Lunasin functionally enhances LDL uptake via inhibiting PCSK9 and enhancing LDLR expression in vitro and in vivo
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Lili Gu1, Yue Wang1, Yaqiong Xu1, Qinghua Tian1, Gaoxin Lei1, Cheng Zhao1, Zhan Gao1, Qin Pan1, Wenfeng Zhao1, Liu Nong1 and Shuhua Tan1
1State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Shuhua Tan, email: email@example.com
Keywords: lunasin, proprotein convertase subtilisin/kexin type 9, low-density lipoprotein cholesterol, low-density lipoprotein receptor, hepatocyte nuclear factor-1α
Received: June 26, 2017 Accepted: August 04, 2017 Published: August 24, 2017
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.
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