Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo 113-8657, Japan.
Atherosclerosis. 2012 Feb;220(2):369-74. doi: 10.1016/j.atherosclerosis.2011.11.006. Epub 2011 Nov 16.
The hepatocyte low density lipoprotein receptor (LDLR) plays a pivotal role in lipoprotein metabolism by lowering plasma LDL-cholesterol, a risk factor for atherosclerosis. The present study was conducted to investigate the effects of grape polyphenols on LDLR gene expression in human hepatocyte models.
Among the 14 phenolic compounds in red wine, we found that a stilbene trans-resveratrol most strongly up-regulated LDLR gene expression in HepG2 cells. Trans-resveratrol increased the LDLR protein and uptake of fluorescent-labeled LDL. Moreover, it enhanced LDLR gene promoter activity through the proteolytic activation of the sterol regulatory element-binding protein-2 (SREBP-2) as well as SREBP-1. However, sterols completely abolished trans-resveratrol-induced SREBP activation and LDLR gene expression. Finally, AMP-activated protein kinase (AMPK) knockdown analyses by siRNA revealed that AMPK activation was unnecessary for the effects of trans-resveratrol.
Trans-resveratrol up-regulated hepatic LDLR expression via proteolytic activation of SREBPs. We concluded that trans-resveratrol exhibits the anti-atherogenic effect, at least in part, by increased hepatic LDLR expression and subsequent LDL uptake.
肝细胞低密度脂蛋白受体（LDLR）通过降低血浆 LDL-胆固醇（动脉粥样硬化的一个危险因素）在脂蛋白代谢中起着关键作用。本研究旨在探讨葡萄多酚对人肝细胞模型中 LDLR 基因表达的影响。
在红酒中的 14 种酚类化合物中，我们发现一种芪类反式白藜芦醇最能上调 HepG2 细胞中的 LDLR 基因表达。反式白藜芦醇增加 LDLR 蛋白和荧光标记的 LDL 的摄取。此外，它通过固醇调节元件结合蛋白-2（SREBP-2）和 SREBP-1 的蛋白水解激活增强 LDLR 基因启动子活性。然而，固醇完全消除了反式白藜芦醇诱导的 SREBP 激活和 LDLR 基因表达。最后，通过 siRNA 进行的 AMP 激活蛋白激酶（AMPK）敲低分析表明，AMPK 的激活对于反式白藜芦醇的作用不是必需的。
反式白藜芦醇通过 SREBPs 的蛋白水解激活上调肝 LDLR 表达。我们的结论是，反式白藜芦醇通过增加肝 LDLR 表达和随后的 LDL 摄取，至少部分表现出抗动脉粥样硬化作用。
