Non-mammalian models for human lipid metabolism and related diseases

Colloque organisé par Patrick Babin (UMR NuAGe, Université Bordeaux 1) et Steven Farber (Carnegie Institution of Washington, Baltimore) du 15 au 20 novembre 2010

Participants

Kaveh Ashrafi, Patrick Babin, David E. Cohen, Rosalind Coleman, Steven Farber, Alex P. Gould, Ronald Künhlein, Giovanni Lesa, Esther Lubzens, John F. Rawls, Wolfgang J. Schneider, Roger Schneiter, Gregory S. Shelness, Carol C. Shoulders, Angèle Tingaud-Sequiera, Paul P. Van Veldhoven, Heimo Wolinski, Stephen G. Young.

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Compte-rendu

Metabolic diseases in particular have become a worldwide pandemic. Three of these disorders, type 2 diabetes, obesity, and dyslipidemia leading to atherosclerosis, account for the vast majority of morbidity, mortality and worldwide spending. Lipids are vital components of many biological processes and crucial in the pathogenesis of numerous common diseases, but the specific mechanisms coupling extracellular and intracellular lipids to biological targets and signalling pathways are not well understood. This is particularly the case for cells burdened with high lipid storage, trafficking and signalling capacity such as adipocytes, macrophages, enterocytes, and hepatocytes.

Studies in unicellular eukaryotes, like yeast, demonstrated that some intracellular lipid storage and mobilization mechanisms are shared with humans. Multi-cellular animals emerged several million years ago from a common ancestor that had a set of genes, processes, and adaptations, which shaped the metabolic pathways required for lipid synthesis, transport and metabolism. Thus, key aspects of human lipid metabolism can be elucidated by studies that are only possible in other non-human model systems. At present, most studies of lipid and lipoprotein metabolism have focused on adult mammalian tissues or cultured cells. However, a comprehensive whole-organism approach has been difficult, and often not impossible, in mammalian systems. Thus, the knowledge, tools and reagents developed in model systems will open up previously unapproachable, yet extremely important, aspects of lipid metabolism.

This meeting put together scientists involved in studies in yeast (Schneiter, Wolinski), nematode (Ashrafi, Lesa), Drosophila (Gould, Kühnlein), zebrafish (Babin, Farber, Lubzens, Rawls, Tingaud-Sequiera), chicken (Schneider), and mammals (Cohen, Coleman, Shelness, Shoulders, Van Veldhoven, Young), while some of them perform comparative studies at both molecular and physiological levels (Babin, Shelness). Drosophila, chick, and more recently zebrafish and nematode embryos have a long and distinguished history as major model systems for elucidating fundamental aspects of development by exploiting the ability to perform forward genetic screens (How does one cell lead to a highly patterned organism containing a variety of tissues and cell types?). However, only recently has it become apparent that the very features that made these systems ideal for developmental studies are also useful to study physiology and metabolism. For example, the optical clarity of the zebrafish embryo enables the visualization of lipid transport together with fluorescently labelled proteins within the intestinal cells of a live animal. These kinds of investigations are not presently possible in mammals. This coupling of molecular methods with new genetic approaches offers exciting possibilities for the study of lipid and lipoprotein metabolism. The in vivo biological approach used with yeast, zebrafish, Drosophila, and nematode offers distinct advantages over current tissue culture, organ culture, and histological methods. The tools and approaches we are developing will likely be sought out by researchers world-wide because they can be applied to any cell type within the live animal, thereby enabling the study of countless cell biological problems. Thus, the aim of the meeting was to bring together leaders in the field in order exchange ideas and to propose innovative collaborative research programs that exploit the tremendous advantages of these model systems.

The meeting was organized in oral communications and discussions. Three workshops were then performed. The first one was about the delineation of conserved and non conserved metabolic lipid pathways during evolution. The topic of the second one was related to the identification of human lipid diseases that need non-mammalian models. The discussion was on how the models can help for discovering molecular targets and processes related to lipid metabolism and related diseases, e.g. cardiovascular diseases, metabolic diseases, obesity, neurological disorders, and how the models can help for drug screening and translational research. The third workshop was on the technical opportunities and challenges in our various non-mammalian systems. Two general discussion sessions were then organized. The first one was to discuss a review manuscript entitled “Non-mammalian models for human lipid metabolism and related diseases” i.e. a manuscript explaining the interest to working on those models in a human perspective. The second session was on how to promote international networking among principal investigators attempting to set roadmaps for strategic actions. We therefore discussed the writing of a white paper to be forwarded to the national and international research agencies (e.g. NIH, ERC, ANR, MRC and other grant awarding bodies) enable to open future calls in that field.

During the meeting, one of the afternoons was free and the participants visited the Le Thoronet Abbey and then the very nice garden and grottes at Villecroze village. The last afternoon was devoted to a walk inside Les Treilles domain enabling friendly discussions among participants.

In conclusion, the meeting brought together leading scientists working on a variety of non-mammalian model systems to share their knowledge and expertise with scientists working on human lipid metabolism. This effort serves to promote innovative and collaborative research programs between participants. As expected, several new collaborations have been initiated and will foster research efforts to identify genes, metabolic processes, and genetic adaptations that influence human lipid metabolism and related diseases.