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Here and now: The lipid revolution

Lipidomics Gateway (30 December 2009) [doi:10.1038/lipidmaps.2009.35]

Lipidomics is revolutionizing lipid research, uniting disparate themes into coherent output that will inform wider biology.

Seeing is believing: Brain PC imaged by MALDI mass spectrometry. From: Brown, H. A. & Murphy, R. C. Nat. Chem. Biol. 5, 602-606 (2009) doi:10.1038/nchembio0909-602

Amidst the twenty-first century revolution in lipid biology, 2009 felt like a landmark year. Since the turn of the millennium, unprecedented details of lipid species, signaling pathways and membrane properties have flooded in. Powerful new techniques have transformed the field, and the stage is set for the real revolution: the integration of lipid science into wider biology. In 2009, more than 10,000 new structures were added to the LIPID MAPS Structure Database (LMSD), nearly doubling its size. Meanwhile, the Journal of Lipid Research celebrated its 50th anniversary with a special edition, including a major review of cholesterol and SREBP advances by Michael Brown and Joe Goldstein. The International Lipid Classification and Nomenclature Committee published its updated comprehensive classification system for lipids 1 to accommodate current knowledge and future expansion, and new identifiers for LMSD entries were introduced to allow cross referencing with other major biological databases. The May launch of the Lipidomics Gateway reflected new confidence among lipid scientists, eager, and increasingly able, to share their knowledge.

We asked a few prominent lipid researchers to help us sum up the year in lipids, and to give us their perspectives for the future. These are our themes of 2009:

Lipidomics: Fat, in profile

Advances in chromatography and mass spectrometry during the 1950s and 60s spawned modern lipid research, but despite tweaks to techniques, "not much really changed in lipid analysis from the late fifties to the late nineties", says Alex Brown. It was the marriage of these approaches with systems biology at the end of the nineties that launched the revolution 2 . "Lipidomic analysis is becoming standard procedure, rather than a rare occurrence", says Al Merrill, who highlights two new families of compounds identified in humans this year: 1-deoxysphingoid bases and ceramide phosphoethanolamines (see Signaling lipids) 3 4 . Other new compounds, among the astonishing variety, include our Lipid of the Month, ether-linked phosphatidylserine. For Michael Wakelam, whose lab now routinely quantifies more than 700 lipid species present in biological samples at the nanogram level, publication of the first lipidome of an organism, by Andrej Shevchenko and colleagues 5 , was a significant milestone this year. Other lipidomes are coming, of organelles, cells, tissues and organisms. Lipid droplets (see below) are one such target. Much of the work, says Ed Dennis, is now aimed at specific diseases, "so rich in lipid relevance".

Signaling lipids: Signs of the times

Fritz Spener describes this time as "the renewed heydays of phospholipid metabolism". The combination of knockout approaches, pharmacological developments and lipidomics is revealing surprising new roles for phospholipids and their metabolites, including in the Golgi (see below). For example, Dennis Vance and colleagues reported that defective metabolism of phosphatidylcholine causes a form of muscular dystrophy in mice 6 . Sarah Spiegel's group showed that sphingosine-1-phosphate (S1P) is produced in the nucleus, where it binds to and inhibits histone deacetylases 7 , "linking nuclear sphingolipid metabolism and S1P to gene expression and epigenetic regulation". Related to S1P (but lacking the hydroxyl group that would be phosphorylated to generate it) are the 1-deoxysphingoid bases. "It is amazing that these compounds have hidden under the radar of biochemists for so long" says Al Merrill, pointing out that they were identified as anticancer agents from a clam 8 , and are now implicated in human neurological disease 9 and the action of a mycotoxin 3 . Normal pathways regulated by these compounds may well await discovery.

Inflammation is a well-known signaling arena for eicosanoid lipids. 2009, says Alex Brown, has seen an 'explosion' of interest in lipids involved in the resolution of inflammation. The maresins work of Charles Serhan et al. is a key example 10 . Dennis Voelker and colleagues also showed that anionic phospholipids, minor constituents of a pulmonary lipoprotein complex, have important anti-inflammatory properties 11 .

Pharmacology: Oily targets

A sure sign that lipid research is maturing is the increased commercial interest that, as Michael Wakelam reports, is now evident at lipid meetings. In the phosphatidylinositol-3 kinase (PI3K) field, clinical trials of inhibitors as anticancer agents are reaching Phase III. Likewise, the compound FTY720 is in Phase III trials for the treatment of multiple sclerosis. This immunosuppressant pro-drug is phosphorylated in vivo to form a mimetic of S1P, and causes retention of T lymphocytes in the lymph nodes. Furthermore, notes Sarah Spiegel, a paper in Nature this year identified FTY720 as a potential treatment for osteoporosis 12 . Exciting developments like these are attracting big pharma to look to lipid signaling for potentially lucrative new treatments for a variety of diseases. Inhibitors of lipid signaling enzymes are incredibly useful to researchers. Michael pinpoints the development of phospholipase D inhibitors by Alex Brown and colleagues as a highlight of the year 13 . Alex says "these inhibitors are a powerful complementary approach to existing RNAi approaches". He hopes that they will help to clarify apparent contradictions in lipid signaling outcomes.

