A small-molecule lycorine derivative reveals Na<sup>+</sup>/K<sup>+</sup>-ATPase α3 as an anti-obesity target

doi:10.1101/2022.08.24.505199

	A small-molecule lycorine derivative reveals Na⁺/K⁺-ATPase α3 as an anti-obesity target
	Zhou, Y.1; Zhang, H.1; Chen, D.2; Chen, Z.1; Li, Y.1; Tian, C.3; Zhang, C.1; Li, C.4; Chang, B.1; Zeng, R.; Li, J.1; Song, X.1; Chen, Y.5; Hao, X.2; Li, L.1,3,5
	2022-08-26
状态	已发表
摘要	Obesity poses a global public health challenge and there is a huge unmet medical need for effective and safe anti-obesity therapeutics. Here, we discovered a small-molecule lycorine derivative designated as HLY72 that could potently promote lipolysis and reduce body weight in mice. Further study revealed that Na⁺/K⁺-ATPase α3 is the target of HLY72, and the Na⁺/K⁺-ATPase inhibitor digitoxin, but not istaroxime which could not go through blood-brain barrier, exhibits similar activities of reducing food intake and promoting lipolysis as HLY72 does in mice. Consistent with these findings, in knockin mice with a digitoxin-binding mutation T807C in Na⁺/K⁺-ATPase α3, but not in 1 gene, both digitoxin and HLY72 lose their activities. Furthermore, either chemical inhibition by HLY72 or genetic inhibition by T807C mutation of Na⁺/K⁺-ATPase 3 could effectively protect mice from diet-induced obesity. Therefore, we uncovered a previously unknown function of Na⁺/K⁺-ATPase α3 in the regulation of lipolysis and energy balance; and revealed a potential treatment and prevention strategy for obesity by targeting Na⁺/K⁺-ATPase α3.
关键词	Obesity Na⁺/K⁺-ATPase &alpha 3 cardiac glycosides (CGs) lipolysis Hormone-sensitive lipase (HSL)
语种	英语
DOI	10.1101/2022.08.24.505199
相关网址	查看原文
出处	bioRxiv
收录类别	PPRN.PPRN
WOS记录号	PPRN:15104563
WOS类目	Physiology
资助项目	National Natural Science Foundation of China["XDB19030000","92053201"]
文献类型	预印本
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/348417
专题	生命科学与技术学院
通讯作者	Hao, X.; Li, L.
作者单位	1.Univ Chinese Acad Sci, Inst Biochem & Cell Biol, Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci,State Key Lab Mol Biol,State Key Lab Cell Biol, Shanghai 200031, Peoples R China 2.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West China, Kunming 650204, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 4.Chinese Acad Sci, Inst Biochem & Cell Biol, CAS Ctr Excellence Mol Cell Sci, CAS Key Lab Syst Biol, Shanghai 200031, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Nutr & Hlth, CAS Key Lab Nutr Metab & Food Safety, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Zhou, Y.,Zhang, H.,Chen, D.,et al. A small-molecule lycorine derivative reveals Na⁺/K⁺-ATPase α3 as an anti-obesity target. 2022.