title: A Class of Diacylglycerol Acyltransferase 1 Inhibitors Identified by a Combination of Phenotypic High-throughput Screening, Genomics, and Genetics.
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.
authors.affiliation: 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.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Tschapalda
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, USA.
authors.forename: Ya-Qin
authors.initials: YQ
authors.lastname: Zhang
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, USA.
authors.forename: Kseniya
authors.initials: K
authors.lastname: Golovnina
authors.affiliation: Systems Biology of Lipid Metabolism, Heinrich Heine University Düsseldorf, Germany; Institute for Mathematical Modeling of Biological Systems, Heinrich Heine University Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schlemper
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Austria.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Eichmann
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, USA.
authors.forename: Madhu
authors.initials: M
authors.lastname: Lal-Nag
authors.affiliation: Department of Medicine, Division of Endocrinology University of Maryland School of Medicine, USA.
authors.forename: Urmila
authors.initials: U
authors.lastname: Sreenivasan
authors.affiliation: Department of Medicine, Division of Endocrinology University of Maryland School of Medicine, USA.
authors.forename: John
authors.initials: J
authors.lastname: McLenithan
authors.affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
authors.forename: Slava
authors.initials: S
authors.lastname: Ziegler
authors.affiliation: 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.
authors.forename: Carole
authors.initials: C
authors.lastname: Sztalryd
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Austria.
authors.forename: Achim
authors.initials: A
authors.lastname: Lass
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Auld
authors.affiliation: National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Oliver
authors.affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, USA.
authors.forename: Zhuyin
authors.initials: Z
authors.lastname: Li
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Boxer
authors.affiliation: 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.
authors.forename: Mathias
authors.initials: M
authors.lastname: Beller
mesh_terms: D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002522:Chlorocebus aethiops; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004843:Epistasis, Genetic; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D023281:Genomics; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D010641:Phenotype; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017423:Sequence Analysis, RNA; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005227:Fatty Acids; D011758:Pyrroles; D054852:Small Molecule Libraries; C521801:thienopyrrole; D051048:Diacylglycerol O-Acyltransferase