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EBioMedicine. 2016 Jun;8:49-59. doi: 10.1016/j.ebiom.2016.04.014. Epub 2016 Apr 16.

A Class of Diacylglycerol Acyltransferase 1 Inhibitors Identified by a Combination of Phenotypic High-throughput Screening, Genomics, and Genetics.

Author information

1
Systems Biology of Lipid Metabolism, Heinrich Heine University Düsseldorf, Germany; Institute for Mathematical Modeling of Biological Systems, Heinrich Heine University Düsseldorf, Germany; Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany; Department of Molecular Developmental Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
2
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, USA.
3
National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, USA.
4
Systems Biology of Lipid Metabolism, Heinrich Heine University Düsseldorf, Germany; Institute for Mathematical Modeling of Biological Systems, Heinrich Heine University Düsseldorf, Germany.
5
Institute of Molecular Biosciences, University of Graz, Austria.
6
Department of Medicine, Division of Endocrinology University of Maryland School of Medicine, USA.
7
Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
8
Department of Medicine, Division of Endocrinology University of Maryland School of Medicine, USA; Baltimore VA Medical Center, VA Research Service, Geriatric Research, Education and Clinical Center (GRECC) and VA Maryland Health Care System, Department of Medicine, Division of Endocrinology University of Maryland School of Medicine, USA.
9
Systems Biology of Lipid Metabolism, Heinrich Heine University Düsseldorf, Germany; Institute for Mathematical Modeling of Biological Systems, Heinrich Heine University Düsseldorf, Germany. Electronic address: mathias.beller@hhu.de.

Abstract

Excess lipid storage is an epidemic problem in human populations. Thus, the identification of small molecules to treat or prevent lipid storage-related metabolic complications is of great interest. Here we screened >320.000 compounds for their ability to prevent a cellular lipid accumulation phenotype. We used fly cells because the multifarious tools available for this organism should facilitate unraveling the mechanism-of-action of active small molecules. Of the several hundred lipid storage inhibitors identified in the primary screen we concentrated on three structurally diverse and potent compound classes active in cells of multiple species (including human) and negligible cytotoxicity. Together with Drosophila in vivo epistasis experiments, RNA-Seq expression profiles suggested that the target of one of the small molecules was diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in the production of triacylglycerols and prominent human drug target. We confirmed this prediction by biochemical and enzymatic activity tests.

PMID:
27428418
PMCID:
PMC4919474
DOI:
10.1016/j.ebiom.2016.04.014
[Indexed for MEDLINE]
Free PMC Article

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