology to the limit should try it out on milk fat. I am therefore greatly impressed by a new publication in which 3454 molecular species of triacylglycerols were identified with 65 fatty acid constituents (Liu, Z.Q. et al. Comprehensive characterization of bovine milk lipids: triglycerides. ACS Omega, 5, 12573-12582 (2020); DOI - open access). Regio- and stereo-isomers were not resolved, unsurprisingly, but this is still a quite exceptional achievement.
There is as ever a "but". What can outside observers do with this information? Over the years, I have produced a number of review papers comparing triacylglycerol compositions from different species, tissues and so forth, but I have never been able to tabulate molecular species data in making comparisons - this is simply impractical. Rather, I have tabulated and compared positional distributions, most recently on a web page here... No recently acquired data are listed as few are available. I extolled the virtues of stereospecific analysis methods for biosynthesis and metabolic studies in a recent blog, and this seemed to generate some interest. Therefore, I have substantially adapted, rewritten and updated an older article on the subject, and this is now online on this website here... There has been a tendency in the literature to assume that position sn-2 of triacylglycerols is most important, simply because it has been so easy to determine by means of hydrolysis with pancreatic lipase and now by mass spectrometry. However, position sn-3 can have an equally distinctive composition, and position sn-1 is not far behind.
I am sure that I am not alone in being confused by nutritional recommendations regarding the intake of fatty acids. A new review takes issue with American Heart Association (AHA) for strongly recommending a reduction in dietary saturated fats, and it suggests that "the strength of the evidence for the recommendation to limit SFAs for heart disease prevention may be overstated and in need of reevaluation" (Heilson, J.L. Dietary saturated fat and heart disease: a narrative review. Nutr. Rev., 78, 474-485 (2020); DOI). I have only seen the abstract of the paper, but I enjoy butter and cream and at my age I am passed caring.
June 24th, 2020
Arsenic-containing
organic compounds soluble in organic solvents and therefore termed 'arsenolipids' have
long been known to exist in nature, but those I would describe as true lipids, defined as containing aliphatic chains and arsenic,
are more recent discoveries. They are potentially a cause for concern as they are found as minor components of fish oils.
So far, it appears that only hydrocarbons containing arsenic present a toxicity problem, and these are detected at such low levels that
they are not seen as a threat. The other source of arsenolipids in the human diet are seaweeds, which are in fact multicellular algae.
These contain a distinctive glycophospholipid in which the arsenic-containing unit is a monosaccharide unit.
A new study describes the determination of molecular species compositions and positional distributions of this lipid in seaweeds
harvested for human consumption by using a combination of mass spectrometry and regiospecific enzymatic hydrolysis
(Coniglio, D. et al. Arsenosugar phospholipids (As-PL) in edible marine algae: an interplay between liquid chromatography
with electrospray ionization multistage mass spectrometry and phospholipases A1 and A2 for regiochemical assignment.
J. Am. Soc. Mass Spectrom., 31, 1260-1270 (2020);
DOI).
Although it is not the first time comparable methodology has been used for this particular lipid class, I wanted to draw attention to this paper in view of my comments in my last blog and in earlier posts about what I perceive as the relative neglect of methods involving regiospecific hydrolysis of lipids. In the past I have challenged readers to compare positional distributions determined solely by mass spectrometry, with those that are more precise, for minor components especially, by using regio- or stereospecific enzymes. So far no takers!
I don't suppose that all viruses function in the same way, but a new review of the sneaky ways that the hepatitis C virus takes over lipid metabolism in its host is worth a read (Bley, H. et al. Whole lotta lipids-from HCV RNA replication to the mature viral particle. Int. J. Mol. Sci., 21, 2888 (2020); DOI). This review covers just the last 5 years or so of research, but may demonstrate how much needs to be done before we have as full an understanding of Covid.
June 17th, 2020
As should be well known, natural triacylglycerols are chiral molecules and all three positions can be occupied by different fatty acids. Perhaps the best known example is cow's milk, in which the short-chain fatty acids (4:0 and 6:0) are exclusively in position sn-3. However, there are many other natural triacylglycerols with distinctive distributions and you can find a summary here... Chiral phase chromatography is only able to resolve a few enantiomeric triacyl-sn-glycerol species, and it is a significant achievement to show that this can be accomplished for some with uncommon fatty acid components, for example - (Palyzova, A. and Rezanka, T. Enantiomeric separation of triacylglycerols containing fatty acids with a ring (cyclofatty acids). J. Chromatogr. A, 1622, 461103 (2020); DOI).
For a good part of my research career, I was interested in methodology to determine the compositions of each of the three positions, and this has always been something of a technical challenge. I last reviewed this online some years ago here.. Several methods have been developed with most having a preliminary step in which triacyl-sn-glycerols are hydrolysed to a mixture of sn-1,2- and sn-2,3-diacylglycerols, which can be derivatized in various ways for chiral separation or for reaction with stereospecific enzymes. All are time-consuming and require some technical skill, and it is disappointing to report that it is some years since I last saw a paper in which the methodology was applied. Yet it is surely as important now to be able to distinguish the compositions of the three positions as it ever was if we are to understand fully the enzymology of triacylglycerol biosynthesis and hydrolysis. Mass spectrometry cannot distinguish between positions sn-1 and sn-3 in triacylglycerols, i.e., it is regiospecific not stereospecific, and my concern is that the new generation of lipid analysts are unwilling to tackle problems that cannot be solved by this technique.
If I had to pick one natural sample for full stereospecific analysis, I would select a unique triacylglycerol that is a single molecular species consisting of only three fatty acids 16:1-12:0-18:1 in an organelle termed the midbody in dividing cells in humans (Atilla-Gokcumen, G.E. et al. Dividing cells regulate their lipid composition and localization. Cell, 156, 428-439 (2014); DOI) and subsequently in rodents. I am sure that this must have a distinctive structure and function.
