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.
authors.affiliation: Institute for Chemical Research, Kyoto University, Uji, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kamisuki
authors.forename: Qian
authors.initials: Q
authors.lastname: Mao
authors.forename: Lutfi
authors.initials: L
authors.lastname: Abu-Elheiga
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Gu
authors.forename: Akira
authors.initials: A
authors.lastname: Kugimiya
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
authors.forename: Tokuyuki
authors.initials: T
authors.lastname: Shinohara
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kawazoe
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Sato
authors.forename: Koko
authors.initials: K
authors.lastname: Asakura
authors.forename: Hea-Young Park
authors.initials: HY
authors.lastname: Choo
authors.forename: Juro
authors.initials: J
authors.lastname: Sakai
authors.forename: Salih J
authors.initials: SJ
authors.lastname: Wakil
authors.forename: Motonari
authors.initials: M
authors.lastname: Uesugi
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005227:Fatty Acids / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051779:Sterol Regulatory Element Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011725:Pyridines; C102196:SREBP cleavage-activating protein; D051779:Sterol Regulatory Element Binding Proteins; D013844:Thiazoles; C545733:fatostatin