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

Shinji Kamisuki; Qian Mao; Lutfi Abu-Elheiga; Ziwei Gu; Akira Kugimiya; Youngjoo Kwon; Tokuyuki Shinohara; Yoshinori Kawazoe; Shin ichi Sato; Koko Asakura; Hea Young Park Choo; Juro Sakai; Salih J. Wakil; Motonari Uesugi

doi:10.1016/j.chembiol.2009.07.007

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

Shinji Kamisuki, Qian Mao, Lutfi Abu-Elheiga, Ziwei Gu, Akira Kugimiya, Youngjoo Kwon, Tokuyuki Shinohara, Yoshinori Kawazoe, Shin ichi Sato, Koko Asakura, Hea Young Park Choo, Juro Sakai, Salih J. Wakil, Motonari Uesugi

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

223 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	882-892
Number of pages	11
Journal	Chemistry and Biology
Volume	16
Issue number	8
DOIs	https://doi.org/10.1016/j.chembiol.2009.07.007
State	Published - 28 Aug 2009

Bibliographical note

Funding Information:
This work was supported in part by grants to M.U. from the U.S. Department of Defense Prostate Cancer Research Program, the Suzuken Memorial Foundation, the Kato Memorial Bioscience Foundation, theHoh-ansha Foundation, and MEXT (Grant-in-Aid 18390002 and 21310140), and by grants to S.J.W. from the Hefni Technical Training Foundation and the National Institutes of Health (GM-63115). We thank William C. Heird, Department of Pediatrics, Children's Nutrition Research Center, for conducting the fatty acid analyses. We also thank T. Orihara, T. Morii, and T. Hasegawa for encouragement and experimental support. S.K. is a postdoctoral fellow of JSPS. The Kyoto research group participates in the Global COE program “Integrated Materials Science” (#B-09). The upgrade of the confocal microscope was supported by NEDO and Yokogawa Electric Corporation.

Keywords

CELLBIO
CHEMBIO

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10.1016/j.chembiol.2009.07.007

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title = "A Small Molecule That Blocks Fat Synthesis By Inhibiting the Activation of SREBP",

abstract = "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.",

keywords = "CELLBIO, CHEMBIO",

author = "Shinji Kamisuki and Qian Mao and Lutfi Abu-Elheiga and Ziwei Gu and Akira Kugimiya and Youngjoo Kwon and Tokuyuki Shinohara and Yoshinori Kawazoe and Sato, {Shin ichi} and Koko Asakura and Choo, {Hea Young Park} and Juro Sakai and Wakil, {Salih J.} and Motonari Uesugi",

note = "Funding Information: This work was supported in part by grants to M.U. from the U.S. Department of Defense Prostate Cancer Research Program, the Suzuken Memorial Foundation, the Kato Memorial Bioscience Foundation, theHoh-ansha Foundation, and MEXT (Grant-in-Aid 18390002 and 21310140), and by grants to S.J.W. from the Hefni Technical Training Foundation and the National Institutes of Health (GM-63115). We thank William C. Heird, Department of Pediatrics, Children's Nutrition Research Center, for conducting the fatty acid analyses. We also thank T. Orihara, T. Morii, and T. Hasegawa for encouragement and experimental support. S.K. is a postdoctoral fellow of JSPS. The Kyoto research group participates in the Global COE program “Integrated Materials Science” (#B-09). The upgrade of the confocal microscope was supported by NEDO and Yokogawa Electric Corporation. ",

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AU - Kamisuki, Shinji

AU - Mao, Qian

AU - Abu-Elheiga, Lutfi

AU - Gu, Ziwei

AU - Kugimiya, Akira

AU - Kwon, Youngjoo

AU - Shinohara, Tokuyuki

AU - Kawazoe, Yoshinori

AU - Sato, Shin ichi

AU - Asakura, Koko

AU - Choo, Hea Young Park

AU - Sakai, Juro

AU - Wakil, Salih J.

AU - Uesugi, Motonari

N1 - Funding Information: This work was supported in part by grants to M.U. from the U.S. Department of Defense Prostate Cancer Research Program, the Suzuken Memorial Foundation, the Kato Memorial Bioscience Foundation, theHoh-ansha Foundation, and MEXT (Grant-in-Aid 18390002 and 21310140), and by grants to S.J.W. from the Hefni Technical Training Foundation and the National Institutes of Health (GM-63115). We thank William C. Heird, Department of Pediatrics, Children's Nutrition Research Center, for conducting the fatty acid analyses. We also thank T. Orihara, T. Morii, and T. Hasegawa for encouragement and experimental support. S.K. is a postdoctoral fellow of JSPS. The Kyoto research group participates in the Global COE program “Integrated Materials Science” (#B-09). The upgrade of the confocal microscope was supported by NEDO and Yokogawa Electric Corporation.

PY - 2009/8/28

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N2 - 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.

AB - 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.

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DO - 10.1016/j.chembiol.2009.07.007

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SN - 1074-5521

VL - 16

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EP - 892

JO - Chemistry and Biology

JF - Chemistry and Biology

IS - 8

ER -

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

Abstract

Bibliographical note

Keywords

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