2324dihydrocucurbitacinbpromoteslipidclearancebydualtranscriptionalregulationofldlrandpcsk9

doi:10.1038/s41401-019-0274-0

	2324dihydrocucurbitacinbpromoteslipidclearancebydualtranscriptionalregulationofldlrandpcsk9
	Li Huihui 1; Li Jun 1; Zhang Xianjing 1; Li Jiaomeng 1; Xi Cong 1; Wang Wenqiong 1; Lu Youli 2; Xuan Lijiang 1
刊名	actapharmacologicasinica
	2020
卷号	41 期号:3 页码:327
关键词	23 24-dihydrocucurbitacin B lipid-lowering agent LDLR PCSK9 HNF1α SREBP2
ISSN号	1671-4083
DOI	10.1038/s41401-019-0274-0
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 μM) dosedependently promoted DiI-LDL uptake in HepG2 cells by upregulating low-density lipoprotein receptor (LDLR) protein. In HepG2 cells, 23,24-dihydrocucurbitacin B (1–10 μM) 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 HNF1α (hepatocyte nuclear factor-1α) 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 (30mg · 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 HNF1α 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.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280723]
专题	中国科学院上海药物研究所
作者单位	1.中国科学院上海药物研究所 2.Shanghai Xuhui Central Hospital/Zhongshan-Xuhui Hospital
推荐引用方式 GB/T 7714	Li Huihui,Li Jun,Zhang Xianjing,et al. 2324dihydrocucurbitacinbpromoteslipidclearancebydualtranscriptionalregulationofldlrandpcsk9[J]. actapharmacologicasinica,2020,41(3):327.
APA	Li Huihui.,Li Jun.,Zhang Xianjing.,Li Jiaomeng.,Xi Cong.,...&Xuan Lijiang.(2020).2324dihydrocucurbitacinbpromoteslipidclearancebydualtranscriptionalregulationofldlrandpcsk9.actapharmacologicasinica,41(3),327.
MLA	Li Huihui,et al."2324dihydrocucurbitacinbpromoteslipidclearancebydualtranscriptionalregulationofldlrandpcsk9".actapharmacologicasinica 41.3(2020):327.