1. Discovery of a potent FKBP38 agonist that ameliorates HFD-induced hyperlipidemia via mTOR/P70S6K/SREBPs pathway
- Author
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E-Hu Liu, Chun Zeng, Yu-jia Kuang, Ping Li, Ping-Ting Xiao, Shi-yu Liu, and Xie Zhishen
- Subjects
Agonist ,medicine.drug_class ,Regulator ,Endogeny ,RM1-950 ,Pharmacology ,FKBP38 ,SREBP ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Hyperlipidemia ,medicine ,General Pharmacology, Toxicology and Pharmaceutics ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,0303 health sciences ,Chemistry ,food and beverages ,Lipid metabolism ,3,5,6,7,8,3ʹ,4ʹ-heptamethoxyflavone ,medicine.disease ,030220 oncology & carcinogenesis ,Lipogenesis ,mTOR ,lipids (amino acids, peptides, and proteins) ,Original Article ,Therapeutics. Pharmacology - Abstract
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., Graphical abstract FKBP38 suppresses mTOR/P70S6K/SREBPs signaling and lipid level. HMF targets FKBP38 to ameliorate HFD-induced hyperlipidemia via suppressing mTOR/P70S6K/SREBPs pathway.Image 1
- Published
- 2021