Tanshinone IIA Modulates Low Density Lipoprotein Uptake via Down-Regulation of PCSK9 Gene Expression in HepG2 Cells

doi:10.1371/journal.pone.0162414

CNU IR > Pharmacy and Science > Dept. of Biotechnology (including master's program) > Periodical Articles > Item 310902800/31064

Please use this identifier to cite or link to this item: https://ir.cnu.edu.tw/handle/310902800/31064

Title:	Tanshinone IIA Modulates Low Density Lipoprotein Uptake via Down-Regulation of PCSK9 Gene Expression in HepG2 Cells
Authors:	Chen, Hung-Chen Chen, Pei-Yi Wu, Ming-Jiuan Tai, Mi-Hsueh Yen, Jui-Hung
Contributors:	Tzu Chi Univ, Dept Mol Biol & Human Genet Buddhist Tzu Chi Gen Hosp, Ctr Med Genet Chia Nan Univ Pharm & Sci, Dept Biotechnol
Keywords:	ldl receptor target genes cholesterol homeostasis transcription factor oxidative stress degradation disease binding model mice
Date:	2016-09
Issue Date:	2018-01-18 11:40:56 (UTC+8)
Publisher:	Public Library Science
Abstract:	Tanshinone IIA, one of the most pharmacologically bioactive phytochemicals isolated from Salvia miltiorrhiza Bunge, possesses several biological activities such as anti-inflammation, anti-cancer, neuroprotection and hypolipidemic activities. In this study, we aim to investigate the hypocholesterolemic effect of tanshinone IIA in hepatic cells. We demonstrated that tanshinone IIA significantly increased the amount of low-density lipoprotein receptor (LDLR) and LDL uptake activity in HepG2 cells at the post-transcriptional regulation. We further demonstrated that tanshinone IIA inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and mature protein, which may lead to an increase the cell-surface LDLR in hepatic cells. We further identified a regulatory DNA element involved in the tanshinone IIA-mediated PCSK9 down-regulation, which is located between the -411 and -336 positions of the PCSK9 promoter. Moreover, we found that tanshinone IIA markedly increased the nuclear forkhead box O3a (FoxO3a) level, enhanced FoxO3a/PCSK9 promoter complexes formation and decreased the PCSK9 promoter binding capacity of hepatocyte nuclear factor 1 alpha (HNF-1 alpha), resulting in suppression of PCSK9 gene expression. Finally, we found that the statin-induced PCSK9 overexpression was attenuated and the LDLR activity was elevated in a synergic manner by combination of tanshinone IIA treatment in HepG2 cells. Overall, our results reveal that the tanshinone IIA modulates LDLR level and activity via down-regulation of PCSK9 expression in hepatic cells. Our current findings provide a molecular basis of tanshinone IIA to develop PCSK9 inhibitors for cholesterol management.
Relation:	Plos One, v.11 n.9, e0162414
Appears in Collections:	[Dept. of Biotechnology (including master's program)] Periodical Articles

Files in This Item:

File	Description	Size	Format
31064.pdf		5532Kb	Adobe PDF	385	View/Open
index.html		0Kb	HTML	1499	View/Open

Loading...