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.

DOI: 10.1016/j.ebiom.2016.04.014

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@inproceedings{Tschapalda2016ACO, title={A Class of Diacylglycerol Acyltransferase 1 Inhibitors Identified by a Combination of Phenotypic High-throughput Screening, Genomics, and Genetics}, author={Kirsten Tschapalda and Ya-Qin Zhang and Li Liu and Kseniya Golovnina and Thomas Schlemper and Thomas Oliver Eichmann and Madhu A Lal-Nag and Urmila T Sreenivasan and John Mclenithan and Slava Ziegler and Carole Sztalryd and Achim Lass and Douglas S. Auld and Brian Oliver and Herbert Waldmann and Zhuyin Li and Min Shen and Matthew B. Boxer and Mathias Beller}, booktitle={EBioMedicine}, year={2016} }