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Oncotarget

Oncotarget

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Lunasin functionally enhances LDL uptake via inhibiting PCSK9 and enhancing LDLR expression in vitro and in vivo

Published:24 August 2017 DOI: 10.18632/oncotarget.20590 PMID: 29113347
Lili Gu, Yue Wang, Yaqiong Xu, Qinghua Tian, Gaoxin Lei, Cheng Zhao, Zhan Gao, Qin Pan, Wenfeng Zhao, Liu Nong, Shuhua Tan

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease which regulates serum low-density lipoprotein cholesterol (LDL-C) levels by promoting the degradation of the hepatic low-density lipoprotein receptor (LDLR), and has become an attractive therapeutic target for cholesterol lowering intervention. Lunasin, a 43-amino acid polypeptide initially isolated from soybean, has been previously proven to possess cholesterol lowering activity. Here we identified the down-regulation of PCSK9 expression by lunasin as one new mechanism that increased cell-surface LDLR level and enhanced LDL uptake in vitro and in vivo. Treatment of HepG2 cells with lunasin inhibited the expression of PCSK9 at mRNA and protein levels in a dose-and-time dependent manner via down-regulating hepatocyte nuclear factor-1α (HNF-1α), thereby contributing to increasing LDLR level and functionally enhancing LDL uptake. ApoE-/- mice receiving lunasin administration by intraperitoneal injection at doses of 0.125~0.5 μmol/kg·day for 4 weeks had significantly lower PCSK9 and higher LDLR levels in hepatic tissue, as well as remarkably reduced total-cholesterol (T-CHO) and LDL-C in blood as compared to mice in vehicle control group. Furthermore, we identified that LDLR expression was up-regulated by lunasin via PI3K/Akt-mediated activation of SREBP-2 in HepG2 cells. Taken together, our findings suggest that lunasin inhibits PCSK9 expression by down-regulating HNF-1α and enhances LDLR expression via PI3K/Akt-mediated activation of SREBP-2 pathway, thereby functionally enhances LDL uptake in HepG2 cells and in ApoE-/- mice.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
LY 294002 Hydrochloride 154447-36-6 C19H17NO3 404 suppliers $12.00-$3350.00
LY 294002 Hydrochloride 154447-36-6 C19H17NO3 404 suppliers $12.00-$3350.00
LY 294002 Hydrochloride 154447-36-6 C19H17NO3 404 suppliers $12.00-$3350.00
LY 294002 Hydrochloride 154447-36-6 C19H17NO3 404 suppliers $12.00-$3350.00

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