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Structural Medicine II: the Importance of Lipidomics for Health and Disease1

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Structural Medicine II: the Importance of Lipidomics for Health and Disease1 SCIENCE POLICY BRIEFING • June 2008 31 Structural Medicine II: The Importance of Lipidomics for Health and Disease1 Contents 1 - Foreword 4 - Understanding Lipid Metabolism 8 - Expert Group on Structural Medicine II: 2 - Introduction 5 - Lipid Signalling and Disease The Importance of Lipidomics for Health and Disease 3 - Major Diseases of Mankind Involve Lipids 5 - Enabling Technologies 4 - Dynamics and Supramolecular 6 - Statements and Recommendations Organisation of Lipids Foreword The time has come for generating broad insights Alzheimer’s disease also have a lipid involvement. In addition to these into the role of lipids in physiology and pathology. disorders of epidemic proportions, there are many other diseases that Given that thousands of different lipids are present are directly caused by inherited defects in lipid metabolic enzymes and within a single cell and that many of these lipids transporters, such as defects in cholesterol synthesis and lipid storage are involved in modulating the processes of life in diseases. Lipids also play major roles in autoimmune diseases and an area that is upcoming, lipidomics describes and act as (co-)receptors for bacteria, viruses and toxins. An increase quantitatively analyses the full complement of lipids, in our knowledge of disease-related changes in lipid patterns and its in- in the human body for example body fluids, cells tegration into proteomic and genomic data will provide new basic bio- and tissues. Lipidomics integrates these data with medical insights; thus, far-reaching possibilities for diagnostic applica- knowledge of their protein targets, i.e. the meta- tion (prognostic assessment, diagnosis and monitoring) as well as for bolic enzymes and transporters, and of the relevant the development of prevention and new therapeutic approaches can be genes and the regulatory aspects of these physio- expected. logical systems. Above all, an understanding of cell membranes is only possible with a comprehensive The European Medical Research Councils (EMRC) at the European Science understanding of their lipid constituents. Foundation (ESF) established a task force comprised of leading European scientists in the field of lipid science with the goal to develop a science Lipids are commonly known as high-energy fuel policy briefing (SPB) addressed to national and European research fund- and storage molecules for cellular maintenance. ing and performing organisations.The scientific experts were nominated In addition, lipids are the building blocks of cell through the European Lipidomics Initiative, a specific support action of membranes, providing these membranes with their the European Commission 2005-2007, and by broad consultation within physical characteristics. It is now understood that the European scientific community. The task force met on several occa- membranes are not the fluid, homogeneous two-di- sions to address scientific issues and to formulate recommendations for mensional liquid as proposed in the famous Singer this policy briefing. The draft SPB was presented to the EMRC Standing and Nicholson fluid mosaic bilayer model (1972), Committee which reviewed the recommendations in the wider context of but that the various lipids display transverse and medical research priorities. lateral heterogeneities that are dynamic and gov- erned by specific chemical and physical mecha- Coordination and integration of interdisciplinary research efforts have nisms that include lipid metabolism. The realisation been recognised by the EMRC at ESF as an essential ingredient to pro- that cell membranes can subcompartmentalise to mote Structural Medicine as a discipline in Europe. The recommendations form dynamic liquid-ordered platforms (sphingo- put forward in this policy document will be an important step towards the lipid-cholesterol rafts) has given lipid research a goal of joint efforts by European research funding organisations and the new emphasis. In addition, a host of dedicated research community devoted to Structural Medicine. lipids, but also many intermediates of lipid metab- olism serve a second function as primary or sec- ondary messengers. Their synthesis and clearance Professor Marja Makarow Professor Liselotte Højgaard is under strict regulatory control. Finally, a variety Chief Executive, ESF Chair, EMRC of lipids serves to anchor proteins and glycans to membrane surfaces, thereby affecting and regulat- ing their functions. Most important is the fact that many of the wide- spread diseases that plague humankind in- volve lipids. Prime examples are cardiovascular disease, obesity-related type-2 diabetes, and stroke. Other major diseases such as cancer