The LipidWeb blank

Lipid Matters - A Personal Blog

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

February 26th, 2020

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

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

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

February 19th, 2020

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

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

February 12th, 2020

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

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

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

February 5th, 2020

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

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

January 29th, 2020

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

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

January 22nd, 2020

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

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

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

January 15th, 2020

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

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

January 8th, 2020

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

December 30th, 2019

Scottish thistleLipids are essential components of bacterial cell walls. If we are to defeat pathogenic Gram-negative bacteria, we must understand how their anatomy (for want of a better word) and how it functions. I imagine that most microbiologists are familiar with the nature of the cell envelope, but I was ignorant of it until I decided that my Lipid Essentials section would be incomplete without a web page on lipid A. In fact, the cell wall consists of two bilayer membranes, separated by an aqueous phase, the periplasm, which contains a layer of peptidoglycan molecules. Lipid A is a multi-acylated disaccharide that serves to anchor a complex polysaccharide component to the outer leaflet of the outer membrane, so that the latter acts as an interface or barrier to the environment including the immune system of host animals including us. One of the most interesting aspects of the biochemistry is how the organism manages to construct and then transport such a large amphiphilic molecule across two bilayer membranes plus an aqueous phase and insert it correctly into the outer membrane. The answer is that it uses a kind of protein bridge made up of seven distinct proteins. A new review describes this in some detail but illustrates it with a superb diagrammatic representation, which greatly clarified the process for me (Sperandeo, P. et al. The Lpt ABC transporter for lipopolysaccharide export to the cell surface. Res. Microbiol., 170, 17981-17990 (2019);  DOI). I am envious of modern authors who have access to such artistic abilities.

The cell envelope of Mycobacterium tuberculosis is even more complex and includes a range of unique lipids that include mycolic acids, sulfoglycolipids, lipoarabinomannans and phosphatidylinositol mannosides. According to a new review, it has a sneaky habit of changing to accommodate different conditions, i.e. "to manipulate the human immune system, tolerate antibiotic treatment and adapt to the variable host environment" (Dulberger, C.L. et al. The mycobacterial cell envelope - a moving target. Nature Rev. Microbiol., 18, 47-59 (2020);  DOI). Again, this has a superb diagrammatic illustration of the cell wall that greatly aided my understanding.

December 18th, 2019

Every year at this time, I look over the LipidWeb to try to work out which areas have seen the most changes over the year as assessed by my log of daily updates, especially in the Lipid Essentials section. Often, the web pages on phosphatidylinositol and sphingosine-1-phosphate appear to be the most dynamic, and again both have been prominent in this regard but not as much as in past years. The clear winner this year as last has been my web page on mono-oxygenated eicosanoids (HETE), closely followed by the pages dealing with prostaglandins, and those of some of the other oxylipins. In comparison to previous years, I suspect that if I could break down these updates further across the relevant web pages, a much higher proportion would have been concerned with esterified oxylipins in relation both to signalling and lipoxidation reactions (for which two major review volumes have been published), as opposed to those in unesterified form. Indeed, my web page dealing with Bioactive aldehydes and oxidized phospholipids has probably seen the most substantial updates (and I am still working on it). As to other lipid classes, web pages on proteolipids and lipoproteins have seen numerous updates, but my sphingolipid pages do not seem to have developed as quickly as in past years, especially those dealing with the more complex glycosphingolipids. These comments always come with the caveat that the literature surveys on which my updates are based are highly subjective. I try to take a broad view, but my personal interests always emerge.

Formula of N-palmitoyl-O-phosphocholineserineMy selection for the novel lipid of the year is N-palmitoyl-O-phosphocholineserine (the most abundant species in its class), which has been found in patients with the genetic disorder Niemann-Pick disease type C1 (DOI) and was highlighted in one of my July blogs. A second group has now confirmed the structure (DOI - open access).

May I wish all my readers a very happy Christmas and good health and happiness in the New Year!

