Abstract
Adipose triglyceride lipase (ATGL) is rate limiting in the mobilization of fatty acids from cellular triglyceride stores. This central role in lipolysis marks ATGL as an interesting pharmacological target as deregulated fatty acid metabolism is closely linked to dyslipidemic and metabolic disorders. Here we report on the development and characterization of a small-molecule inhibitor of ATGL. Atglistatin is selective for ATGL and reduces fatty acid mobilization in vitro and in vivo.
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Acknowledgements
This work was funded by the Austrian Science Fund (FWF) projects (W901-B05 DK Molecular Enzymology (R. Zimmermann, R.B.), Translational Program TRP4 (R. Zimmermann), Wittgenstein Award 2007 (grant no. Z136, R. Zechner)) and by the Forschungsförderungsgesellschaft und Bundesministerium für Wissenschaft und Forschung (Austrian Genome Project GEN-AU: Genomics of Lipid-Associated Disorders (GOLD, R. Zechner, R. Zimmermann) and Platform for Chemical Biology in Austria (PLACEBO, R.B.)). We are grateful to B. Grumm and B. Wölfl for skillful help in the synthesis of Atglistatin. Furthermore, we thank P. Jacobsen and H. Tornqvist from Novo Nordisk for helpful discussions and for the provision of lead compounds.
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R. Zimmermann, R.B., R. Zechner, G.H. and C.F. conceived the study design. N.M., M.S., M.R., T.O.E., J.I., E.F., G.F.G., A.L., C.H. and I.M. performed the experiments. R. Zimmermann and R.B. analyzed the data and wrote the paper. All of the authors read, revised and approved the manuscript.
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N.M., M.S., M.R., R. Zimmermann and R.B. have filed for a patent on lipase inhibitors.
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Supplementary Results, Supplementary Table 1, Supplementary Figures 1–9 and Supplementary Note. (PDF 3322 kb)
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Mayer, N., Schweiger, M., Romauch, M. et al. Development of small-molecule inhibitors targeting adipose triglyceride lipase. Nat Chem Biol 9, 785–787 (2013). https://doi.org/10.1038/nchembio.1359
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DOI: https://doi.org/10.1038/nchembio.1359
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