The Lipid Library

ARCHIVE - A LIPID BLOG

Past entries from an occasional series of notes on publications or other items dealing with lipid science that seemed to be of particular interest. They will be held here for about six months.

22/7/08

Triacylglycerols have never been looked upon as especially exciting molecules. They sit in tissues doing little most of the time, and don’t participate in signalling or enzyme function, for example. However, their importance towards the metabolic syndrome, obesity and all the associated disease states is ensuring that they are not forgotten. A new review by a former colleague of mine Victor Zammit highlights the importance of the diacylglycerol acyltransferase, the first enzyme dedicated to triacylglycerol biosynthesis specifically (Zammit, V.A. et al. Diacylglycerol acyltransferases: Potential roles as pharmacological targets. Pharm. Therapeut., 118, 295-302 (2008)). A review with a different perspective on this topic was published last year and shows that scientists are sometimes permitted a sense of humour (Turkish, A. and Sturley, S.L. Regulation of triglyceride metabolism. I. Eukaryotic neutral lipid synthesis: "Many ways to skin ACAT or a DGAT". Am. J. Physiol. Gastrointest. Liver Physiol., 292, G953-G957 (2007)).

Fat mobilization is an equally important reaction in animals and especially the developing seed, and a substantial review by Ian Graham provides an elegant summary of the topic in relation to the latter (Graham, I.A. Seed storage oil mobilization. Ann. Rev. Plant Biol., 59, 115-142 (2008)).

Finally, I was intrigued to read that three of the thirteen lipid molecules that are integral components of crystalline bovine heart cytochrome c oxidase are triacylglycerols. It seems that even these ‘inert’ molecules have a function in stabilizing protein structures (Shinzawa-Itoh, K. et al. Structures and physiological roles of 13 integral lipids of bovine heart cytochrome c oxidase. EMBO J., 26, 1713-1725 (2007)).

I was aware that N-acetyl-neuraminic acid is the only sialic acid in human gangliosides, while N-glycolyl-neuraminic acid (differing in one hydroxyl group) was absent - but found in most other animals. However, I have only just been alerted (by a popular newspaper article) to the fact that the great apes also differ from humans in that they have the second sialic acid. Not only do humans lack the enzyme that produces the N-glycolyl derivatives, but they lack a number of relevant genes. It seems apparent that this must have occurred very early and may have been a major branch point in human evolution. Gangliosides are important in a host of processes, including the developmental stages of all cell types, but especially in brain. The key reference is - Altheide et al. System-wide genomic and biochemical comparisons of sialic acid biology among primates and rodents. Evidence for two modes of rapid evolution. J. Biol. Chem., 281, 25689-25702 (2006).

The August issue of the Journal of Lipid Research contains two short review articles, which I have found to be exceptionally interesting (Pruett ,S.T. et al. Biodiversity of sphingoid bases (‘sphingosines’) and related amino alcohols. J. Lipid Res., 49, 1621-1639 (2008); Schlame, M. Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes. J. Lipid Res., 49, 1607-1620 (2008)). They are also very readable - not as common a virtue as it should be.

If I had to give a prize for the most unusual natural fatty acids, it would have to go to the ladderanes, which are produced by certain bacteria that can oxidize ammonia anaerobically. The structures are composed of three or five linearly concatenated cyclobutanes attached to the terminal carbon of a short- to medium-chain fatty acid acid, and occur in the organisms as the free acid or glycerol esters; related structures are found as alcohols or as alkylglycerols of various kinds, or with 6-membered rings attached to the fused cyclobutane rings. They are present in the phospholipids and are believed to provide a dense membrane around the anammoxosome, the presumed site of nitrogen oxidation.

A new paper describes the occurrence of these strange lipids in four genera of bacteria (Rattray,J.E. et al. Ladderane lipid distribution in four genera of anammox bacteria. Arch. Microbiol., 190, 51-66 (2008).)

It is well known that ceramides have a pivotal role in lipid metabolism. Sphingoid bases released as products of catabolism can be re-utilized for ceramide biosynthesis through the action of a ceramide synthase. This has been termed the ‘salvage’ pathway and is important in both quantitative and biological terms. For example, there are reasons to believe that ceramides derived from the salvage pathway are spacially and thence functionally distinct from those synthesised de novo. A recent review gives a clear account of this important topic (Kitatani, K., Idkowiak-Baldys, J. and Hannun, Y.A. The sphingolipid salvage pathway in ceramide metabolism and signalling. Cellular Signalling, 20, 1010-1018 (2008)).

I have just come across a paper published last year, which describes the discovery of the first sulfated fatty acids to be found in nature. Four such compounds were identified in the oral secretions of a species of grasshopper and termed 'caeliferins'. They are believed to elicit the release of volatile organic compounds as a defense response when the insects graze upon plants. That illustrated is the disulfate derivative of 1,16-dihydroxy-palmitic acid (Alborn, H.T. et al. Novel disulfoxy fatty acids from the American bird grasshopper Shistocerca americana, elicitors of plant volatiles. Proc. Natl. Acad. Sci. USA, 104, 12976-12981 (2007)).

I was lead to this paper by an interesting new review (Howe, G.A. and Jander, G. Plant immunity to insect herbivores. Ann. Rev. Plant Biol., 59, 41-66 (2008)). The title may not appear to relate to lipids at first glance, but it deals in large measure with the jasmonates, linolenic acid metabolites that are produced rapidly when plants are damaged by insects. These trigger genes that produce proteases and other compounds, which deter further predation.

