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Up-regulation of hepatic low-density lipoprotein receptor-related protein 1: a possible novel mechanism of antiatherogenic activity of hydroxymethylglutaryl-coenzyme A reductase inhibitor Atorvastatin and hepatic LRP1 expression

Authors
 Jae Hoon Moon ; Saet Byol Kang ; Bong Soo Cha ; Hyun Chul Lee ; Chul Woo Ahn ; Eun Seok Kang ; Byung Wan Lee ; Jong Suk Park 
Citation
 Metabolism-Clinical and Experimental, Vol.60(7) : 930~940, 2011 
Journal Title
 Metabolism-Clinical and Experimental 
ISSN
 0026-0495 
Issue Date
2011
Abstract
Low-density lipoprotein receptor-related protein 1 (LRP1) binds to apolipoprotein E and serves as a receptor for remnant lipoproteins in the liver, thus playing an important role in clearing these atherogenic particles. In this study, we investigated the effect of atorvastatin, a hydroxymethylglutaryl-coenzyme A reductase inhibitor, on hepatic LRP1 expression. We used HepG2 and Hep3B cells for in vitro study, and Otsuka Long-Evans Tokushima fatty and Sprague-Dawley rats for in vivo study. We used relatively high pharmacologic dose of atorvastatin in this study (in vitro, 0.5 μmol/L in culture media, for 48 hours; in vivo, 20 mg/[kg d], for 6 weeks). Atorvastatin increased LRP1 and low-density lipoprotein (LDL) receptor expression in HepG2 and Hep3B cells and induced hepatic LRP1 and LDL receptor expression in chow diet-fed Sprague-Dawley rats and high-fat diet-fed Otsuka Long-Evans Tokushima fatty rats. Atorvastatin decreased intracellular sterol level and increased the amount of the nuclear form of sterol response element-binding protein-2 (SREBP-2) in both HepG2 and Hep3B cells as well as in two animal models. Treatment of HepG2 cells with LDL increased intracellular sterol level and reduced LRP1, LDL receptor, and SREBP-2. When SREBP-2 in HepG2 cells was knocked down by small interfering RNA, the induction of LRP1 expression by atorvastatin did not take place. In conclusion, up-regulation of hepatic LRP1 might be a novel mechanism by which statin treatment decreases remnant lipoproteins. In addition, SREBP-2 acts as a mediator of atorvastatin-induced up-regulation of hepatic LRP1. Future studies using standard doses of atorvastatin in humans are needed to elucidate clinical relevance of these findings.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/93744
DOI
10.1016/j.metabol.2010.08.013
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Medical Research Center
1. 연구논문 > 1. College of Medicine > Dept. of Internal Medicine
Yonsei Authors
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Link
 http://www.sciencedirect.com/science/article/pii/S002604951000301X
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