Pinostrobin Inhibits Proprotein Convertase Subtilisin/Kexin-type 9 (PCSK9) Gene Expression through the Modulation of FoxO3a Protein in HepG2 Cells

doi:10.1021/acs.jafc.8b02559

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Title:	Pinostrobin Inhibits Proprotein Convertase Subtilisin/Kexin-type 9 (PCSK9) Gene Expression through the Modulation of FoxO3a Protein in HepG2 Cells
Authors:	Gao, Wan-Yun Chen, Pei-Yi Chen, Shih-Fen Wu, Ming-Jiuan Chang, Heng-Yuan Yen, Jui-Hung
Contributors:	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
Keywords:	pinostrobin flavonoid PCSK9 LDLR FoxO3a
Date:	2018-06-20
Issue Date:	2019-11-15 15:43:14 (UTC+8)
Publisher:	AMER CHEMICAL SOC
Abstract:	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.
Relation:	Journal of Cleaner Production, v.66, n.24, pp.6083-6093
Appears in Collections:	[Dept. of Biotechnology (including master's program)] Periodical Articles

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