June 10th, 2020
On the face of it the nematode Caenorhabditis elegans seems a strange model for the study of lipids in animals, but the ease of dietary supplementation and genetic manipulation permits examination of the function of polyunsaturated fatty acids and oxylipins in many biological processes over short time-scales that include aging, reproduction, and neurobiology, as discussed in a new review (Mokoena, N.Z. et al. Synthesis and function of fatty acids and oxylipins, with a focus on Caenorhabditis elegans. Prostaglandins Other Lipid Mediators, 148, 106426 (2020); DOI). However, it is the differences from the pathways in higher animals that immediately catch the eye, as these organisms have all the enzymes to produce the full suite of polyunsaturated fatty acids considered essential in the latter. They have a wide range of CYP450 enzymes to produce C20 oxylipins also, but they lack the cyclooxygenase enzymes to synthesise prostaglandins. On the other hand, they are able to produce a molecule that appears identical to prostaglandin F2α (subject to a check on stereochemistry) by some as yet unknown mechanism. Although not discussed in this review, nematodes have an unusual requirement for branched-chain fatty acids, while in the reproductive stage, they produce unusual glycolipids - ascarosides.
The English language is reputed to contain several times more words than any other, but there is always room for one more as in the title of this review (Hofer, P. et al. The lipolysome - a highly complex and dynamic protein network orchestrating cytoplasmic triacylglycerol degradation. Metabolites, 10, 147 (2020); DOI - open access). "Lipolysome" is defined as the complex lipolytic machinery in cytoplasmic droplets.
June 3rd, 2020
Methods of increasing technical sophistication and therefore cost are being applied more and more to the analysis of the lipidome. However, from time to time, I have the impression that relatively straight-forward methods from the pre-lipidomics era, i.e., 20 years ago, are being forgotten. I have described before how my mentor Frank Gunstone characterized the first natural epoxy fatty acid, vernolic acid, in the 1950s without any kind of chromatography or spectroscopic equipment, but merely a balance, a burette and his knowledge of chemistry (this blog, January, 2019).
Not that I recommend going back to those days, but if we consider simply determination of double bond positions, branch points, etc, in fatty acids and other aliphatic compounds, there are a number of simple chemical reactions that can give detailed structural information with the aid of gas chromatography and the simplest of bench-top mass spectrometers. For example, if there is only one double bond, a one-pot reaction with dimethyl disulfide gives an adduct that enables both the position and the geometry of the double bond to be determined. If the carboxyl group is derivatized to produce pyrrolidides, 4,4‑dimethyloxazolines or 3‑pyridylcarbinols, highly complex natural fatty acid mixtures with many different functional groups in the alkyl chains can be characterized definitively by GC-MS. My colleagues and I were able to identify as many as 120 different fatty acids in single samples of marine origin by this means, for example. Indeed, a surprising amount of structural information can be obtained on branched-chain and polyunsaturated fatty acids simply from methyl ester derivatives (see the Mass Spectrometry pages on this web site).
Please do not think that I am trying to denigrate what is being achieved by modern mass spectrometric methodology for fatty acid analysis in intact lipids by using ozonolysis, the Paternò-Büchi reaction and others, as I sometimes regret that I reached the age of retirement before such techniques were available or affordable. I merely want to point out to a younger generation that alternative methodologies are tried, tested and efficient, and may offer advantages in many situations.
May 27th, 2020
Leaf
and other tissues in plants contain a range of sterol glycosides and sterol acyl-glycosides in which the hydroxyl group at C3
on the sterol is linked to the sugar by a β-glycosidic bond.
Such lipids have only rarely been found in animal tissues, although cholesterol glucoside
(1-O-cholesteryl-β-D-glucopyranoside) and less often cholesterol acyl-glucoside have been detected,
and were found first in the skin of snakes and birds.
Now both cholesterol glucoside and galactoside have been shown to be present throughout development in mouse brain from the start of
myelination in embryos through to adults, with biosynthesis involving a transfer of glucose/galactose from cerebrosides
to cholesterol catalysed by a lysosomal β-glucocerebrosidase (Akiyama, H. et al. Glucocerebrosidases catalyze
a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol. J. Biol. Chem.,
295, 5257-5277 (2020); DOI).
It will be interesting to know what their function is there.
In plants, sterol glycosides are synthesised by a very different mechanism, i.e., from free sterols with a glucose unit catalysed by a sterol glycosyltransferase, or by reaction of the sterol with uridine diphosphoglucose (UDP-glucose) and UDP-glucose:sterol glucosyltransferase on the cytosolic side of the plasma membrane. In this instance, they are believed to have a number of biological functions, for example in the adaptation of plant membranes to low temperatures and other stresses, in the response to fungal pathogens and in signal transmission. A new review discusses findings that through acting as immunoadjuvants, sterol glycosides are efficacious in protecting animals against lethal Cryptococcal infections (Normile, T.G. et al. Steryl glycosides in fungal pathogenesis: an understudied immunomodulatory adjuvant. J. Fungi, 6, 25 (2020); DOI - open access). Does this give us a clue as to the function of the endogenously synthesised lipid in animals?
Last question - is the correct nomenclature "sterol glycosides" or "steryl glycosides"?
May 20th, 2020
Two publications dealing with analytical methodology have caught my eye this week, and happily both are open access. The first deals with a particularly taxing problem, i.e., the analysis of those acyl moieties attached to acyl-carrier proteins, which are of course not only intermediates but the products of fatty acid synthesis in plants (Nam, J.-W. et al. A general method for quantification and discovery of acyl groups attached to acyl carrier proteins in fatty acid metabolism using LC-MS/MS. Plant Cell, 32, 820-832 (2020); DOI). The authors were able to identified acyl-ACP elongation intermediates (3-hydroxy-acyl-ACPs and 2,3-trans-enoyl-ACPs and medium-chain-ACPs, together with polyunsaturated long-chain acyl-ACPs (16:3) that might not have been anticipated. The methodology will of course be invaluable for the development of genetically modified seed oils, as the authors intend, but interesting questions regarding fatty acid metabolism in chloroplasts are also posed. Although the method is described for plants, it should be applicable to mammalian systems as it involves a preliminary step of hydrolysis at a highly conserved amino acid sequence in ACPs retaining the phosphopantetheinyl linker to which acyl groups attach.
