A Class of Diacylglycerol Acyltransferase 1 Inhibitors Identified by a Combination of Phenotypic High-throughput Screening, Genomics, and Genetics.
EBioMedicine
; 8: 49-59, 2016 Jun.
Article
en En
| MEDLINE
| ID: mdl-27428418
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Genómica
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Inhibidores Enzimáticos
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Diacilglicerol O-Acetiltransferasa
Tipo de estudio:
Diagnostic_studies
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Screening_studies
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
EBioMedicine
Año:
2016
Tipo del documento:
Article