Continuing on this theme, many advances in biology require advances in analytical chemistry. A recent paper on the biochemistry of jasmonates illustrates this (Glauser, G. et al. Spatial and temporal dynamics of jasmonate synthesis and accumulation in Arabidopsis in response to wounding. J. Biol. Chem., 283, 16400-16407 (2008)).

I consult the site - ABC ChemistRy – free full text journals at regular intervals as it keeps me up-to-date on what is available for free on-line access. It has made me aware that the complete archive of the defunct journal Acta Chemica Scandinavica is now available to all on-line. Many of the important early papers on mass spectrometry of lipids were published here, including the first dealing with unsaturated esters, glycerol ethers, sphingoid bases and double bond location.

We are used to reading negative findings regarding lipids, so it is a pleasant change to find a review article dealing with a potent anti-cancer lipid, the endocannabinoid anandamide or N-arachidonoylethanolamine (Flygare, J. and Sander, B. The endocannabinoid system in cancer - Potential therapeutic target? Seminars Cancer Biol., 18, 176-189 (2008)).

I have long had an interest in waxes and especially the waxy coating on plants. As every green leaf has a coating of this material, it has been argued that this may be the most abundant lipid in nature. While, we know a great deal about how it is synthesised within the epidermal cells, we know very little about how in crosses the plasma membrane and cell wall until it invades the cutin layer on the surface. However, two families of transporter proteins have now been identified and are the main subject of two new review publications (Bird, D.A. The role of ABC transporters in cuticular lipid secretion. Plant Sci., 174, 563-569 (2008); Samuels, L., Kunst, L. and Jetter, R. Sealing plant surfaces: cuticular wax formation by epidermal cells. Ann. Rev. Plant Biol., 59, 683-707 (2008)).

Coenzyme A is at the centre of most aspects of lipid metabolism for esterification to oxidation. It is concentrated in cells and does not cross membranes easily. Not surprisingly, when anything goes wrong with its metabolism, the consequences can be serious - often chronic illness. I have found a useful new review dealing with this topic (Mitchell, G.A., Gauthier, N., Lesimple, A., Wang, S.P., Mamer, O. and Qureshi, I. Hereditary and acquired diseases of acyl-coenzyme A metabolism. Mol. Genetics Metab., 94, 4-15 (2008)).

The latest issue of Progress in Lipid Research carries an interesting article that relates the physical properties of lipids with its biological function and metabolism in membranes (Lange, Y. and Steck, T.L. Cholesterol homeostasis and the escape tendency (activity) of plasma membrane cholesterol. Prog. Lipid Res., 47, 319-332 (2008)).

June 2008

The latest issue of the Journal of Lipid Research carries a fascinating review in its ongoing series on glycerophospholipids on phosphatidylethanolamine and phosphatidylserine, with particular emphasis on how closely the metabolisms of these two lipids are related (Vance, J.E. Phosphatidylserine and phosphatidylethanolamine in mammalian cells: two metabolically related aminophospholipids. J. Lipid Res., 49, 1377-1387 (2008)). I have already had to review my webpage on the latter.

Back to business after a pleasant holiday in the sunshine away from computers, phones, etc - and the only lipids the ones on my plate.

The Japanese Journal of Oleo Science is not indexed in Current Contents or the Web of Science, but does contain some useful papers. I therefore review it manually from time to time. Thankfully, it has an open access policy so all publications can be freely downloaded. For example, there is an interesting methodology paper on the isolation of gangliosides in the current issue (Kato, T., Kasuya, M.C.Z. and Hatanaka, K. Rapid separation of gangliosides using strong anion exchanger cartridges. J. Oleo Sci., 57, 397-400 (2008)).

On the other hand, I don’t know what to make of a recent paper that uses Raman Spectroscopy to claim that the content of trans double bonds in the lipids of HeLa cells is equal to those of cis. Either they have a very unusual cell preparation or there is something wrong with the method (Onogi, C., Motoyama, M. and Hamaguchi, H. High concentration trans form unsaturated lipids detected in a HeLa cell by Raman microspectroscopy. J. Raman Spectroscopy, 39, 555-556 (2008)).

The journal Molecular and Cellular Endocrinology has devoted a special supplement (Volume 286 Supplement 1) to the biochemistry of anandamide and other endocannabinoids.

I have now had an opportunity to read two of the papers in the recent mini-review series published by the Journal of Biological Chemistry. In particular, that on cholesterol oxidation by Murphy and Johnson (Cholesterol, reactive oxygen species, and the formation of biologically active mediators. J. Biol. Chem., 283, 15521-15525 (2008)) has given me some new insights that have caused me to revise the oxysterol page on this website. For example, I was not aware that cholesterol in a membrane environment was more susceptible than polyunsaturated fatty acids to oxidation. In contrast, in plasma, polyunsaturated fatty acids are 30 times as readily oxidized as cholesterol. This is an area where modern methods of electrospray mass spectrometry are enabling rapid advances, as it is now possible to analyse directly even the reactive hydroxy-, hydroperoxy- and ozonide-containing oxysterols.

The second paper to have stimulated me is that on isoprostanes, where again I have had to revise my notes (Milne, G.L., Yin, H. and Morrow, J.D. Human biochemistry of the isoprostane pathway. J. Biol. Chem., 283, 15533-15537 (2008)). There have been a number of published reviews on this topic recently, but this has given me a new perspective on the subject, as well as pointing me in the direction of papers I had missed when first published, e.g. those on the efficacy of antioxidants against oxidative stress in vivo. I will have some catching up to do when I return from my annual vacation

It has always struck me as strange that the skin, and structures associated with skin tend to contain so many unique and distinctive fatty acid components. For example, the skin itself contains very-long-chain omega-hydroxy fatty acids in the ceramides. 50% of the fatty acids that are integral components of hair in all species are 18-methyl-eicosanoic acid. Sebum lipids in humans contain high proportions of 6-hexadecenoic and 5,8-octadecadienoic acids. If we look more widely, wool of sheep contains a vast range of branched and hydroxy acids, together with other unusual waxy components, preen glands of birds have a range of branched-chain fatty acids not found elsewhere, while meibomian glands contain unusual waxy components. Does anything connect this odd assortment of facts? Is there any evolutionary significance?