The second publication is a review less of analysis per se but more of the results of analyses of carnitines and acyl-carnitines (Bene, J. et al. Mass spectrometric analysis of L-carnitine and its esters: potential biomarkers of disturbances in carnitine homeostasis. Curr. Mol. Med., 20, 336-354 (2020); DOI). As is well known, carnitine plays a vital role in the mitochondrial oxidation of long-chain fatty acids by enabling them to cross the inner mitochondrial membrane, although it has wider functions in cells by controlling the acyl-CoA/CoA ratio thereby influencing innumerable enzyme systems. Screening of the carnitine ester profile of newborn infants is well established and can lead to the detection of more than 30 metabolic disorders, but this methodology is now proving useful in investigating diseases of adult patients, including diabetes and cardiovascular diseases.
The Journal of Lipid Research and the Journal of Biological Chemistry already have enlightened access policies, but I was delighted to learn that they will become fully open access soon. Now if only the major chemical societies would follow suit - over to you ACS and RSC!
May 13th, 2020
When I was starting to write my web pages on different lipid classes in the Lipid Essentials section of this website, I had most problems with that on cytidine diphosphate diacylglycerol (CDP-DAG), in spite of the fact that it is a key intermediate that occupies a branch point in the biosynthesis of certain complex glycerolipids, especially phosphatidylinositol and cardiolipin. For example, it was extremely difficult to find any compositional data, and I had to rely on a publication from 1976 (as an aside, I should not apologize for this, as the work is probably as sound as anything published more recently). Modern mass spectrometric methods do not appear to be sufficiently sensitive to detect this lipid in natural tissues - if anyone out there is interested, it might be a useful project for someone to find a means of concentrating this lipid so it can be analysed more easily in order to have compositional information for different tissues. There have been some valuable new findings in recent years, especially the characterization of three distinct CDP-DAG synthases with differing subcellular distributions and differing products. Now, two substantial reviews on the topic have come along at the same time (Blunsom, N.J. and Cockcroft, S. CDP-diacylglycerol synthases (CDS): gateway to phosphatidylinositol and cardiolipin synthesis. Front. Cell Dev. Biol., 8, 63 (2020); DOI: and - Jennings, W. and Epand, R.M. CDP-diacylglycerol, a critical intermediate in lipid metabolism. Chem. Phys. Lipids, 230, 104914 (2020); DOI).
We need now to take note that CDP-DAG synthases, as a regulators of phospholipid metabolism and the rate-limiting enzyme in phosphatidylinositol biosynthesis, have a key role in the regulation of signal transduction processes dependent upon this lipid and thence indirectly in diseases related to faulty lipid metabolism. Similarly, it influences the availability of phosphatidic acid for biosynthesis both of triacylglycerols and of complex lipids and for its signalling activities.
May 6th, 2020
In some types of glycosylphosphatidylinositols (protein anchors), the first mannose unit is decorated by the addition of a short oligosaccharide sequence starting with N-acetylgalactosamine, before galactose is added. A new publication shows that this step involves the action of a GM1 ganglioside synthase and requires the presence of lactosylceramide (Wang, Y. et al. Cross-talks of glycosylphosphatidylinositol biosynthesis with glycosphingolipid biosynthesis and ER-associated degradation. Nature Commun., 11, 860 (2020); DOI - open access). It is thus an interesting link between glycerolipid and sphingolipid metabolism.
Some years ago, in the question session after a presentation, I was asked if I knew of links of this kind. Only two sprang immediately to mind - the biosynthesis of sphingomyelin requiring phosphatidylcholine as precursor, while ethanolamine phosphate derived from the catabolism of sphingolipids via sphingosine 1-phosphate is recycled for the biosynthesis of phosphatidylethanolamine. I was sure there were more and of course, once I was on my way home, I thought of others. I began to make a list, and eventually, I decided that this should be shared so I added a short section to my web page Introduction to Sphingolipids. Although more items have been added from time to time, I am sure that this list is far from complete, so I would be grateful for suggestions of further examples.
We must all be rethinking our relationship with the world and our environment during the Covid crisis. A new review on the application of lipidomics adds food for thought (Koelmel, J.P. et al. Environmental lipidomics: understanding the response of organisms and ecosystems to a changing world. Metabolomics, 16, 56 (2020); DOI). Incidentally, there are three further reviews of various aspects of lipidomics in the current reference list(May) in the Literature Survey section of this web site.
April 29th, 2020
A paper
in press suggests a novel potential application of a common simple lipid as an antibiotic in nasal, tracheal, and bronchial epithelial cells
(Verhaegh, R. et al. Sphingosine kills bacteria by binding to cardiolipin. J. Biol. Chem., in press
(2020); DOI).
The authors show that unesterified sphingosine in protonated form rapidly causes death in a number of important bacterial pathogens by binding
to the negatively charged lipid cardiolipin in bacterial plasma membranes.
The suggestion is that the mechanism involves rapid permeabilization of the plasma membrane by promoting clustering of cardiolipin molecules
in the membrane to generate gel- or even crystal-like structures.
Sphingosine administered for antibiotic purposes is unlikely to reach cardiolipin in mitochondria in animal tissues,
but I wonder whether some of the biological properties assigned separately to sphingosine and cardiolipin present endogenously in cells
might be due to the two lipids acting in concert.
On a number of occasions over the last 15 years in this blog, I have drawn attention to the poor career prospects of most post-doctoral researchers in British Universities (not that the UK is unique in this respect). They may not be regarded overtly as a source of cheap and disposable labour, but this is the often the result. Nothing seems to change. The problem is likely to be exacerbated by the current financial problems of universities, and may even have become a feminist issue, as an article in the Guardian newspaper suggests.