December 11th, 2019

Since the discovery of prostaglandins, thousands of papers have appeared on the chemistry and biochemistry of eicosanoids and docosanoids, but relatively few on the octadecanoids (C18), i.e. the oxylipins derived from linoleic acid. Yet octadecanoids (HODE) are reported to be the most abundant oxylipins in human plasma. Now, a new report suggests that they are also the main components of the oxylipins in the brains of rat pups (Hennebelle, M. et al. Linoleic acid-derived metabolites constitute the majority of oxylipins in the rat pup brain and stimulate axonal growth in primary rat cortical neuron-glia co-cultures in a sex-dependent manner. J. Neurochem., in press (2019);  DOI). 13S-HODE in particular increased axonal outgrowth cortical neurons in male rat pups significantly, but not in female pups where linoleic acid per se displayed this activity. These data contrast with many more negative reports of the biological activities of octadecanoids, which may for example be inflammatory and atherogenic through the induction of pro-inflammatory cytokines.

α-Linolenic acid tends to be of low abundance in animal tissues and I have not been able to find anything in the literature on the occurrence of oxylipins derived from this precursor in animals. I guess the best place to look for them would be in vegans, or better in non-ruminant herbivores such as the horse. My understanding is that linoleic acid is now regarded as an essential fatty acid in its own right, not simply as a precursor of arachidonic acid and eicosanoids, because of its vital functions in skin lipids as well as its conversion to bioactive oxylipins. In contrast, α-linolenic acid may only be essential for conversion to EPA and DHA and their metabolites.

Last week, I discussed briefly the therapeutic properties of bile acids. This week, a new review discusses their potential role as anticancer drugs (Goossens, J.F. and Bailly, C. Ursodeoxycholic acid and cancer: From chemoprevention to chemotherapy. Pharmacol. Therapeut., 203, 107396 (2019);  DOI). Paradoxically, ursodeoxycholic acid inhibits apoptosis in epithelial cells while promoting it in cancer cells.

December 4th, 2019

For much of my research career, I have been hearing about how bad lipids are for health - total fat intake, saturated fats, trans-fatty acids, cholesterol and so forth - are all anathema to nutritionists. This is perhaps why I am always fascinated now to learn of the therapeutic applications of specific lipids. As a non-subscriber, it will be a year before I can read anything other than the abstract, but a new publication from Serhan's group suggests that a resolvin may be of value in the treatment of deep vein thrombosis (Cherpokova, D. et al. Resolvin D4 attenuates the severity of pathological thrombosis in mice. Blood, 134, 1458-1468 (2019);  DOI). It is reported that this specialized pro-resolving mediator not only has a direct effect by significantly reducing the thrombus burden, but it also promotes "the biosynthesis of other D-series resolvins involved in facilitating resolution of inflammation".

For 160 years after the discovery of cholic acid in 1838, bile acids were considered to be simply a form of detergent that functioned to solubilize dietary lipids to facilitate their absorption. That has changed, and there have been a number of useful reviews on their other biological properties in recent years. However, I was attracted by the opening sentence of the abstract of new review, which happily is open access, and to quote - "Of all the novel glucoregulatory molecules discovered in the past 20 years, bile acids are notable for the fact that they were hiding in plain sight" (Ahmad, T.R. and Haeusler, R.A. Bile acids in glucose metabolism and insulin signalling - mechanisms and research needs. Nature Rev. Endocrin., 15, 701-712 (2019);  DOI). Now they are known to act through the nuclear receptor FXR and many others, and to have appreciable therapeutic potential. In fact, the hydrophilic secondary bile acid ursodeoxycholic acid (3α,7β-dihydroxy-5β-cholan-24-oic acid) and its taurine conjugate are already used clinically for cholesterol gallstone dissolution and in the treatment of primary biliary cirrhosis. This particular review concentrates on the manner in which bile acids regulate glucose homeostasis. Incidentally, I was intrigued to read in the review that bile acids are important for the biosynthesis of anandamide and other bioactive amides.