May 2008

The Journal of Biological Chemistry (Issue of June 6th) has a number of fascinating mini-review articles dealing with the non-enzymic formation of oxidised lipids by reactive oxygen species and the biological properties of the products. The topics include isoprostanes, cholesterol oxides, DNA adducts with oxidized lipids, and nitro-fatty acids.

Also, a recent issue of the Plant Journal is devoted to the subject of ‘harnessing plant biomass for biofuels and biomaterials’. It includes a number of articles of interest to plant lipid biochemists.

The Journal of Lipid Research has two invaluable series of thematic reviews running at present, one dealing with sphingolipids and the other with sphingolipids. The June issues has articles from both series - two from that dealing with sphingolipids. The other by Li and Vance deals with phosphatidylcholine and choline homeostasis. If you don't have direct access immediately, the journal has an enlightened policy of making the original manuscripts freely available.

One of the important reactions in the biosynthesis of the plant hormone jasmonic acid is the cyclization step, catalysed by an allene oxide cyclase, which guarantees that the only biologically active cyclopentenone isomer is formed. A recent review article discusses the structural and molecular mechanisms underlying this important reaction (Hofmann, E. and Pollmann, S. Molecular mechanism of enzymatic allene oxide cyclization in plants. Plant Physiol. Biochem., 46, 302-308 (2008)).

There has rightly been a great deal of interest in recent years in those membrane domains enriched in sphingolipids and cholesterol and termed rafts. However, I long have been intrigued by the idea that as a corollary to these findings, there must be regions of membranes that are depleted in cholesterol and enriched in polyunsaturated fatty acids. Such membrane domains must of necessity be less easy to study in vivo but might have distinctive properties, which are just as interesting as those of rafts. The May issue of Chemistry and Physics of Lipids is devoted to papers relating to docosahexaenoic acid - its physical and biological properties. Among many papers of interest, I was struck especially by one dealing with these 'anti-rafts' (Wassall, S.R. and Stillwell, W. Docosahexaenoic acid domains: the ultimate non-raft membrane domain. Chem. Phys. Lipids, 153, 57-63 (2008)).

I was saddened to learn of the recent death of Lindsay J. Morris. Lindsay was perhaps best known as a pioneer of silver ion chromatography and published the first ever paper on silver ion thin-layer chromatography in Chemistry and Industry in 1962. He published an important review of the topic in the Journal of Lipid Research in 1967 (there is a link from our Silver Ion Menu page). I followed in his footsteps in my early career, 4 or 5 years behind. He obtained his Ph.D. in the laboratory of Prof. Frank Gunstone in St. Andrews University, before doing post-doctoral research in the laboratory of Prof. Ralph Holman at the Hormel Institute in Austin, Minnesota. He returned to the UK to work for Unilever in the plant lipid biochemistry unit established by A.T. James. There he worked on plant desaturases, and was recognized by the award of the Colworth Medal of the Biochemical Society in 1970. In his later years, he left research to become an administrator for the company. I have pleasant memories of convivial evenings spent in his company.

It is now possible to obtain a free download of all the Chapters for Volume 432 of Methods in Enzymology, which were written by members of the Lipid Maps consortium, as a single PDF file from the home page of the Lipid Maps website - www.lipidmaps.org. They include an number of important review articles dealing with lipidomics and mass spectrometric analysis of lipids.

It is almost axiomatic that sphingolipids only contain very-long-chain saturated and monoenoic fatty acids, sometimes with 2-hydroxyl groups. This simple picture was disrupted when it was observed that sphingomyelin in testes contained polyunsaturated fatty acids, then later it was shown that complex fucolipids in this organ also contained such fatty acids. In relation to the latter class of lipids, a new paper confirms that both the complex carbohydrate moieties and the polyunsaturated fatty acids are essential for spermatogenesis (Rabionet et al. Male germ cells require polyenoic sphingolipids with complex glycosylation for completion of meiosis. A link to ceramide synthase-3. J. Biol. Chem., 283, 13357-13369 (2008)).

Lipid analysis is of value in some surprising circumstances, and three recent papers highlight its value in detecting and monitoring alcohol abuse, either through the determination of phosphatidylethanol or of fatty acid ethyl esters. It seems that living or dead they can find you out via your lipids (Bendroth et al. Comparison of ethyl glucuronide in hair with phosphatidylethanol in whole blood as post-mortem markers of alcohol abuse. Forensic Sci. Int., 176, 76-81 (2008); Gareri et al. Prevalence of fetal ethanol exposure in a regional population-based sample by meconium analysis of fatty acid, ethyl esters. Ther. Drug Monitoring, 30, 239-245 (2008); Pragst and Yegles. Determination of fatty acid ethyl esters (FAEE) and ethyl glucuronide (EtG) in hair: A promising way for retrospective detection of alcohol abuse during pregnancy? Ther. Drug Monitoring, 30, 255-263 (2008)).