April 22nd, 2020
I can remember when lysophospholipids were regarded merely as nasty lipids that would disrupt cell membranes if they were not rapidly catabolized or re-esterified. Their occurrence in lipid extracts was viewed as an artefact of a faulty extraction procedure (still true if too abundant). Now they are listed among the more important of lipid mediators with key functions in signalling, especially if sphingosine-1-phosphate is included in their number. I highlighted their potential use to deliver polyunsaturated fatty acids to brain in my blog of two weeks ago. Now a new publication describes yet another important function. It is reported that the phospholipase iPLA2γ hydrolyses fatty acids from position sn-1 of phospholipids to generate polyunsaturated sn-2-acyl lysophospholipids. In murine myocardium and in isolated platelets, human platelet-type 12-lipoxygenase (12-LOX) can then directly catalyse the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine and 2-arachidonoyl-lysophosphatidylethanolamine to produce 2(S)-HETE products, which can initiate signalling pathways. As these increase in concentration with age, they "may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions" (Liu, X. et al. 12-LOX catalyzes the oxidation of 2-arachidonoyl-lysolipids in platelets generating eicosanoid-lysolipids that are attenuated by iPLA2γ knockout. J. Biol. Chem., 295, 5307-5320 (2020); DOI). There is a growing list of oxidized phospholipids that have biological activity in intact form (on this website see - here.. and here..)
I am grateful to a correspondent who pointed out an error in my structural formulae for the furanoid fatty acids (via the link) highlighted in my last blog; corrections or suggestions for improvements are always welcome. Another correspondent has drawn my attention to a useful online data base of plant fatty acids. He also sent a copy of a new review on a related topic, which I will enjoy reading in self-isolation (Cahoon, E.B. and Li-Beisson, Y. Plant unusual fatty acids: learning from the less common. Curr. Opinion Plant Biol., 55, 66-73 (2020); DOI).
April 15th, 2020
For many years, I was puzzled by the appearance of minor components in GC-MS traces of fish oil methyl esters, the mass spectra of which bore no resemblance to conventional fatty acids. Eventually, a colleague suggested that they were furanoid fatty acids, and this proved to be correct. Once I knew what to look for I found them in every fish oil sample that I looked at, and especially in fish oil concentrates prepared for nutraceutical purposes (analysed by Mylnefield Lipid Analysis to which I was a consultant until recently). I am sceptical of a recent claim that they can be formed artefactually from EPA and DHA in pharmaceutical preparations. However, their precise origin is uncertain, although it is believed to be somewhere in the marine food chain, probably algae. In fish, they tend to be concentrated in reproductive tissues, although their function is unknown.
When consumed by humans, furanoid fatty acids have generally been suggested to have benign functions as antioxidants with cardioprotective effects. However, short-chain metabolites or "urofuranic acids", beta-oxidation metabolites of the longer-chain components from fish in the diet, are found in plasma, and when kidney function is impaired one isomer in particular, i.e., 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), can accumulate and is reported to be a significant uremic toxin. Its concentration increases in plasma of patients who progress from prediabetes to type 2 diabetes also, and it may be a marker for this disease; it increases oxidative stress and impairs insulin secretion. Analysis has always been a technical challenge, but a new LC-MS/MS technique with charge-reversal derivatization appears to be the answer (Xu, L. et al. Development of a sensitive and quantitative method for the identification of two major furan fatty acids in human plasma. J. Lipid Res., 61, 560-569 (2020); DOI). Hopefully, the availability of the method will enable a better understanding of the metabolic consequences.
April 8th, 2020
I don't believe that I am unique in being confused by nutritional science in relation to recommendations for the intake of specific fatty acids, especially for eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. As far as I can understand it, the evidence that supplementation in the early years of life is a good idea seems to be fairly solid. On the other hand, this may not continue to be true as children get older. Unfortunately for myself, increased intake of these fatty acids does not seem to help with cognitive decline in the elderly, and the jury seems to be out on whether it helps with neurological diseases. On the other hand, there is a school of thought that conventional supplementation of the diet with these fatty acids does not help because they cannot cross the blood-brain barrier with sufficient rapidity to enter the brain where they are needed. There have been a few publications recently suggesting that this problem can be circumvented if they are administered as esters of lysophosphatidylcholine. A new paper describes this work and especially a relatively stable analogue, i.e., 1-acetyl,2-docosahexaenoyl-glycerophosphocholine, which has the potential to be supplied orally (Hachem, M. et al. Brain targeting with docosahexaenoic acid as a prospective therapy for neurodegenerative diseases and its passage across blood brain barrier. Biochimie, 170, 203-211 (2020); DOI).
The most recent paper I have seen on analysis of fatty acid esters of hydroxy fatty acids (FAHFA) nearly doubles the number of reported molecular species in rat adipose tissue to over 300 (Zhu, Q.F. et al. FAHFA footprint in the visceral fat of mice across their lifespan. Biochim. Biophys. Acta, 1865, 158639 (2020); DOI). They are known to have anti-inflammatory and anti-diabetic effects. I suppose that we must classify them as oxylipins, although we tend to think of most such lipids as being produced under strict stereospecific and regiospecific control. It is not yet known whether FAHFA have a specific receptor, but if so does it really handle such a wide range of isomeric compounds?
April 4th, 2020
News of the untimely death of Michael Wakelam from Covid-19 came as a great shock. I first met him when he was a lecturer at Glasgow University in the 1980s, and I followed his career via his publications with great interest thereafter. It was he who invited me to add my blog and later this website to that of LipidMaps. Lipid science will be much the poorer for his passing.
April 1st, 2020
Two further brief autobiographies of lipid scientists have appeared this week - good reading matter at any time, but especially when in self-isolation. The first is by Howard Goldfine (Life without air. J. Biol. Chem., 295, 4124-4133 (2020); DOI - open access). I first became aware of his work on cyclopropane fatty acids when I worked briefly on their chemical synthesis in my post-doc years. More recently, among a substantial body of work on microbial lipids, his work on plasmalogen biosynthesis in anerobic bacteria is ground-breaking, even if we don't have all the answers yet; unlike animal systems, the required enzymes do not need molecular oxygen.