November 27th, 2019

Scottish thistleThe journal Free Radical Biology & Medicine has devoted a special issue to the topic of "Redox lipidomics and adductomics - Advanced analytical strategies to study oxidized lipids and lipid-protein adducts" with more than 300 pages of articles. The editors have contributed a useful commentary, which is open access, with this title (Cruciani, G. et al. Free Rad. Biol. Med., 144, 1-5 (2019);  DOI). I have only had time to read of few of these, but my eye was drawn to a short series of papers on the sub-topic of "Advances in analysis of nitrated lipids". Nitro fatty acids are produced while in esterified form in lipids, but it is the unesterified acids that have attracted most of the attention, as they are believed to be important mediators in physiopathological processes such as inflammation. Research seems to be an early stage and mainly with model systems in vitro, but it would be not at all surprising if, after nitration, intact lipids were found to have significant biological activities as is now recognized for oxidized phospholipids. "Adductomics" is a new word for my omics collection.

Text books tend to discuss autoxidation as a product of two reactions, the Haber-Weiss and Fenton reactions. However, it appears that in terms of living systems at least, the Haber-Weiss reaction can be discounted as negligible, and I have to confess that I was in error in over emphasizing its importance in my web page on isoprostanes (see - Filipovic, M.R. and Koppenol, W.H. The Haber-Weiss reaction - The latest revival. Free Rad. Biol. Med., 145, 221-222 (2019);  DOI). Although I have now made an appropriate correction, I should have been aware of this earlier.

November 20th, 2019

Lipid A is the glycolipid component that serves as the anchor for the lipopolysaccharides that make up a large part of the external cell walls of Gram-negative bacteria, including a great number of human pathogens. Unfortunately for us, once inside a human host, lipid A is recognized as a pathogen-associated molecule by many different receptors on immune cells and stimulates a robust inflammatory response, which can cause tissue damage and in the worst scenario septic shock and death of the host. However, some bacteria produce lipid A forms that act as antagonists to the toxic molecules, and it is apparent that the gut microbiome may be a good source of these (Di Lorenzo, F. et al. Lipopolysaccharide structures of Gram-negative populations in the gut microbiota and effects on host interactions. FEMS Microbiol. Rev., 43, 257-272 (2019);  DOI). The immune system must be able "to distinguish the beneficial microbes from the pathogens, even if the commensal bacteria have molecular patterns resembling those of the pathogenic counterparts." Hopefully, a better understanding of the molecular mechanisms involved in these interactions will lead to a new approach to the treatment of bacterial infections.

The gut microbiome is now known to be the source of a further health-promoting lipid, i.e. α-galactosylceramide (normally present in tissues with a β-anomeric linkage), which activates invariant natural killer T cells with benefits against viral as well as bacterial infections (see a research publication and commentary in the November issue of the Journal of Lipid Research, for example). Perhaps I am naive, but I hope that such findings for these lipid classes could be utilized to produce nutraceuticals containing appropriate bacteria that are analogous to those containing Lactobacillus casei and are already available commercially. Anything that reduces the demand for antibiotics must be good.

November 13th, 2019

It is almost an axiom among nutritionists that dietary palmitic acid is bad for you, and I can even remember a newspaper headline 30 years ago to the effect that palmitic acid was "a poison produced by cows". Palm oil is widely derided in Western countries for its high content of palmitate and for the destruction of so many tropical habitats for palm plantations. Why then should plant biochemists strive to increase the content of palmitic acid in position sn-2 of triacylglycerols in seed oils as described in a new paper (van Erp, H. et al. Engineering the stereoisomeric structure of seed oil to mimic human milk fat. PNAS, 116, 20947-20952 (2019);  DOI). The title of the paper gives the game away, as human milk fat (and that of many other species) has a high content of palmitic acid in position 2. It appears that during digestion in the human infant, 2-palmitoylglycerols are produced that are absorbed in the intestines with relative ease. Infant formulae are now produced by technological means to have this distinctive structure, so the intention is to avoid chemicals in producing milk fat substitutes. On the other hand, I can imagine there will be howls of indignation in some quarters about the use of genetically modified crops for this purpose and the phrase "Frankenstein foods" will be used.