Membrane morphology: Golgi, tubes and cubes

Two areas in particular highlight how the phospholipid content, and the fatty acid composition within phospholipids, affects membrane function: the Golgi and cubic membranes. Several phospholipid-modifying enzymes have this year been discovered to regulate the functional organization of the Golgi. "Continual phospholipid turnover by phospholipases, phospholipid acyltransferases, and flippases can be used to modify membrane shape and recruit effector proteins" says Bill Brown. An isoform of phospholipase A2 (PLA2) regulates anterograde trafficking, and contributes to the formation of membrane tubules 14 15 , whereas a PLA1 is involved in COPI-independent retrograde traffic 16 . The opposite enzymatic activity of PLA2 is carried out by a lysophospholipid acyltransferase, and this is required to maintain Golgi traffic and morphology 17 . Furthermore, a yeast type IV P-type ATPase that was long suspected to be a phospholipid flippase was finally confirmed as such 18 . This protein, Drs2p, is known to be involved in vesicle-mediated transport from the Golgi and endosomes. These enzymatic activities have a common implication, Bill says; "generation of membrane asymmetry is important for Golgi function".

Cubic membranes are another intriguing area that saw significant developments in 2009. These highly organized three dimensional folds are reversibly induced by starvation in the mitochondrial membranes of amoeba. Yuru Deng et al. showed that the fatty acid composition of the membrane is critical for this process, and also observed the structures in vivo for the first time 19 . Meanwhile, Kai Simons and colleagues published a new approach to understanding how cubic membranes are formed 20 .

Lipid droplets: Organelle of the year

Lipid droplets were historically viewed as inert bags of fat, simply stored in the cell. Many functions are now associated with them, and they are the focus of intense interest. Fritz Spener explains; "interest has taken off since a feature in Science in 2006 21 . In the US, special lipid droplet meetings have been convened, and in Europe the collaborative project LipidomicNet is working on the dynamics of the lipid droplet lipidome and related metabolome. An impressive level of knowledge was gained in 2009". Now recognized as organelles, lipid droplets are sites of eicosanoid metabolism involved in atherosclerotic disease 22 23 24 .

Imaging: Seeing is believing

The imaging of lipids is currently a hugely dynamic field. Mass spectrometric-based imaging techniques are now part of the lipidomics approach, says Ed Dennis. These, and emerging metabolic labeling techniques 25 , allow imaging of lipid localization within tissues, and everybody is excited about what the future holds. Says Al Merrill: "Tissue-imaging mass spectrometry of lipids is one of the most exciting technologies to emerge in the last few years because it is expanding the ability of lipidomics to know what and how much of a compound is present to include where it is located".

2010: The future of lipids

If 2009 proved to be an exceptional year for lipid research, 2010 holds even more promise. Collaborative efforts like the LIPID MAPS consortium and LipidomicNet are making exponential progress. Online projects like the Lipid Corner of the lipid research division of the American Society for Biochemistry and Molecular Biology, the LipidomicNet-Wiki, and of course the Lipidomics Gateway, are bringing researchers together, organizing their findings and making them accessible to non-lipid scientists. However, more could be done, particularly to attract young researchers to the field, says Dan Raben of the Lipid Corner. He thinks more cooperation between different branches of the field, and different geographical areas, would make lipids more attractive to outsiders.

So what do our contributors think will be the big themes of 2010? "I predict a continuing dramatic increase in the interest in lipids among basic scientists and the biomedical world" says Ed Dennis, adding that the critical role of lipids in disease will be more appreciated. For Michael Wakelam, it is all about the subcellular visualization of lipids. Sarah Spiegel agrees: "we expect great developments in technology in 2010 to measure spatial distribution of sphingolipids and their metabolites, including S1P, within tissues and cells, and dynamic imaging of S1P receptor modulation and coupling to signaling pathways is just on the horizon". Fritz Spener has another wish – to see the existence of cubic membranes in vivo confirmed by any method other than transmission electron microscopy.

Whatever the big stories prove to be, the Lipidomics Gateway will strive to bring you the highlights. If you have any suggestions for us, please get in touch.

We wish you all a very happy and productive New Year in lipids.

Related Research Highlights from 2009:

Lipidomics
Jul 09:    Fat finding in disease: Lipids coming 'ome
Aug 09:    Targeted lipidomics: Planned discovery
Nov 09:    Brain lipids: Male mice show their age
Signaling
May 09:    Fungal toxicity: Based in sphinganine
Aug 09:    Sphingosine 1-phosphate signaling: Treg or not Treg, that is the question
Oct 09:    Lipid signaling: S1P's nuclear program
Nov 09:    Lipid signaling: LPA's ways of actin
Golgi
Jun 09:    Golgi sorting: Rafting to the top
Sep 09:    Lipids and Golgi function: An acyltransferase stops traffic
Dec 09:    Golgi vesicle formation: Flipping coincidence
Imaging
Oct 09:    Choline phospholipids: Now you see them
Lipid droplets
Aug 09:    Macrophage lipid droplets: Inert? Eicosa' not!

Acknowledgements:

Many thanks to H. Alex Brown (Vanderbilt University, Tennessee, USA), William J. Brown (Cornell University, New York, USA) Edward A. Dennis (University of California in San Diego, USA), Alfred H. Merrill, Jr. (Georgia Institute of Technology, USA), Daniel M. Raben (Johns Hopkins University, Baltimore, Maryland, USA), Friedrich (Fritz) Spener (University of Graz, Austria), Sarah Spiegel (Virginia Commonwealth University, USA), and Michael J. O. Wakelam (Babraham Institute, UK) for contributions to this article, and ongoing suggestions for Gateway editorial content.

Emma Leah

- Copyright © 2010 Nature Publishing Group, a division of Macmillan Publishers Limited; used with permission

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