The second of these autobiographies is by Robert C. Murphy (Lipid mass spectrometry: A path traveled for 50 years. J. Mass Spectrom., e4492 (2020); DOI), who will be well known to users of the LipidMaps website, and whose name is synonymous with mass spectrometry of lipids. His book on this topic in the Handbooks in Lipid Research series was a well-used item on my book shelf, and now probably resides with one of my former colleagues. I had forgotten his early contribution to what was then known as the "slow reacting substance of anaphylaxis", which on sabbatical at the Karolinska Institute in Sweden he identified as the lipid mediator we now know as leukotriene C4. Since then, he has produced an enviable number of publications that are truly pioneering on the chemistry and biochemistry of eicosanoids, as well as on complex lipids. His studies based on the use of mass spectrometry have enabled us to look at the biochemistry of lipids in living systems at minute concentration that were unthinkable to earlier generations of scientists. He is one of the first I would list among those who have established "lipidomics" as a science.
A useful summary paper concludes a thematic series on the biological functions of phosphatidylserine (Calianese, D.C. and Birge, R.B. Biology of phosphatidylserine (PS): basic physiology and implications in immunology, infectious disease, and cancer. Cell Comm. Signal., 18, 41 (2020); DOI). The various parts have been appearing over recent months.
March 25th, 2020
In the
cell envelope of Gram-positive bacteria, there are usually two types of polyanionic polymers linked either to membrane
diglycosyldiacylglycerols, i.e., lipoteichoic acids (LTA), or to peptidoglycans,
i.e., wall teichoic acids (WTA), which together form a dense protective layer against the environment.
The anionic polymer units in both appeared to be superficially the same in that they consisted of repeating glycerol-phosphate units
decorated in various ways. However, it is evident that degradative enzymes discriminate between the two.
It has now been demonstrated that in LTA, the repeating units consist of sn-glycerol-1-phosphate while in WTA they are
sn-glycerol-3-phosphate.
In other words, they are stereochemically distinct (Walter, A. et al. Phosphoglycerol-type wall and lipoteichoic acids
are enantiomeric polymers differentiated by the stereospecific glycerophosphodiesterase GlpQ. J. Biol. Chem., 295,
4024-4034 (2020); DOI - open access as author's choice).
This adds weight to my recent blog in which I stressed the importance of the difference between regiospecific and stereospecific nomenclatures
for glycerol derivatives.
I am appreciative of the policy of the Journal of Lipid Research in providing commentaries on articles, which the editors consider of special importance. Like most scientists, I scan the titles of innumerable new publications every week, and it is very easy to miss some that I ought to read. It is impossible to be an expert on everything, and I am grateful for any help that I can get. One such commentary appeared in press this week to discuss a paper also in press describing how unesterified fatty acids cross membranes (Pownall, H.J. J. Lipid Res., DOI - open access). The conclusion is that this occurs largely by a simple diffusion mechanism or 'flip-flop'. The process is not unregulated as sometimes suggested, nor is it controlled via the activity of specific transporters, but simply by the "balance between intracellular triacylglycerol synthesis versus hydrolysis, which transfer long-chain fatty acids into or liberate them from fat droplets, respectively".
March 18th, 2020
Some years ago, a colleague was contacted by a poultry company because the yolks of their eggs had a peculiar consistence. Not surprisingly, it turned out that they were using a less costly unrefined cotton seed oil in their feed, as it was well established that traces of cyclopropenoid fatty acids in this oil reacted with thiol groups and in particular inhibited stearoyl-CoA desaturase with dramatic effects upon the fatty acid composition and thence upon the properties of eggs. However, I was rather surprised to find in a new review that this activity now has clinical potential for use of this fatty acid as an adjuvant in diseases such as cancer, nonalcoholic steatohepatitis and skin disorders. It may also have a protective roles in retinal diseases such as age-related macular degeneration (Pelaez, R. et al. Sterculic acid: the mechanisms of action beyond stearoyl-CoA desaturase inhibition and therapeutic opportunities in human diseases. Cells, 9, 140 (2020); DOI - open access).
Gangliosides are another class of lipids involved in human disease states. Meat eaters and milk drinkers, including the human neonate, consume small amounts of these, but I had not realized that they had an influence upon human metabolism as dietary constituents. After all they are catabolized in intestinal tissues with release of their lipid and carbohydrate constituents. However, it appears that the sialic acid residues are re-utilized for ganglioside synthesis within tissues, and in particular that N-glycolylneuraminic acid (Neu5Gc), not normally found in human tissues, is used for ganglioside synthesis in some cancers. Now there is evidence that dietary control can regulate the expression levels of gangliosides in tissues, and it is hoped that this may helpful in treating ganglioside-related diseases (Okuda, T. Dietary control of ganglioside expression in mammalian tissues. Int. J. Mol. Sci., 21, 177 (2020); DOI - open access).
If you are stuck at home in isolation because of Covid-19, why not spend a little time browsing through the Lipid Essentials pages (and other web pages) on this site. I am always grateful for feedback - suggestions for improvements, correction of errors, etc - as these pages are not peer reviewed, and like all humankind I am fallible.
March 11th, 2020
I can heartily recommend the personal reflections of Professor Sarah Spiegel (My journey with sphingosine-1-phosphate) that have just been published (Spiegel, S. Sphingosine-1-phosphate: From insipid lipid to a key regulator. J. Biol. Chem., 295, 3371-3384 (2020); DOI - open access). Aside from being a remarkable account of the discovery of the manifold functions of this key lipid, which has inspired countless new research efforts, it is an enlightening story of how physical and personal difficulties were overcome to accomplish so much seminal work. Reading it caused me to reflect on how women in science have fared during my own research career. At high school in the 1950s, I only encountered two female teachers, who were both unmarried (then the norm), while girls were subtly directed away from the sciences. At University, I was never taught any course by a female lecturer/professor, and in my subsequent post-doctoral research at the Hormel Institute in Minnesota there were no female staff in tenured positions. This was also true for senior positions in my first permanent post at the Hannah Research Institute until the late 1970s. I am not in a position to judge now whether we have a truly level playing field in employment, and I don't suppose that we will be able to make such a judgment until we can discuss someone's research career without making an important issue of their gender.
