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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).


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).

Blogs for the previous year (2019) can be located here..

Author: William W. Christie Updated: July 1st, 2020 Contact/credits/disclaimer LipidWeb logo