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    Please use this identifier to cite or link to this item: http://ir.cnu.edu.tw/handle/310902800/32160


    標題: Pinostrobin Inhibits Proprotein Convertase Subtilisin/Kexin-type 9 (PCSK9) Gene Expression through the Modulation of FoxO3a Protein in HepG2 Cells
    作者: Gao, Wan-Yun
    Chen, Pei-Yi
    Chen, Shih-Fen
    Wu, Ming-Jiuan
    Chang, Heng-Yuan
    Yen, Jui-Hung
    貢獻者: Tzu Chi Univ, Dept Mol Biol & Human Genet
    Tzu Chi Univ, Sch Postbaccalaureate Chinese Med
    Buddhist Tzu Chi Gen Hosp, Ctr Med Genet
    Chia Nan Univ Pharm & Sci, Dept Biotechnol
    關鍵字: pinostrobin
    flavonoid
    PCSK9
    LDLR
    FoxO3a
    日期: 2018-06-20
    上傳時間: 2019-11-15 15:43:14 (UTC+8)
    出版者: AMER CHEMICAL SOC
    摘要: Pinostrobin, a flavonoid phytochemical found in variety of plants, has been demonstrated to possess numerous bioactivities such as antioxidant, anti-inflammatory, anticancer, and neuroprotective properties. The aim of this study was to investigate the hypocholesterolemic effect of pinostrobin on the regulation of the gene expression of PCSK9 and its underlying mechanisms in hepatic cells. We found that pinostrobin (20 and 40 mu M) significantly inhibited the PCSK9 promoter activity from 1.00 +/- 0.16 (fold) to 0.85 +/- 0.06 and 0.54 +/- 0.05, respectively, as well as the suppression of PCSK9 mRNA expression from 1.00 +/- 0.11 (fold) to 0.81 +/- 0.07 and 0.58 +/- 0.07, respectively, in HepG2 cells. Pinostrobin significantly reduced the mature form of the PCSK9 protein, inhibited the catalytic activity of PCSK9, and increased the protein level of LDLR and the LDL uptake activity in HepG2 cells. We further demonstrated that pinostrobin markedly increased the level of nuclear forkhead box 03a (FoxO3a) protein, enhanced FoxO3a/PCSK9 promoter complexes formation, and attenuated the promoter binding capacity of nuclear HNF-1 alpha. The knockdown of FoxO3a in HepG2 cells by small interference RNA (siRNA) abolished the pinostrobin-mediated PCSK9 reduction. Finally, we demonstrated that pinostrobin attenuated simvastatin-induced PCSK9 overexpression in HepG2 cells. Our current findings reveal that pinostrobin is a PCSK9 inhibitor and down-regulates the PCSK9 gene expression through the up-regulation of the FoxO3a level in hepatic cells. Pinostrobin with potential PCSK9 inhibitory activity may serve as a novel agent for cholesterol regulation and lipid management.
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