While palmitic acid has many essential functions in animal tissues, not least for the synthesis of sphingoid bases, there seems to be little doubt that dietary palmitic acid in excess is undesirable. In particular, it has inflammatory properties as discussed in a new review (Korbecki, J. and Bajdak-Rusinek, K. The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms. Inflam. Res., 68, 915-932 (2019);  DOI).

November 6th, 2019

From time to time, I enjoy reading a review that challenges accepted dogma, and one such discusses the biosynthesis of polyunsaturated fatty acids of the omega-3 family (Metherel, A.H. and Bazine, R.P. Updates to the n-3 polyunsaturated fatty acid biosynthesis pathway: DHA synthesis rates, tetracosahexaenoic acid and (minimal) retroconversion. Prog. Lipid Res., 76, 101008 (2019);  DOI). The measured rates of DHA biosynthesis in animals are very low, but the authors argue that this cannot be true. Among the authors' explanations are that DHA is used as quickly as it is produced for purposes other than for incorporation into membranes. They also have questions regarding the role of EPA in DHA synthesis and the proposed retroconversion mechanisms, and they point out that DHA is both a product and a precursor to tetracosahexaenoic acid (24:6(n-3)).

The same journal provided further food for thought with an intriguing article on the role of dietary C18 trans fatty acids in heart disease (Valenzuela, C.A. et al. Eighteen-carbon trans fatty acids and inflammation in the context of atherosclerosis. Prog. Lipid Res., 76, 101009 (2019);  DOI). I have always been sceptical of the suggestion that trans fatty acids of industrial origin are harmful, although those in dairy products are not - could it be fear of offending the massive dairy farming lobby? However, the authors accept that differences do indeed exist, which may be related to differences in the composition of the different isomers (and I bow to their superior knowledge). Dairy products have relatively high concentrations of trans-11-18:1 (vaccenic acid) in comparison to products of industrial hydrogenation, and importantly of conjugated linoleic acid (cis-9, trans-11-18:2 or CLA). The latter can also be produced in animal tissues by desaturation of ingested vaccenic acid, as can trans-11,cis-13-18:2. While the authors consider that CLA may be a cause of the perceived differences, one possible mechanism that they do not mention is that CLA is the preferred substrate for the formation of nitro fatty acids, which have pronounced anti-inflammatory effects.

October 30th, 2019

Scottish thistleA recent publication caused me to look up what I had written on lipoxygenase metabolites of eicosapentaenoic acid (EPA or 20:3(n-3)) in my web page here - to find not a word - and I soon found that I was not alone in this regard, as they are not mentioned in several major reviews on the topic, other than that 18-HEPE is a precursor for the E-series resolvins. A quick and relatively superficial survey found several brief mentions in the literature but only a little substantive information. It will be a year before I have access, but the paper that provoked my interest is by Leiria, L.O. et al. (12-Lipoxygenase regulates cold adaptation and glucose metabolism by producing the omega-3 lipid 12-HEPE from brown fat. Cell Metab., 30, 768-783.e7 (2019);  DOI). To quote from the abstract "The cold-induced 12-LOX product 12-HEPE was found to be a batokine that improves glucose metabolism by promoting glucose uptake into adipocytes and skeletal muscle through activation of an insulin-like intracellular signaling pathway".