There have been two papers in the last year on the biochemistry of platelet activating factor, which have added important new information and have caught my eye. Studies with a purified lyso-PAF:acetyltransferase show that with cells in the resting state, the enzyme can utilize arachidonoyl-CoA to produce the membrane-bound PAF precursor 1-alkyl-2-arachidonoyl-glycerophosphocholine with even greater facility than the generation of PAF per se. Only when the cells are subjected to acute inflammatory stimulation does the activated enzyme produce PAF, while simultaneously arachidonate is released for eicosanoid production (Shindou et al. A single enzyme catalyzes both platelet-activating factor production and membrane biogenesis of inflammatory cells. Cloning and characterization of acetyl-CoA:lyso-PAF acetyltransferase. J. Biol. Chem., 282, 6532-6539 (2007)). To complement this work, a novel lyso-PAF acetyltransferase has now been discovered that operates under non-inflammatory conditions, i.e. it is constitutively expressed (Harayama et al. Identification of a novel noninflammatory biosynthetic pathway of platelet-activating factor. J. Biol. Chem., 283, 11097-11106 (2008)).

April 2008

Most so-called 'arsenolipids' are not really lipids by any definition that I would accept. However, two new fatty acids have been isolated from codliver oil, which certainly fit this description. One is a stearic acid analogue (as illustrated) and the other an oleic acid analogue. The authors suggest that the primer molecule in their biosynthesis is dimethyl-arsinoylacetic acid (Rumpler, et al., Arsenic-containing long-chain fatty acids in cod-liver oil: A result of biosynthetic infidelity? Angew. Chem. Int. Ed., 47, 2665-2667 (2008)).

My comments regarding sphingolipids in my last notes, are even more appropriate now. The March issue of Biochimica et Biophysica Acta - General Subjects contains 36 articles under the title “Glycobiology and Sphingobiology”. The lead article is - Hakomori, S.I. Structure and function of glycosphingolipids and sphingolipids: recollections and future trends. Biochim. Biophys. Acta, 1780, 325-346 (2008). I count on such publications to keep my website section ‘All about Lipids’ up-to-date, but I suspect that it will be some time before I can do justice to reading through all of these.

There has been no shortage of review articles dealing with sphingolipids in recent years. Not that I am complaining, as it is encouraging to see how the world is beginning to appreciate the importance of any aspect of lipid metabolism. A substantial new review (Sabourdy et al. Functions of sphingolipid metabolism in mammals - lessons from genetic defects. Biochim. Biophys. Acta, 1781, 145-183 (2008)) appears to offer a good overview of this wide subject.

I have strictly avoided comment on nutritional issues relating to fatty acids on this website, as it has always seemed a potential mine field for the unwary. No sooner do I think I understand some aspect of the problem, that someone publishes a meta analysis or criticizes the statistics or design of the experiments and comes up with the opposite conclusion. That said, I still like to keep up to date in the field and two new review articles are helpful (Harris, W.S., Miller, M., Tighe, A.P., Davidson, M.H. and Schaefer, E.J. Omega-3 fatty acids and coronary heart disease risk: Clinical and mechanistic perspectives. Atherosclerosis, 197, 12-24 (2008); Hadders-Algra, M. Prenatal long-chain polyunsaturated fatty acid status: the importance of a balanced intake of docosahexaenoic acid and arachidonic acid. J. Perinatal Med., 36, 101-109 (2008)).

A further new review paper discusses present knowledge concerning intestinal fat absorption, and the cellular uptake and trafficking of long-chain fatty acids in relation to lipoprotein synthesis. The paper is in French (Petit, V., Niot, I., Poirier, H. and Besnard, P. Fatty acids intestinal absorption: facts and uncertainties. Nutr. Clin. Metabolisme, 21, 38-45 (2007).

To the uninitiated, the title of a recent review article may seem to have little relevance to lipids (Ma, G., Xiao, Y. and He, L. Recent progress in the study of Hedgehog signalling. J. Genetics Genomics, 35, 129-137 (2008)). It certainly has little relevance to small spiky mammals. However, biochemists will recognise that the hedgehog proteins are modified by a covalently linkage to cholesterol, which ensures that they are firmly located in specific membranes where they can carry out their signalling functions. This article provides a useful review of these proteolipids, and provides a reminder of the importance of cholesterol in the proper functioning of animal tissues.

I have only recently become aware of a website - Journalseek - that is extremely useful for locating the websites of scientific journals. It tells you immediately who is the publisher and whether or the journal has a website with online access, while providing a direct link to it.

I have now had an opportunity to browse through the Oily Press book on phospholipids mentioned in my previous contribution, and I am sure it will prove useful to anyone with an industrial interest in phospholipids, with chapters, on "sources, composition and processing", "enzymatic modifications", "use as functional ingredients", "physical properties" and "chemical modifications". However, there are also useful chapters on "biological functions", "clinical and nutritional properties" and "sphingolipids" that will interest a wider audience

The Oily Press have just published a new book - "Phospholipid Technology and Applications", edited by my colleague Frank D. Gunstone (Volume 22 in The Oily Press Lipid Library). Web page: http://www.pjbarnes.co.uk/op/pta.htm

The acidic phospholipids, such as phosphatidic acid and phosphatidylserine have always present problems to chromatographers because of tailing on adsorbents. An interesting new paper appears to have solved the problem for reversed-phase HPLC at least (Ogiso, H., Suzuki, T. and Taguchi, R. Development of a reverse-phase liquid chromatography electrospray ionization mass spectrometry method for lipidomics, improving detection of phosphatidic acid and phosphatidylserine. Anal. Biochem., 375, 124-131 (2008)). The authors use a mobile phase with a very high water content. For example, one component of the gradient used is Isopropanol-methanol-water (5:1:4 by volume) supplemented with 0.2% formic acid, 0.028% ammonia, and 5 µM phosphoric acid. It would be useful now to have a normal phase method that could give sharp peaks for these lipids.

