西亚试剂：A Small Molecule That Blocks Fat Synthesis By Inhibiting th

A Small Molecule That Blocks Fat Synthesis By Inhibiting the Activation of SREBP

Shinji Kamisuki1,5,Qian Mao2,5,Lutfi Abu-Elheiga2,5,Ziwei Gu2,Akira Kugimiya1,Youngjoo Kwon2,4,Tokuyuki Shinohara1,Yoshinori Kawazoe1,Shin-ichi Sato2,Koko Asakura2,Hea-Young Park Choo1,4,Juro Sakai3,Salih J. Wakil2,,andMotonari Uesugi1,2,,

1 Institute for Chemical Research and Institute for Integrated Cell-Material Sciences, Kyoto University, Uji, Kyoto 611-0011, Japan
2 The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
3 Research Center for Advanced Science and Technology, University of Tokyo, Meguro, Tokyo 153-8904, Japan

Sterol regulatory element binding proteins (SREBPs) are transcription factors that activate transcription ofthe 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.

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