I have now partially rectified my omissions, but I need to do more work on the topic. For example, it appears that 18-HEPE per se has cardioprotective properties and inhibits metastasis in a cancer model, while 5-HEPE enhances the induction of regulatory T cells (Tregs) that modulate the immune system and prevent autoimmune diseases. Fortuitously, the September issue of the journal International Immunology contains some relevant reviews in an open-access series on the theme of "Lipids in Inflammation". Perhaps surprisingly, I found more in my brief survey on the functions of lipoxygenase metabolites of EPA as plant oxylipins, as they are produced by marine algae as defense compounds against bacteria and other predators.

October 23rd, 2019

It is not at all easy to find data on the composition of cytidine diphosphate diacylglycerol (CDP-DAG) in animal tissues although it is a key intermediate in the biosynthesis of many complex glycerolipids, and I have to list data from a 1976 paper in my contribution on the topic here. I guess that it turns over so quickly that the levels in tissues remain too low to be easily detected by lipidomics methodology. It is relatively uncommon to even find this lipid as the major topic of a research publication. Mitochondria have their own unique CDP-diacylglycerol synthase (translocator assembly and maintenance protein 41 or Tam41), first characterized in yeast, and this is of course a key enzyme in the biosynthesis of cardiolipin with its myriad of essential functions. Although I will have to wait a year to read the paper, the structure of this enzyme has now been published and should help us understand how the enzyme functions (Jiao, H.Z. et al. Structures of the mitochondrial CDP-DAG synthase Tam41 suggest a potential lipid substrate pathway from membrane to the active site. Structure, 27, 1258-1269e4 (2019);  DOI). It appears that a binding pocket for the precursor/product has been identified in the structure, where phosphatidic acid may enter and CDP-DAG may exit, while the C-terminal region is crucial for membrane association.

In considering the metabolism of arachidonic acid and thence of the eicosanoids, one enzyme that has been somewhat neglected is the acyl-coenzyme A synthetase 4, which preferentially converts unesterified arachidonic acid to its CoA ester for incorporation into phospholipids when remodelling occurs. This enzyme is important in the earliest stages that might ultimately lead to the eicosanoid cascade, and a new study describes how it is required to maintain the content of highly unsaturated fatty acids to aid the inflammatory response (Kuwata, H. et al. Long-chain acyl-CoA synthetase 4 participates in the formation of highly unsaturated fatty acid-containing phospholipids in murine macrophages. Biochim. Biophys. Acta, 1864, 1606-1618 (2019);  DOI).

October 16th, 2019

Milk is fascinating stuff as the only animal food designed by evolution for oral consumption by other animals. It is not only nutritious but dairy products taste good. Of course, cow's milk is ideal food for calves, but it has its drawbacks for human nutrition, especially because of the low content of essential fatty acids. I can't comment on the taste of human milk (it is a long time since I was a baby!), but it obviously contains the perfect balance of nutrients for human infants. The lipids from the two sources are very different in composition, and both must be among the most studied of all natural products. However, surprises still occur. Now the emphasis is not on the bulk constituents, but on minor lipids that may be biologically active and perhaps should be added to infant formulae.

The nature of the specialized proresolving mediators in human milk, were the subject of my blog 2-3 years ago. Now a new paper discusses the properties of glycerol monolaurate in milk (Schlievert, P.M. et al. Glycerol monolaurate contributes to the antimicrobial and anti-inflammatory activity of human milk. Sci. Rep., 9, 14550 (2019);  DOI - open access). This lipid occurs at a concentration twenty times greater in milk of humans (3000μg/ml) compared to cows (and not at all in infant formulae) and has antimicrobial activity against a number of common bacteria. A second paper reports the presence of side-chain oxysterols in human milk, i.e. 24-, 25- and 27-hydroxycholesterol, throughout lactation with the last of these especially abundant in colostrum (Civra, A. et al. Antiviral oxysterols are present in human milk at diverse stages of lactation. J. Steroid Biochem. Mol. Biol., 193, 105424 (2019);  DOI). This was shown to be active against the pathogenic human rotavirus and rhinovirus of importance in pediatrics. What next for milk lipids?