The journal Advanced Drug Delivery Reviews has devoted a special issue (Number 6 of this year) to the topic of “Lipid-based systems for the enhanced delivery of poorly water-soluble drugs”.

Unfortunately I don’t have easy access to ACS publications, but judging by the abstract alone there is an important paper on cholesterol in one of their physical chemical journals (Poyry, S., Rog, T., Karttunen, M. and Vattulainen, I. Significance of cholesterol methyl groups. J. Phys. Chem. B, 112, 2922-2929 (2008)). During evolution. some of the methyl groups have been removed from one face of the molecule to smooth its structure. The authors ask the question whether the remaining methyl groups are necessary, and the answer seems to be undoubtedly yes for various subtle reasons. In particular the C18 methyl group is required for proper orientation of the sterol in membranes.

March 2008

The March issue of the journal Current Topics in Medicinal Chemistry contains five review articles dealing with the topic of “medicinal chemistry of agents targeting the endogenous cannabinoid system”.

The latest issue of the journal Progress in Lipid Research is now available online. I have yet to check it out in detail, but I note that Dennis Vance and colleagues continue to find something new and interesting to report regarding phosphatidylcholine.

The most recent issue of the Journal of Biological Chemistry contained two publications that were of particular interest to me. The first (Rouzer, C.A. and Marnett, L.J. Non-redundant functions of cyclooxygenases: oxygenation of endocannabinoids. J. Biol. Chem., 283, 8065-8069 (2008)) reviews aspects of the specificity of the cycolooxygenase(COX)-2 enzyme, which will react with neutral lipid substrates, especially the endocannabinoids 2-arachidonoylglycerol and anandamide, in addition to free arachidonic acid to produce esterified prostanoids. These may constitute a new class of lipid mediator.

The second (Zhao, Y. et al. Identification and characterization of a major liver lysophosphatidylcholine acyltransferase. J. Biol. Chem., 283, 8258-8265 (2008)) describes a long-sought enzyme that is involved in the remodelling of newly synthesised phosphatidylcholine to generate the eventual fatty acid composition. The process of lipid remodelling in animal tissues has not received the attention it deserves over the years, but has recently become more intensively studied especially in relation to cardiolipin.

The March issue of the journal Current Opinion In Clinical Nutrition And Metabolic Care contains seven articles under the general title of “Lipid metabolism and therapy”, and edited by Philip C. Calder and Richard J. Deckelbaum.

It is surprising how many new fatty acids continue to be discovered. For example, novel fatty acids containing centrally located five- and six-membered rings with sulfur atoms as part of the structure have been identified by means of gas chromatography-mass spectrometry in garlic (Dembitsky, V.M., Abu-Lafi, S. and Hanus, L.O. Separation of sulfur-containing fatty acids from garlic, Allium sativum, using serially coupled capillary columns with consecutive nonpolar, semipolar, and polar stationary phases. Acta Chromatogr., 19, 206-216 (2007)). I had not come across this journal before, but it is open access.

I have recently found some interesting reports of GC-MS of unusual fatty acids in another open access journal - the Proceedings of the Bulgarian Academy of Science (Comptes rendus de l'Académie bulgare des Sciences).

The October issue (2007) of Seminars in Cell & Developmental Biology is devoted to a series of articles with the general theme of “Membrane lipid microdomains: roles in signalling and disease and 3D chromatin”. The physical chemistry of raft formation from cholesterol and sphingolipids is discussed, together with the role of lipid rafts in signalling.

I admire the Japanese Journal Archive in making so much of the current output of Japanese scientists freely accessible (www.journalarchive.jst.go.jp/). For example, the latest issue of the Tohoku Journal of Experimental Medicine contains two interesting review articles – “Lipid messenger, diacylglycerol, and its regulator, diacylglycerol kinase, in cells, organs, and animals: History and perspective” (Goto, K., Hozumi, Y., Nakano, T., Saino-Saito, S. and Martelli, A.M. Tohoku J. Exp. Med., 214, 199-212 (2008)) – and “Fatty acid binding protein: Localization and functional significance in the brain” (Owada, Y. Tohoku J. Exp. Med., 214, 213-220 (2008)).

I have found a very useful website dealing with lipids and membranes www.cytochemistry.net/Cell-biology/membrane.htm, which I thoroughly recommend.

Membranes have very distinct phospholipid compositions on each leaflet of the bilayer. The means by which this is achieved and then maintained is discussed in a recent review (Lenoir, G., Williamson, P. and Holthuis, J.C.M. On the origin of lipid asymmetry: the flip side of ion transport. Current Opinion Chem. Biol., 11, 654-661 (2007)). In particular, it appears that most of the aminophospholipids are directed to the cytosolic membrane leaflet by means of ATP-fuelled flippases or translocases.

As someone whose best years, physically and mentally, are behind them, I was greatly interested in a recent review by Das (Das, U.N. Folic acid and polyunsaturated fatty acids improve cognitive function and prevent depression, dementia, and Alzheimer's disease—But how and why? Prostaglandins, Leukotrienes Essential Fatty Acids, 78, 11-19 (2008)). I will obviously have to study it carefully if I wish to keep up the standards in the ‘Lipid Library’.

