A Small Molecule That Blocks Fat Synthesis By Inhibiting the Activation of SREBP
A Small Molecule That Blocks Fat Synthesis By Inhibiting the Activation of SREBP
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DOI：
10.1016/j.chembiol.2009.07.007
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发表时间：
2009-08-28
影响因子：
--
通讯作者：
Uesugi, Motonari
中科院分区：
文献类型：
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作者：
Kamisuki, Shinji;Mao, Qian;Uesugi, Motonari
固醇调节元件结合蛋白（SREBP）是激活胆固醇和脂肪酸生物合成相关基因转录的转录因子。在本研究中，我们发现，我们以前发现的一个小的合成分子，阻止脂肪形成是一个抑制剂的SREBP激活。二芳基噻唑衍生物，现在称为法图他汀，损害SREBP的激活过程，从而降低细胞中脂肪生成基因的转录。我们的分析表明，法图他汀抑制ER高尔基体易位的SREBP通过结合到他们的护送蛋白，SREBP裂解激活蛋白（SCAP），在一个不同的网站从甾醇结合域。法托他汀阻断肥胖ob/ob小鼠体重、血糖和肝脏脂肪蓄积的增加，即使在不受控制的食物摄入下也是如此。Fatostatin可作为进一步了解SREBP调控的工具。
Sterol regulatory element binding proteins (SREBPs) are transcription factors that activate transcription of the genes involved in cholesterol and fatty acid biosynthesis. In the present study, we show that a small synthetic molecule we previously discovered to block adipogenesis is an inhibitor of the SREBP activation. The diarylthiazole derivative, now called fatostatin, impairs the activation process of SREBPs, thereby decreasing the transcription of lipogenic genes in cells. Our analysis suggests that fatostatin inhibits the ER-Golgi translocation of SREBPs through binding to their escort protein, the SREBP cleavage-activating protein (SCAP), at a distinct site from the sterol-binding domain. Fatostatin blocked increases in body weight, blood glucose, and hepatic fat accumulation in obese ob/ob mice, even under uncontrolled food intake. Fatostatin may serve as a tool for gaining further insights into the regulation of SREBP.