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

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/P70 S6 K/SREBPs pathway.3,5,6,7,8,3’,4’-Heptamethoxyflavone(HMF),a citrus flavonoid,was found to target FKBP38 to suppress the mTOR/P70 S6 K/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/P70 S6 K/SREBPs pathway is a potential therapeutic strategy for hyperlipidemia,and HMF could be a leading compound for development of anti-hyperlipidemia drugs.