Chia Nan University of Pharmacy & Science Institutional Repository:Item 310902800/31064
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    標題: Tanshinone IIA Modulates Low Density Lipoprotein Uptake via Down-Regulation of PCSK9 Gene Expression in HepG2 Cells
    作者: Chen, Hung-Chen
    Chen, Pei-Yi
    Wu, Ming-Jiuan
    Tai, Mi-Hsueh
    Yen, Jui-Hung
    貢獻者: Tzu Chi Univ, Dept Mol Biol & Human Genet
    Buddhist Tzu Chi Gen Hosp, Ctr Med Genet
    Chia Nan Univ Pharm & Sci, Dept Biotechnol
    關鍵字: ldl receptor
    target genes
    cholesterol homeostasis
    transcription factor
    oxidative stress
    degradation
    disease
    binding
    model
    mice
    日期: 2016-09
    上傳時間: 2018-01-18 11:40:56 (UTC+8)
    出版者: Public Library Science
    摘要: 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.
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