Incidentally, I also encountered a new review from Spiegel's laboratory on sphingosine-1-phosphate and cancer (Singh, S.K. and Spiegel, S. Sphingosine-1-phosphate signaling: A novel target for simultaneous adjuvant treatment of triple negative breast cancer and chemotherapy-induced neuropathic pain. Adv. Biol. Regul., 75, 100670 (2020); DOI - open access).
Improved analytical methodology invariably leads to novel biological findings, and a new mass spectrometric technique applied to the much-studied gangliosides of human brain has revealed many novel molecular species, including those with up to seven sialylations, and with O-fucosylations and O-acetylations (Ica, R. et al. Orbitrap mass spectrometry for monitoring the ganglioside pattern in human cerebellum development and aging. J. Mass Spectrom., e4502 in press (2020); DOI.
Two books on lipid biochemical topics have been published by Springer for those with access (not me) - Bioactive Ceramides In Health And Disease: Intertwined Roles Of Enigmatic Lipids. (Ed.: Stiban, J.), Adv. Exp. Med. Biol., Vol. 1159 (2019); and Role Of Bioactive Lipids In Cancer, Inflammation And Related Diseases (Eds.: Honn, K.V. and Zeldin, D.C.), Adv. Exp. Med. Biol., Vol. 1161 (2019).
March 4th, 2020
One of the key unknowns regarding plasmalogen biosynthesis has been identification of the enzyme responsible for introducing the double bond into position 1 of the alkyl chain. This has at last been identified as the orphan human protein designated TMEM189, following the identification of an analogous enzyme in bacteria (Gallego-Garcia, A. et al. A bacterial light response reveals an orphan desaturase for human plasmalogen synthesis. Science, 366, 128-132 (2019); DOI). Now this opens the way to learning much more of the functions of plasmalogens in tissues. While they may have roles in membrane organization, signalling, and as antioxidants, my impression in that the data in some areas are not as solid as they could be.
I was also greatly interested in a lipidomics paper dealing with ether lipids that show appreciable differences in the nature and concentrations of specific alkyl and alkenyl ethers between centenarians and other age groups (Pradas, I. et al. Exceptional human longevity is associated with a specific plasma phenotype of ether lipids. Redox Biology, 21, 101127 (2019); DOI). Unfortunately, there does not appear to be any way that I can use this information to my advantage to guarantee another 20 years of this blog.
My apologies if some of the external links from the Lipid Library have not been working correctly in recent weeks, especially DOI addresses. The problem should now have been corrected.
February 26th, 2020
Cardiolipin
is a unique lipid in many ways, and in a new review it is described as a functional "glue" that binds components of the
mitochondrial respiratory chain into an integrated system to provide efficient transfer of electrons and protons (Shilovsky, G.A. et al.
Biological diversity and remodeling of cardiolipin in oxidative stress and age-related pathologies.
Biochemistry (Moscow), 84, 1469-1483 (2019);
DOI).
The oxidation of cardiolipin is a part of much studied route to apoptosis in mitochondria, but this review provides a new slant (to me at least)
to the topic by describing what happens during aging, a subject close to my heart both literally and metaphorically.
Oxidation triggers apoptosis and this review suggests that this is in part due to the loss of symmetry in the molecule that inevitably occurs.
Also, during aging, there is a gradual loss of cardiolipin in mitochondria, and this is accompanied by changes in the fatty acid composition
with higher polyunsaturated fatty acids replacing some of the linoleate.
This also implies a loss of symmetry in the molecule and leads to a reduction in the efficiency of the respiratory chain.
If this goes too far, it can result in mitochondrial dysfunction and the age-related pathologies of the title.
Incidentally, I wanted to check a point from a 1991 reference cited in this publication, but found that our Institute license did not cover this. It seems unlikely that publishers generate significant revenue from their back catalogue and it must deter proper bibliographic research. Young scientists probably think that anything published in the last century is the scientific equivalent of the stone age. Don't believe it!
I once had my own a Facebook page, and although I never added anything to it, it enabled me to keep abreast of the activities of my grandchildren. Now, they have reached an age where they don't want me to know what they are doing! Until recently, I had never bothered with Twitter, but I must admit that I find the Twitter feed to LipidMaps rather useful in making me aware of important references that I might otherwise miss.
February 19th, 2020
Bacterial lipopeptides from the genera/families Paenibacillaceae, Bacillus, Streptomyces and Pseudomonas are fascinating molecules in many ways, not least because of their potential to produce new antibiotics. However, it is easy to forget that the main reasons for the synthesis of these product is not to aid humans, they often have the opposite effects, but to aid the interaction with other bacteria and the environment and to create and sustain symbiotic relationships in mixed bacterial communities. The non-ribosomal synthetases responsible for their production are also distinctive and are organized into mega-enzyme complexes with molecular weights greater than 1.0 MDa in some instances. These are arranged in a systematic modular manner in assembly lines that permit the structural alteration of lipopeptide products by swapping domains or modules to create novel molecular structures. In general, the order of these modules is co-linear with the peptide sequence of the product, and each module contains multiple domains that are responsible for catalysing different enzymatic activities. For example, conversion of an L-amino acid to the D-isomer is carried out by an epimerization domain on the module that activates this and incorporates it into the growing peptide. It is the modular nature of these enzyme complexes that has lead to the hope that they can be manipulated to our benefit. As I have been reading in a new review, the biochemical mechanism in Pseudomonads has much in common with that for Bacillus and other species, but the two are evolutionarily distinct and there are some important differences (Götze, S. and Stallforth, P. Structure, properties, and biological functions of nonribosomal lipopeptides from pseudomonads. Nat. Prod. Rep., 37, 29-54 (2020); DOI - free access to non-subscibers on registration).