The most recent issue of Progress in Lipid Research, now available online, is also largely devoted to polyunsaturated fatty acids and their metabolites. It includes a typically forthright critique of much of the dogma on fatty acid nutrition by Bill Lands (Lands, B. A critique of paradoxes in current advice on dietary lipids. Prog. Lipid Res., 47, 77-106 (2008)). It confirms that my decision to avoid nutritional comments in my own articles here was a sound one.

There is a fascinating paper in the February issue of Lipids that describes a robotic method for transesterifying plasma lipids for rapid GC analysis. The system can handle up to 200 samples per day, so is obviously well suited to large-scale clinical trial. My colleagues and I are rather envious, but the price of the system means that none of us is likely to be replaced by a robot in the near future (Masood, M.A. and Salem, N. High-throughput analysis of plasma fatty acid methyl esters employing robotic transesterification and fast gas chromatography. Lipids, 43, 171-180 (2008)).

February 2008

I have been advised that the Lipidat web site, dedicated to recording data on the physical properties of lipids, has now moved to a new URL www.lipidat.ul.ie. Unfortunately, it is no longer being updated.

The February issue of Nature Reviews in Molecular and Cell Biology is largely devoted to lipid topics, i.e. ‘Membrane lipids: where they are and how they behave’, ‘Cellular cholesterol trafficking and compartmentalization’, ‘Principles of bioactive lipid signalling: lessons from sphingolipids’, ‘Inositol derivatives: evolution and functions’, and ‘Lipid signalling in disease’. Everyone with an interest in the biochemistry and biological function of lipids will obtain new insights here.

While browsing through the journal mentioned in the previous blog entry, I came across a fascinating recent review on the biological properties of isoprostanes, which I can recommend (Comporti, M., Signorini, C., Arezzini, B., Vecchio, D., Monaco, B. and Gardi, C. F₂-isoprostanes are not just markers of oxidative stress. Free Rad. Biol. Med., 44, 247-256 (2008)).

The biological function of tocopherols has become surprisingly contentious. This may be in part because meta-analyses appear to show that dietary supplements of vitamin E do not protect against atherosclerosis and may even be harmful. I have no intention in joining in this debate. Until recently, it was considered that the only function of tocopherols in animal tissues was to act as antioxidants, but many now consider that this may be secondary to other biological functions. I have therefore enjoyed reading a new review article that is highly relevant to this topic (Atkinson, J., Epand, R.F. and Epand, R.M. Tocopherols and tocotrienols in membranes: A critical review. Free Rad. Biol. Med., 44, 739-764 (2008)). The authors are indeed ‘critical’ and explain the technical difficulties in translating experiments in vitro to the situation in vivo.

Lipids are known to be involved in cellular metabolism at every possible level. A new review discusses the role of polyphosphoinositides, derived from phosphatidylinositol, on the regulation of aspects of nuclear responses including gene expression (Alcazar-Roman, A.R. and Wente, S.R. Inositol polyphosphates: a new frontier for regulating gene expression. Chromosoma, 117, 1-13 (2008)). At least 37 distinct inositol phosphates have been described and each of these appears to have its own distinct functions and must be produced in a highly coordinated manner relative to the others.

A simple new method for the isolation of endocannabinoids, such as anandamide and 2-arachidonoylglycerol, followed by analysis by GC-MS appears to show that levels of these important metabolites in brain are much higher than has been reported hitherto (Muccio, G.G. and Stella, N. An optimized GC-MS method detects nanomolar amounts of anandamide in mouse brain. Anal. Biochem., 373, 220-228 (2008)).

The latest issue of the Journal of Biological Chemistry contains two interesting articles on the function of phosphatidylserine. I was not aware until now that phosphatidylserine is an essential component of the lipid-calcium-phosphate complexes that initiate mineral deposition during the formation of bone. Its capacity to chelate with calcium ions is obviously of great importance in this respect (Wu, L.N.Y., Genge, B.R. and Wuthier, R.E. Analysis and molecular modeling of the formation, structure, and activity of the phosphatidylserine-calcium-phosphate complex associated with biomineralization. J. Biol. Chem., 283, 3827-3838 (2008)).

The second paper deals with the role of phosphatidylserine in apoptosis, when it is transported to the outer membrane of cells to interact with macrophages. Recognition is enhanced through binding to specific plasma proteins (Maiti et al., J. Biol. Chem., 283, 3761-3766 (2008)).

In my last note, I mentioned a link to a web page on Archaeal lipids. This reminded me that I needed to update my own brief paragraphs on this topic substantially. In so doing I was greatly helped by a recent review article (Koga,Y. and Morii,H. Biosynthesis of ether-type polar lipids in Archaea and evolutionary considerations. Microbiol. Mol. Biol. Rev., 71, 97-120 (2007)). The result is a new full webpage on Archaeal ether lipids here. Reading up on the topic also revealed to me one of the great unsolved problems of lipid biochemistry - how do the two methyl termini of the phytanyl groups in the C₂₀ archaeol link via carbon-carbon bonds to form the C₄₀ bipolar lipids? However it occurs, this reaction must be unprecedented in biochemistry.

I use the “Web of Science” for my weekly literature updates, and of course it is also of value for specific topics. However, I find that I am using Google Scholar more and more when I am looking for a specific paper or researching any topic that comes up when I am revising any of my web documents. It seems to compliment The Web of Science in that it finds a few papers that the latter misses (and vice versa). Also, it often leads directly to a free on-line version of an article. For example, I have just come across a review on marine lipids that I missed when it first came out (Bergé, J.-P. and Barnathan, G. Fatty acids from lipids of marine organisms: molecular biodiversity, roles as biomarkers, biologically active compounds, and economical aspects. Adv. Biochem. Engin. Biotechnol., 96, 49-125 (2005)). I was able to read a copy on-line at Ifremer's Institutional Archive (but not at the primary journal).

