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

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...

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Autores principales:	Ping-Ting Xiao, Zhi-Shen Xie, Yu-Jia Kuang, Shi-Yu Liu, Chun Zeng, Ping Li, E-Hu Liu
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	FKBP38 Hyperlipidemia 3,5,6,7,8,3ʹ,4ʹ-heptamethoxyflavone mTOR SREBP Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/cfa9a0e661eb4e1d9abff4d535cf5f73
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spelling	oai:doaj.org-article:cfa9a0e661eb4e1d9abff4d535cf5f732021-12-02T05:01:21ZDiscovery of a potent FKBP38 agonist that ameliorates HFD-induced hyperlipidemia via mTOR/P70S6K/SREBPs pathway2211-383510.1016/j.apsb.2021.03.031https://doaj.org/article/cfa9a0e661eb4e1d9abff4d535cf5f732021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2211383521001039https://doaj.org/toc/2211-3835The 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.Ping-Ting XiaoZhi-Shen XieYu-Jia KuangShi-Yu LiuChun ZengPing LiE-Hu LiuElsevierarticleFKBP38Hyperlipidemia3,5,6,7,8,3ʹ,4ʹ-heptamethoxyflavonemTORSREBPTherapeutics. PharmacologyRM1-950ENActa Pharmaceutica Sinica B, Vol 11, Iss 11, Pp 3542-3552 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	FKBP38 Hyperlipidemia 3,5,6,7,8,3ʹ,4ʹ-heptamethoxyflavone mTOR SREBP Therapeutics. Pharmacology RM1-950
spellingShingle	FKBP38 Hyperlipidemia 3,5,6,7,8,3ʹ,4ʹ-heptamethoxyflavone mTOR SREBP Therapeutics. Pharmacology RM1-950 Ping-Ting Xiao Zhi-Shen Xie Yu-Jia Kuang Shi-Yu Liu Chun Zeng Ping Li E-Hu Liu Discovery of a potent FKBP38 agonist that ameliorates HFD-induced hyperlipidemia via mTOR/P70S6K/SREBPs pathway
description	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.
format	article
author	Ping-Ting Xiao Zhi-Shen Xie Yu-Jia Kuang Shi-Yu Liu Chun Zeng Ping Li E-Hu Liu
author_facet	Ping-Ting Xiao Zhi-Shen Xie Yu-Jia Kuang Shi-Yu Liu Chun Zeng Ping Li E-Hu Liu
author_sort	Ping-Ting Xiao
title	Discovery of a potent FKBP38 agonist that ameliorates HFD-induced hyperlipidemia via mTOR/P70S6K/SREBPs pathway
title_short	Discovery of a potent FKBP38 agonist that ameliorates HFD-induced hyperlipidemia via mTOR/P70S6K/SREBPs pathway
title_full	Discovery of a potent FKBP38 agonist that ameliorates HFD-induced hyperlipidemia via mTOR/P70S6K/SREBPs pathway
title_fullStr	Discovery of a potent FKBP38 agonist that ameliorates HFD-induced hyperlipidemia via mTOR/P70S6K/SREBPs pathway
title_full_unstemmed	Discovery of a potent FKBP38 agonist that ameliorates HFD-induced hyperlipidemia via mTOR/P70S6K/SREBPs pathway
title_sort	discovery of a potent fkbp38 agonist that ameliorates hfd-induced hyperlipidemia via mtor/p70s6k/srebps pathway
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/cfa9a0e661eb4e1d9abff4d535cf5f73
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Discovery of a potent FKBP38 agonist that ameliorates HFD-induced hyperlipidemia via mTOR/P70S6K/SREBPs pathway

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