and 1 The present policy document was preceded by Part I, the ESF Science Policy Briefing 27 (July 2006) entitled Structural Medicine: The Importance of Glycomics for Health and Disease. www.esf.org monitoring the effect of nutritional and therapeutic Introduction regimens. To counter deficiencies of information on this functionally important class of biomolecules, Europe needs a multidisciplinary research initiative Health research touches us all. Both basic and focusing on lipidology and lipidomics. applied biomedical research are crucial for a better understanding of life processes. Biomedical re- Europe has had a long tradition in lipid research, search that is focused on furthering the fundamen- but interest declined towards the end of the 20th tal knowledge of structures of molecules and their century due to lack of technology to study lipids. interactions is referred to as Structural Medicine. With the recent retirement of many active lipidolo- It will aid in developing improved diagnostic tools gists that started their careers in the 1960s, cur- and appropriate medical treatment. rently the number of qualified researchers in this field is low. On the other hand, in the USA and Japan lipidomics consortia have been created Lipidology and Lipidomics and funded by national grants of tens of millions of dollars, and they have now been working at full While lipidology is the general science of speed for years. The EU Framework Programme lipids, the term ‘lipidomics’ has a different 7, launched in 2006, is trying to catch up and has, connotation. Lipidomics covers everything so far, awarded one major research grant for lipi- connected with the study of the lipidome, domics research. However, there are many more the total complement of lipids. Thus, lipi- research groups all over Europe that are ready to domics covers quantitatively the spatial and take on the lipidomics challenge. The new mass temporal determination of all lipids. In ad- spectrometric methodology for lipid analysis has dition, lipidomics includes the study of the largely been developed in Europe. Major insights lipid-metabolising enzymes and lipid trans- into the organisation of cell membranes and into porters, both of which determine the local the role of specific lipid molecules in cell signal- concentration of a lipid, and of their genes ling come from European laboratories. Thus the and regulation. Finally, lipidomics concerns European lipidomics community is ready to tackle lipid function, which cannot be understood both the basic and the applied research that will be without a thorough understanding of the required to unravel how lipids contribute to cellular physical basis of lipid behaviour, especially and body function and to take on the challenge of lipid-lipid and lipid-protein interactions. of combating the involvement of lipids in disease Lipidomics is part of metabolomics, which is pathogenesis. It is recommended that Europe the systematic study of the unique chemical creates a structure for lipidomics research for fingerprints linked to all cellular processes. the next decades. With this goal in mind Europe should fund initiatives to further develop holistic, high-throughput and high-content lipid analysis, Lipids have long been neglected. Why? Because and to devise standard operating protocols for tools to analyse lipid diversity have not been applying these techniques in the clinic. Europe available until recently. Through the development should take a leading role in integrating the of mass spectrometric methods we can now for information in connected databases containing the first time quantitatively analyse the different the subsets of data in lipid structure, lipid lipid molecular species in biological samples. This metabolomics, proteomics, and genomics; this remarkable breakthrough will make it possible to includes the responsibility for the maintenance of better understand the membrane machineries that such infrastructure. are responsible for producing and storing energy in cells, for the transport across and between cell Considering the potential of quantitative measure- membranes, and for the signalling in and out of ments offered by the new technologies, a true sys- cells, only to name a few examples. The research tems biological approach to lipidomics becomes on these important topics has so far concentrated possible. It will be necessary to attract more on the proteins involved and has largely left the chemists and physicists into this field because the lipids out of the mechanistic dissection. Cells biological and medical relevance of lipids is a result commit large amounts of chemical energy to of their chemical and physical properties. This will synthesise thousands of different lipid molecules require training of researchers with a background and it is now imperative to learn how these in the areas of kinetics and
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