I have found a useful website with a succinct account of the chemistry and biochemistry of the complex ether lipids of methanogenic bacteria (Archaea) http://www.uoeh-u.ac.jp/kouza/ikagaku/research_e.html

The role of carnitine in general and acylcarnitines in particular in plants has been a controversial one. A new paper demonstrates that acylcarnitines are indeed present in the model plant Arabidopsis thaliana, though at very low levels in comparison to animal tissues. There is evidence that they are important in plant metabolism, although it is obvious that much still remains to be learned (Bourdin, B., Adenier, H. and Perrin, Y. Carnitine is associated with fatty acid metabolism in plants. Plant Physiol. Biochem., 45, 926-931 (2007)).

Although I have yet to be able to access it, a new review on acyl carrier protein looks interesting (Byers, D.M. and Gong, H. Acyl carrier protein: structure-function relationships in a conserved multifunctional protein family. Biochem. Cell Biol., 85, 649-662 (2007)).

January 2008

Two interesting new papers on the analysis of lipids have caught my eye. The first is a further application of the charged aerosol detector this time to the separation of molecular species of triacylglycerols by reversed-phase HPLC (Lisa,M., Lynen,F., Holcapek,M. and Sandra,P. Quantitation of triacylglycerols from plant oils using charged aerosol detection with gradient compensation. J. Chromatogr. A, 1176, 135-142 (2007)). The improved linearity in comparison to the evaporative light-scattering detector is obviously a boon here.

A novel application of chiral chromatography for the stereospecific analysis of triacyl-sn-glycerols from Professor Damiani’s lab in Italy should also be worth careful perusal. Rather than separating diastereomeric diacylglycerol derivatives, as has been done by others, they were able to resolve the three isomeric monoacylglycerols classes (sn-1-, sn-2- and sn-3-MAG), so enabling a direct determination of the fatty acid composition of each position (Petrosino,T., Riccieri,R., Blasi,F., Brutti,M., D'arco,G., Bosi,A., Maurelli,S., Cossignani,L., Simonetti,M.S. and Damiani,P. Original normal-phase high-performance liquid chromatographic separation of monoacylglycerol classes from extra virgin olive oil triacylglycerols for their stereospecific analysis. J. AOAC Int., 90, 1647-1654 (2007)).

I was intrigued by the title of a new paper "The lipid whisker model of the structure of oxidized cell membranes" (Greenberg, M.E. et al., J. Biol. Chem., 283, 2385-2396 (2008)). In essence, this suggests that oxidized phospholipids on the surface membrane of cells identify and target the cells for destruction by macrophages as part of the normal mechanism of cellular homeostasis. Recognition is accomplished as the truncated and oxidized fatty acid in position 2 of the phospholipid sticks out into the aqueous phase making it accessible and enabling contact with passing macrophages. The authors thus describe the membrane as “growing whiskers”.

A new brief review summarises the topic of 'Very-long-chain acyl-CoA synthetases' (Watkins, P.A. J. Biol. Chem., 283, 1773-1777 (2008)). The opening sentence illustrates the importance of the apparently simple process, i.e. “Activation of fatty acids by thioesterification to coenzyme A is a fundamental metabolic process that can be found in all organisms from archeae to man”. Several different acyl-coA synthetases have now been described with differing specificities, and there is some debate over their relationship to the fatty acid transport proteins.

The first issue of Physiologia Plantarum of 2008 contains two interesting review articles on the production of genetically modified seed oils containing useful fatty acids. The first deals with fatty acids of nutritional value and the second with those of industrial value.

The journal Pharmacological Research (Vol. 56 (Issue 5) (2007)) is dedicated to the topic ‘the endocannabinoid system and psychopathology’. However, casual readers such as myself will find the various papers heavy going.

Although I don't have access to it, there looks to be a new and interesting paper on N-acylphosphatidylserine. This lipid has been reported from time to time as a minor component of tissues, but this appears to be the first systematic study (Guan, Z., Li, S., Smith, D.C., Shaw, W.A. and Raetz, C.R.H. Identification of N-acylphosphatidylserine molecules in eukaryotic cells. Biochemistry, 46, 14500-14513 (2007)).

The journal Molecular Aspects of Medicine has a special issue (October to December) with the title of "Vitamin E: An overview of major research directions" and edited by Professor Jean-Marc Zingg. Amongst a number of excellent contributions, the editor has contributed two valuable reviews, and there is an interesting paper dealing with the biology of the tocotrienols, which relatively speaking are much neglected. I will have to revise my notes on tocopherols in the light of these papers.

December 2007

It is always interesting to see an old procedure put to a new use. Deacylation of glycerolipids by mild alkaline transesterification enables recovery of a clean spingolipid fraction that is more amenable to the modern mass spectrometric methods (Jiang, X., Cheng, H., Yang, K., Gross, R.W. and Han, X. Alkaline methanolysis of lipid extracts extends shotgun lipidomics analyses to the low-abundance regime of cellular sphingolipids. Anal. Biochem., 371, 135-145 (2007)). Not only are the quantitatively minor but biologically highly important sphingolipids more easily identified, but sphingomyelin species are analysed free of phosphatidylcholine contamination.

The manuscript of a very interesting review on the chemistry and biochemistry of cardiolipin, which is a unique lipid in many ways, is available from the Journal of Lipid Research online ahead of publication (Schlame, M. Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes. In press).