Oleoylethanolamide is another lipid with the potential to benefit humans by its effects upon food consumption and weight management (Tutunchi, H. et al. A systematic review of the effects of oleoylethanolamide, a high-affinity endogenous ligand of PPAR-α, on the management and prevention of obesity. Clin. Exp. Pharmacol. Physiol., in press (2020); DOI - open access). Perhaps I am cynical, but I suspect that whether this can be realized may depend on whether it can be patented to justify the expenditure on clinical trials.
February 12th, 2020
It is not often that I see Shakespeare quoted in a scientific paper, but this occurs both in the preamble and text of a review of oxidized phospholipids (Kagan, V.E et al. Redox phospholipidomics of enzymatically generated oxygenated phospholipids as specific signals of programmed cell death. Free Rad. Biol. Med., 147, 231-241 (2020); DOI - open access). In relation to apoptosis - the "sweetness" of death that liberates from suffering, pain and loathed life. However, the review is not confined to literary appreciation but is a sometimes sobering account of vital biological processes. It appears that, in spite of all that has been learned of oxidation/anti-oxidative processes, not a single clinical trial of potential therapeutic antioxidants against inflammatory diseases has seen a positive outcome. It seems that biological systems are too complex to permit easy solutions.
Just when you think that all the important lipids have been characterized in a well-studied organism such as Escherichia coli, along comes a fascinating new lipopolysaccharide, the structure of which has now been confirmed. This was originally designated as "MPIase", as it appeared to have the biological activity of an enzyme, before its true nature was revealed. In fact, it has a long glycan chain composed of repeating trisaccharide units (GlcNAc, ManNAcA, Fuc4NAc) attached to an anchor composed of pyrophosphate linked in turn to a diacylglycerol. It is believed to alter the physicochemical properties of membranes to drive translocation and integration of proteins in membranes (Fujikawa, K. et al. Novel glycolipid involved in membrane protein integration: structure and mode of action. J. Synth. Org. Chem. Japan, 77, 1096-1105 (2019); DOI - open access).
Before completing my an update on my web page on phosphoglycolipids/glycophospholipids to include a brief note on this lipid, I did a quick literature search with these key words for the last five years in the Web of Science. This turned up 100 references, nearly all to new identifications of bacterial species containing such lipids mostly as "unidentified phosphoglycolipid", etc. Clearly, there is a lot of work to be done, although I suspect that part of the problem is that no standards are available commercially to aid in analysis.
February 5th, 2020
The structural identification of platelet-activating factor (PAF) in 1979 was an exciting milestone in lipid science for those of us who were around then, as it was the first time that an intact phospholipid was found to have biological activity in its own right, and not simply to have a structural function in membranes, or to act via hydrolysis products. Indeed, the activity was remarkable at 10-11M! I dumped my 1977 copy of Lehninger some years ago, but it had only 3 pages on lipid functions - mainly as structural components of membranes and as a source of energy, with a short note on prostaglandins in a side box. There was no mention of the phosphoinositides, which were just beginning to make an impression. Since then it has emerged that virtually every lipid has some distinctive biological activity in its own right, but in my opinion PAF was the real start of a change in how lipids were perceived by the scientific community in general. A new review celebrates the anniversary of the discovery with a historical note - three groups were in competition to identify the molecule - and a lengthy discussion of the potential health benefits of targeting PAF metabolism (Lordan, R. et al. Forty years since the structural elucidation of platelet-activating factor (PAF): historical, current, and future research perspectives. Molecules, 24, 4414 (2019); DOI - open access).
From time to time, I put on my "grumpy old man" hat to complain about some current scientific use of language. Perhaps this is pedantry, but someone has to take a stand if only to educate the new generation. What has caused my ire this week is the use of mass spectrometry to determine "sn-position isomer" compositions. "sn" stands for stereospecific numbering, and mass spectrometry is not stereospecific in this context but "regiospecific", and this is the correct term to use. Of course, when you are dealing with a single glycerolipid enantiomer as with most (but not all) natural phospholipids, the end result is the same, but the term is frequently used also for triacylglycerol positional distributions, where it is entirely inappropriate. If a racemic synthetic phospholipid were to be analysed by mass spectrometry, the primary (mixed sn-1/3) and secondary fatty acids would be determined with the same accuracy as for natural phospholipids. Incidentally, in this blog, I have occasionally challenged analysts to compare the results of determining positional distributions in phospholipids by mass spectrometry with older techniques, such as hydrolysis with the phospholipase A2 of snake venom, against natural samples as opposed to model compounds. So far no takers, but it might be a useful short project for a student.
January 29th, 2020
Skin ceramides are highly distinctive lipids with an essential
function in maintaining the protective barrier to the environment, and a key feature is that they contain very-long-chain fatty acids
with an ω-hydroxyl group that is esterified very specifically to linoleic acid.
The ultimate fate of the ceramides is attachment covalently via the terminal tend of the molecule to the proteins of the corneocyte envelope.
Until now, it was believed that enzymic oxidation of the linoleate molecule facilitated its hydrolysis and attachment of the ceramide
to a protein by esterification of the ω-hydroxyl to a glutamic acid residue by an ester bond.
This may indeed occur to some extent, but a new publication suggests an alternative with a more intimate role for linoleate
in the attachment process (Takeichi, T. and 18 others. SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin
barrier formation. J. Clin. Invest., 130, in press (2020);
DOI - open access).
The suggestion is that the linoleate residue attached to the ω-O-acylceramide is oxidized by 12R-LOX and eLOX3 and
an NAD+-dependent dehydrogenation to a highly reactive 9,10-trans-epoxy,11E-ene,13-keto intermediate
(see our web page on hepoxilins),
which rather than being hydrolysed is able to link non-enzymatically by the Michael addition reaction to cysteine or histidine residues in proteins
of the corneocyte envelope, or by formation of a Schiff base and eventually a pyrrole derivative with a lysine residue.