October 9th, 2019

Carnivorous plants are fascinating biological oddities to botanists and laymen alike, and I suppose that many of us have wondered how they could have evolved to use insects as a source of nutrients - even plants don't have to be vegans! The answer it seems is to do with their lipids, as the capacity to induce digestive enzymes uses a form of the same signalling machinery as that for plant defence against insect predators, i.e. jasmonates (Pavlovič, A. and Mithöfer, A. Jasmonate signalling in carnivorous plants: copycat of plant defence mechanisms. J. Exp. Botany, 70, 3379-3389 (2019);  DOI). In addition, it appears that jasmonate signalling is connected to the electrical signals that induce plants such as the Venus fly trap to close and trap their prey. There are further valuable review articles on jasmonates in the same journal issue, and if you need a brief introduction I can recommend the editorial to the topic (Farmer, E.E. and Goossens, A. What allene oxide synthase does for plants. J. Exp. Botany, 70, 3373–3378 (2019):  DOI - open access). It is the oddities that fascinate a dilettante such as myself, but jasmonates are fascinating oxylipins with structural similarities to the prostaglandins that are presumably of evolutionary significance.

Up until now, jasmonoyl-L-isoleucine was the only metabolite known to be an endogenous ligand of the jasmonate co-receptor, but it has now been demonstrated that the omega-hydroxy analogue, hitherto thought to be inert, differentially activates a subset of the same receptor complex to modify particular jasmonate-dependent responses to improve plant resilience to stress (Jimenez-Alemana, G.H. et al. Omega hydroxylated JA-Ile is an endogenous bioactive jasmonate that signals through the canonical jasmonate signaling pathway. Biochim. Biophys. Acta, 1864, 158520 (2019);  DOI).

October 2nd, 2019

In all of my research career, I threw away the ganglioside fraction, because it remained in the aqueous rather than the organic component after Folch lipid extraction. However, I am grateful for those who have had the persistence to tackle ganglioside biochemistry and analysis as they are proving to have many vital functions in human metabolism. Increasingly, it has emerged that they can be important factors in the development of cancers, and specific gangliosides can have either positive or negative effects upon the regulation of the malignant properties of cancer cells as described in a recent review (Cavdarli, S. et al. Gangliosides: the double-edge sword of neuro-ectodermal derived tumors. Biomolecules, 9, 311 (2019);  DOI - open access). In regard to the latter, the good news is that antibodies to specific gangliosides are proving to be a useful element in therapy for specific cancers, with some current interest focussed upon O-acetylated GD2 (OAcGD2) in breast cancer. Incidentally, the ganglioside GM3 is elevated in the serum of patients with breast cancer and may be a marker for the disease (Li, Q.Y. et al. Gangliosides profiling in serum of breast cancer patient: GM3 as a potential diagnostic biomarker. Glycoconjugate J., 36, 419-428 (2019);  DOI).

Gangliosides are also involved in the action of interactions between microbes and host cells during infections, and cholera toxin, which is an enterotoxin produced by Vibrio cholerae, is a much studied example. The five B-chains of cholera toxin each bind one molecule of ganglioside GM1 and this enables it to enter cells to exert its dire effects. Now it has been established that the botulinus toxin binds to a complex of a polysialoganglioside with the protein synaptotagmin, which together act as a high-affinity receptor complex to enable the neurotoxic effects (Flores, A. et al. Gangliosides interact with synaptotagmin to form the high-affinity receptor complex for botulinum neurotoxin B. PNAS, 116, 18098-18108 (2019);  DOI). Of course, the better we understand these mechanisms, the more likely are we to be able to counter the ill effects. While these make the news, it should not be forgotten that gangliosides have innumerable beneficial functions.

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

2019 2018 2017 2016 2015 2014 2013
Author: William W. Christie Updated: February 26th, 2020 Credits/disclaimer LipidWeb logo