二酰甘油激酶
生物
表型筛选
表型
小分子
计算生物学
酶
脂质代谢
上位性
高通量筛选
模式生物
药物发现
生物化学
遗传学
基因
蛋白激酶C
作者
Kirsten Tschapalda,Yaqin Zhang,Li Liu,Kseniya Golovnina,Thomas Schlemper,Thomas O. Eichmann,Madhu Lal‐Nag,Urmila Sreenivasan,John C. McLenithan,Slava Ziegler,Carole Sztalryd,Achim Lass,Douglas S. Auld,Brian Oliver,Herbert Waldmann,Zhuyin Li,Min Shen,Matthew B. Boxer,Mathias Beller
出处
期刊:EBioMedicine
[Elsevier]
日期:2016-06-01
卷期号:8: 49-59
被引量:15
标识
DOI:10.1016/j.ebiom.2016.04.014
摘要
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.
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