Incidentally, this adds to the argument that linoleic acid is an essential fatty acid in its own right
and is not simply a precursor of arachidonic acid and eicosanoids.
I hate to use a phrase such as - "Nothing is known of the ...." when writing the web pages in my Lipid Essentials section. Happily, I was able to remove these words in updating my web page on Archaeal lipids to introduce new information on how the cyclopentane rings are formed in the isoprenoid chains of the glycerol dibiphytanyl glycerol tetraethers thanks to the identification of two key enzymes (Zeng, Z. et al. GDGT cyclization proteins identify the dominant archaeal sources of tetraether lipids in the ocean. Proc. Natl. Acad. Sci. USA, 116, 22505-22511 (2019); DOI).
January 22nd, 2020
The term 'lipokine' was coined in 2008 at first to define the biological activity of palmitoleic acid and then more generally as lipid molecules derived from adipose tissue that can act as hormonal regulators and coordinate a wide array of cellular processes. Research on such lipids has continued apace, and it is now described in a substantial new review (Hernández-Saavedra, D. and Stanford, K.I. The regulation of lipokines by environmental factors. Nutrients, 11, 2422 (2019); DOI - open access). While I was used to reading about polyunsaturated fatty acids and their oxygenated metabolites as vital molecules in biochemistry and physiology, it came as something of a surprise to me at least to find that a simple monoenoic fatty acid could stimulate muscle insulin action and suppress hepatic lipogenesis (steatosis or 'fatty liver') and triacylglycerol synthesis in the liver in such profound ways. Among many other effects, palmitoleate generation in macrophages is reported to alleviate lipotoxicity-induced stress in the endoplasmic reticulum with beneficial effects on the progression of atherosclerosis while reducing apoptosis. It should not be forgotten that palmitoleic acid has a further essential property in that it is linked very specifically to a conserved serine residue in the Wnt family of proteins involved in tissue development, and it is essential for their function.
A further lipid molecule considered to be a lipokine is 12,13-dihydroxy-9Z-octadecenoate (12,13-diHOME), derived from linoleic acid, synthesis of which is activated by cold exposure and exercise and results in improved whole-body metabolic homeostasis. Similarly, fatty acid hydroxy fatty acids (FAHFAs) constitute a novel lipid class that act as lipokines to improve glucose tolerance and insulin sensitivity, among innumerable other effects. I have always been a little puzzled by the last, as so many isomeric forms are known, between 160 and 300, and we usually expect lipid mediators to have high structural specificity.
It is vitally important that we get the correct fatty acid composition (and other nutrients) in infant formulae, and I have found it strange that there has been no specific recommendation for arachidonic acid levels when eicosanoids are so important in human metabolism. A new publication by an expert panel recommends that arachidonic acid should be added at least at the same levels as DHA (Koletzko, B. and 26 others. Should formula for infants provide arachidonic acid along with DHA? A position paper of the European Academy of Paediatrics and the Child Health Foundation. Am. J. Clin. Nutr., 111, 10-16 (2020); DOI - not immediately available to non-subscribers, unfortunately).
January 15th, 2020
The Lipid Essentials pages on this site are based on essays on individual lipid classes, rather than on chemical, biochemical or physiological processes. In consequence, I have tended to spread general subjects such as lipid autoxidation over several web pages, rather than treating them in a more coherent fashion. One aspect that I have just discovered that I have ignored is photo-oxidation, so I am grateful for a reminder as to its importance (Bacellar, I.O.L. and Baptista, M.S. Mechanisms of photosensitized lipid oxidation and membrane permeabilization. ACS Omega, 4, 21636-21646 (2019); DOI - open access). In animals, photo-oxidation is of course relevant to skin metabolism, but it is now of increasing importance in clinical practice because of the development of photodynamic therapies to treat such diseases as cancer and bacterial infections. The presence of photosensitizers, both natural or added therapeutically, is a key factor. Of course, many of the end results are the same as with other aspects of autoxidation including membrane disruption and cytotoxic effects. This process must be of great importance in photosynthetic tissue and in food spoilage, but this is not discussed here.
Lipid metabolism at membrane contact sites is an important part of the theme of the special January issue of Biochimica Biophysica Acta. However, a separate new review article discusses this topic in relation to the phosphoinositides (Pemberton, J.G. et al. Integrated regulation of the phosphatidylinositol cycle and phosphoinositide-driven lipid transport at ER-PM contact sites. Traffic, 21, 200-2019 (2020); DOI). This is a topic with which I have struggled because of the complexity of the innumerable metabolites and pathways involved, and at first glance I am sure this review will enlighten me - helped by excellent illustrations.
January 8th, 2020
One of the many things I like about the journal "Lipids" is its short but descriptive title, and there are a few more out there like it, such as "Blood", "Bone", "Cells" and "Cancers" that are equally pithy. I turn up my nose at anything that begins with "The International Journal of etc" - what journal of any note is not international? It will be hard to find a journal title that is more succinct than "Gut", and we can be thankful that it is not the "Journal of the British Society of Gastroenterology". At least, with an unwieldy title such as "Proceedings of the National Academy of Sciences of the United States of America", we can abbreviate it to "PNAS", while "Prostaglandins, Leukotrienes and Essential Fatty Acids" is "PLEFA". Not that I am a great fan of acronyms and especially abbreviations in general, and for example I have just come across "DIM lipids" in the title of a publication. This conjured up some interesting mental pictures but when I read the abstract, this turned out to refer to phthiocerol dimycocerosates, the use of the abbreviation only a minor flaw in my opinion at least in an otherwise fascinating study (DOI).
Blogs for the previous year (2019) can be located here..
| © Bill Christie |  |
|
| Updated: January 11th, 2023 | Contact/credits/disclaimer | |