Discovery of a potent FKBP38 agonist that ameliorates HFD-induced hyperlipidemia via mTOR/P70S6K/SREBPs pathway

Acta Pharmaceutica Sinica B

E-Hu Liu¹  Ping Li²  Zhi-Shen Xie³  Chun Zeng⁴  Yu-Jia Kuang⁵  Shi-Yu Liu⁵  Ping-Ting Xiao⁵ 

[1] Corresponding authors. Tel./fax: [phone].;Molecular Medicine, Pediatric Diabetes Research Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA;Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, China;;Departments of Pediatrics and Cellular &State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China;

关键词: FKBP38;    Hyperlipidemia;    3,5,6,7,8,3ʹ,4ʹ-heptamethoxyflavone;    mTOR;    SREBP;   

DOI  :  

来源: DOAJ

【 摘 要 】

The mammalian target of rapamycin (mTOR)-sterol regulatory element-binding proteins (SREBPs) signaling promotes lipogenesis. However, mTOR inhibitors also displayed a significant side effect of hyperlipidemia. Thus, it is essential to develop mTOR-specific inhibitors to inhibit lipogenesis. Here, we screened the endogenous inhibitors of mTOR, and identified that FKBP38 as a vital regulator of lipid metabolism. FKBP38 decreased the lipid content in vitro and in vivo via suppression of the mTOR/P70S6K/SREBPs pathway. 3,5,6,7,8,3ʹ,4ʹ-Heptamethoxyflavone (HMF), a citrus flavonoid, was found to target FKBP38 to suppress the mTOR/P70S6K/SREBPs pathway, reduce lipid level, and potently ameliorate hyperlipidemia and insulin resistance in high fat diet (HFD)-fed mice. Our findings suggest that pharmacological intervention by targeting FKBP38 to suppress mTOR/P70S6K/SREBPs pathway is a potential therapeutic strategy for hyperlipidemia, and HMF could be a leading compound for development of anti-hyperlipidemia drugs.

【 授权许可】

Unknown