23,24-Dihydrocucurbitacin B promotes lipid clearance by dual transcriptional regulation of LDLR and PCSK9

doi:10.1038/s41401-019-0274-0

	23,24-Dihydrocucurbitacin B promotes lipid clearance by dual transcriptional regulation of LDLR and PCSK9
	Li, Hui-hui 1,2; Li, Jun 1,2; Zhang, Xian-jing 1,2; Li, Jiao-meng 1,2; Xi, Cong 1,2; Wang, Wen-qiong 1,2; Lu, You-li 3,4; Xuan, Li-jiang 1,2
刊名	ACTA PHARMACOLOGICA SINICA
	2020-03-01
卷号	41 期号:3 页码:327-335
关键词	23,24-dihydrocucurbitacin B lipid-lowering agent LDLR PCSK9 HNF1 alpha SREBP2
ISSN号	1671-4083
DOI	10.1038/s41401-019-0274-0
通讯作者	Xuan, Li-jiang(ljxuan@simm.ac.cn)
英文摘要	23,24-Dihydrocucurbitacin B (designated as C95 in this article) is a cucurbitane triterpenoid that has been shown to possess a variety of pharmacological activities, such as anti-inflammatory and anti-HIV-1 activities etc. In this study, we investigated the effects of 23,24-dihydrocucurbitacin B on lipid regulation. We showed that 23,24-dihydrocucurbitacin B (1-5 mu M) dose-dependently promoted DiI-LDL uptake in HepG2 cells by upregulating low-density lipoprotein receptor (LDLR) protein. In HepG2 cells, 23,24-dihydrocucurbitacin B (1-10 mu M) dose-dependently enhanced LDLR promoter activity by elevating the mature form of SREBP2 (sterol regulatory element binding protein 2) protein levels on one hand, and inhibited PCSK9 (proprotein convertase subtilisin/kexin type 9) promoter activity by attenuating HNF1 alpha (hepatocyte nuclear factor-1 alpha) protein levels in nuclei on the other hand. Consequently, the expression of LDLR protein markedly increased, whereas the PCSK9-mediated LDLR protein degradation decreased. In a high-cholesterol LVG golden Syrian Hamster model, administration of 23,24-dihydrocucurbitacin B (30 mg . kg(-1). d(-1), intragastric, for 3 weeks) significantly decreased the serum LDL-cholesterol (LDL-C) levels. PCSK9 protein levels in the serum and liver tissues were significantly decreased, whereas LDLR protein levels in liver tissues were significantly increased in the treated animals as compared with the control animals. In conclusion, our study demonstrates for the first time that 23,24-dihydrocucurbitacin B exhibits dual transcriptional regulation of LDLR and PCSK9 in HepG2 cells by increasing SREBP2 protein levels and decreasing HNF1 alpha protein levels in the nuclei. These results propose a new strategy to simultaneously manage LDLR and PCSK9 protein expression and provide a promising lead compound for drug development.
资助项目	Drug Innovation Major Project of China[2018ZX09735001-002-005] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040335] ; National Natural Science Foundation of China[81773863] ; Youth Innovation Promotion Association
WOS关键词	DIHYDROCUCURBITACIN-B ; RECEPTOR ; CHOLESTEROL ; HYPERCHOLESTEROLEMIA ; EXPRESSION ; APOPTOSIS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000514159600005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281431]
专题	中国科学院上海药物研究所
通讯作者	Xuan, Li-jiang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Zhongshan Xuhui Hosp, Shanghai Xuhui Cent Hosp, Shanghai 200031, Peoples R China 4.Chinese Acad Sci, Shanghai Clin Res Ctr, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Li, Hui-hui,Li, Jun,Zhang, Xian-jing,et al. 23,24-Dihydrocucurbitacin B promotes lipid clearance by dual transcriptional regulation of LDLR and PCSK9[J]. ACTA PHARMACOLOGICA SINICA,2020,41(3):327-335.
APA	Li, Hui-hui.,Li, Jun.,Zhang, Xian-jing.,Li, Jiao-meng.,Xi, Cong.,...&Xuan, Li-jiang.(2020).23,24-Dihydrocucurbitacin B promotes lipid clearance by dual transcriptional regulation of LDLR and PCSK9.ACTA PHARMACOLOGICA SINICA,41(3),327-335.
MLA	Li, Hui-hui,et al."23,24-Dihydrocucurbitacin B promotes lipid clearance by dual transcriptional regulation of LDLR and PCSK9".ACTA PHARMACOLOGICA SINICA 41.3(2020):327-335.