I have just come across a review article on the role of N-palmitoylethanolamide in metabolism. I have been accustomed to read of the manifold biological effects of the corresponding arachidonoyl lipid (anandamide), but was much less aware of the potent anti-inflammatory effects of the saturated analogue (Re, G., Barbero, R., Miolo, A., and Di Marzo, V. Palmitoylethanolamide, endocannabinoids and related cannabimimetic compounds in protection against tissue inflammation and pain: Potential use in companion animals. Vet. J., 173, 21-30 (2007)). As this was in the first issue of the year, it is available for the moment as a free download. This is also true of two reviews on endocannabinoids from a recent issue of the British Journal of Pharmacology.

Likewise, you can access an interesting review on jasmonates (Wasternack, C. Jasmonates: An update on biosynthesis, signal transduction and action in plant stress response, growth and development. Annals Botany, 100, 681-697 (2007)). Although they do not occur in animals, I was intrigued to learn that they strongly inhibit growth of human cancer cell lines.

The first issue of the review journal - Progress in Lipid Research for 2008 is now available on line. As usual this contains a mix of high quality review articles on various aspects of the science of lipids. In particular, I found an article dealing with sphingosine phosphorylcholine to be of special interest (Nixon, G.F., Mathieson, F.A. and Hunter, I. The multi-functional role of sphingosylphosphorylcholine. Prog. Lipid Res., 47, 62-75 (2008)), and I have found it necessary to revise my notes on this lipid. The authors have clarified the relationship to sphingosine-1-phosphate, which is attracting so much interest.

In an interesting new paper, the merits of the evaporative light-scattering detector, mass spectrometry and the charged aerosol detector in lipid analyses by HPLC are compared. The last is a new type of detector in which the eluent is evaporated or nebulized and the resulting lipid droplets are given a charge, which is detected and measured by an electrometer. The results for the new detector extend those of an earlier paper by Moreau, and show that it has a much better linear range than other universal detectors. My only doubt is whether it could be used with the polar solvents and ionic species required for complex lipids. See - Hazotte, A., Libong, D., Matoga, A. and Chaminade, P. Comparison of universal detectors for high-temperature micro liquid chromatography. J. Chromatogr. A, 1170, 52-61 (2007).

A very readable review article has appeared on the chemistry, biochemistry and analysis of sphingolipids (Merrill, A.H., Wang, M.D., Park, M. and Sullards, M.C. (Glyco)sphingolipidology: an amazing challenge and opportunity for systems biology. Trends Biochem. Sci., 32, 457-468 (2007)). In the introduction to the review, I was intrigued by the examples that authors had chosen to reflect the main achievements of lipidomics in terms of “new biomolecules” (undecaprenyl diphosphate-MurNAc-pentapeptide-GlcNAc) , “known metabolites in unexpected places “ (arachidonate-derived dihomo-prostaglandin production) and “new functions for pre-existing compounds” (ceramides).

I have just come across another new journal dedicated to the science of lipids, i.e. the Journal of Clinical Lipidology, published by Elsevier. As the name suggests, the emphasis is on medical aspects of lipid research. The first issue is available for free download and contains a number of review articles on lipoprotein metabolism. One particular review caught my eye as being an especially readable account, i.e. Brown, W.V. High-density lipoprotein and transport of cholesterol and triglyceride in blood. J. Clin. Lipidology, 1, 7-19 (2007).

On another topic, it now appears that there is ample evidence that unesterified fatty acids can diffuse across membranes so readily that there is no need to invoke special transport systems. One exception may be when transport is allied to direct metabolism, for example for coA ester formation (Hamilton, J.A. New insights into the roles of proteins and lipids in membrane transport of fatty acids. Prostaglandins, Leukotrienes, Essential Fatty acids, 77, 355-361 (2007)).

The importance of high quality lipid analysis can be seen from a recent paper illustrating that there are depleted levels of glycolipid sulfates in brain at the earliest stages of Alzheimer's disease. This finding enabled the construction of a mechanistic model of the disease (Han, X. Potential mechanisms contributing to sulfatide depletion at the earliest clinically recognizable stage of Alzheimer's disease: a tale of shotgun lipidomics. J. Neurochem., 103, 171-179 (2007)). The suggestion is that there is impaired sulfatide transport mediated by apolipoprotein E, the only known major risk factor for this dreadful illness. A further interesting new review article that is relevant to this topic is - Hartmann, T., Kuchenbecker, J. and Grimm, M.O.W. Alzheimer's disease: the lipid connection. J. Neurochem., 103, 159-170 (2007).

The Journal of Neurochemistry had a special issue in November (Vol. 103. Issue s1) with papers presented at 'The Second ISN Special Neurochemistry Conference on Neural Glycoproteins and Glycolipids', dealing with various aspects of glycosphingolipid metabolism in nervous tissues. Some of these may only be suited to the specialist, but I found much of interest in the first article especially (Hoetzl,S., Sprong,H. and van Meer,G. The way we view cellular (glyco)sphingolipids. J. Neurochem., 103 (s1), 3-13 (2007)).

Indeed, this has been a good week for reviews on aspects of lipid metabolism. The British Journal of Pharmacology (vol. 152. Issue 5) has a special issue on endocannabinoids, such as anandamide and 2-arachidonoylglycerol, and their actions. All of the review articles are available as free downloads from the journal website. Also, the Springer journal Cellular and Molecular Life Sciences (Volume 64, Issue 19-20) has a special issue in which there are a number of reviews under the general theme of lipid sensing and lipid sensors, although these are only available to subscribers alas.

Last updated: 13/10/2008 Credits/disclaimer	Scottish Crop Research Institute (and MRS Lipid Analysis Unit), Invergowrie, Dundee (DD2 5DA), Scotland