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Open AccessArticle

Lunasin Improves the LDL-C Lowering Efficacy of Simvastatin via Inhibiting PCSK9 Expression in Hepatocytes and ApoE−/− Mice

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Kamelija Zarkovic and Neven Zarkovic
Molecules 2019, 24(22), 4140; https://doi.org/10.3390/molecules24224140
Received: 29 September 2019 / Revised: 12 November 2019 / Accepted: 13 November 2019 / Published: 15 November 2019
(This article belongs to the Collection Molecular Medicine)
Statins are the most popular therapeutic drugs to lower plasma low density lipoprotein cholesterol (LDL-C) synthesis by competitively inhibiting hydroxyl-3-methyl-glutaryl-CoA (HMG-CoA) reductase and up-regulating the hepatic low density lipoprotein receptor (LDLR). However, the concomitant up-regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) by statin attenuates its cholesterol lowering efficacy. Lunasin, a soybean derived 43-amino acid polypeptide, has been previously shown to functionally enhance LDL uptake via down-regulating PCSK9 and up-regulating LDLR in hepatocytes and mice. Herein, we investigated the LDL-C lowering efficacy of simvastatin combined with lunasin. In HepG2 cells, after co-treatment with 1 μM simvastatin and 5 μM lunasin for 24 h, the up-regulation of PCSK9 by simvastatin was effectively counteracted by lunasin via down-regulating hepatocyte nuclear factor 1α (HNF-1α), and the functional LDL uptake was additively enhanced. Additionally, after combined therapy with simvastatin and lunasin for four weeks, ApoE−/− mice had significantly lower PCSK9 and higher LDLR levels in hepatic tissues and remarkably reduced plasma concentrations of total cholesterol (TC) and LDL-C, as compared to each monotherapy. Conclusively, lunasin significantly improved the LDL-C lowering efficacy of simvastatin by counteracting simvastatin induced elevation of PCSK9 in hepatocytes and ApoE−/− mice. Simvastatin combined with lunasin could be a novel regimen for hypercholesterolemia treatment. View Full-Text
Keywords: lunasin; simvastatin; proprotein convertase subtilisin/kexin type 9; low density lipoprotein receptor; low density lipoprotein cholesterol; hepatocyte nuclear factor-1α lunasin; simvastatin; proprotein convertase subtilisin/kexin type 9; low density lipoprotein receptor; low density lipoprotein cholesterol; hepatocyte nuclear factor-1α
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MDPI and ACS Style

Gu, L.; Gong, Y.; Zhao, C.; Wang, Y.; Tian, Q.; Lei, G.; Liang, Y.; Zhao, W.; Tan, S. Lunasin Improves the LDL-C Lowering Efficacy of Simvastatin via Inhibiting PCSK9 Expression in Hepatocytes and ApoE−/− Mice. Molecules 2019, 24, 4140. https://doi.org/10.3390/molecules24224140

AMA Style

Gu L, Gong Y, Zhao C, Wang Y, Tian Q, Lei G, Liang Y, Zhao W, Tan S. Lunasin Improves the LDL-C Lowering Efficacy of Simvastatin via Inhibiting PCSK9 Expression in Hepatocytes and ApoE−/− Mice. Molecules. 2019; 24(22):4140. https://doi.org/10.3390/molecules24224140

Chicago/Turabian Style

Gu, Lili; Gong, Yaqin; Zhao, Cheng; Wang, Yue; Tian, Qinghua; Lei, Gaoxin; Liang, Yalin; Zhao, Wenfeng; Tan, Shuhua. 2019. "Lunasin Improves the LDL-C Lowering Efficacy of Simvastatin via Inhibiting PCSK9 Expression in Hepatocytes and ApoE−/− Mice" Molecules 24, no. 22: 4140. https://doi.org/10.3390/molecules24224140

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