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.
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.
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Jae Hoon
JH
Moon
Saet Byol
SB
Kang
Jong Suk
JS
Park
Byung Wan
BW
Lee
Eun Seok
ES
Kang
Chul Woo
CW
Ahn
Hyun Chul
HC
Lee
Bong Soo
BS
Cha
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism*; D000069059:Atorvastatin; D004041:Dietary Fats / Q000009:adverse effects; D056945:Hep G2 Cells; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000096:biosynthesis*; D011758:Pyrroles / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism; D015854:Up-Regulation
D015703:Antigens, CD; D004041:Dietary Fats; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C475476:LRP1 protein, human; D008077:Lipoproteins, LDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011758:Pyrroles; D034741:RNA, Small Interfering; C497390:SREBF2 protein, human; C470194:Srebf2 protein, rat; D051782:Sterol Regulatory Element Binding Protein 2; D051779:Sterol Regulatory Element Binding Proteins; D000069059:Atorvastatin