A small molecule that blocks fat synthesis by inhibiting the activation of SREBP.
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.
Kamisuki
Shinji
S
Institute for Chemical Research, Kyoto University, Uji, Japan.
Mao
Qian
Q
Abu-Elheiga
Lutfi
L
Gu
Ziwei
Z
Kugimiya
Akira
A
Kwon
Youngjoo
Y
Shinohara
Tokuyuki
T
Kawazoe
Yoshinori
Y
Sato
Shin-ichi
S
Asakura
Koko
K
Choo
Hea-Young Park
HY
Sakai
Juro
J
Wakil
Salih J
SJ
Uesugi
Motonari
M
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
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