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

Jae Hoon Moon, Saet Byol Kang, Jong Suk Park, Byung Wan Lee, Eun Seok Kang, Chul Woo Ahn, Hyun Chul Lee, Bong Soo Cha

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)930-940
Number of pages11
JournalMetabolism: Clinical and Experimental
Volume60
Issue number7
DOIs
Publication statusPublished - 2011 Jul 1

Fingerprint

Low Density Lipoprotein Receptor-Related Protein-1
Lipoprotein Receptors
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Sterols
Oxidoreductases
Up-Regulation
Hep G2 Cells
Response Elements
Liver
Carrier Proteins
Proteins
Sprague Dawley Rats
Inbred OLETF Rats
High Fat Diet
Apolipoproteins E
Atorvastatin Calcium
LDL Lipoproteins
Small Interfering RNA
Lipoproteins
Culture Media

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

@article{7b13cbac4a21486aaeebc39640218981,
title = "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",
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.",
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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. / Moon, Jae Hoon; Kang, Saet Byol; Park, Jong Suk; Lee, Byung Wan; Kang, Eun Seok; Ahn, Chul Woo; Lee, Hyun Chul; Cha, Bong Soo.

In: Metabolism: Clinical and Experimental, Vol. 60, No. 7, 01.07.2011, p. 930-940.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Up-regulation of hepatic low-density lipoprotein receptor-related protein 1

T2 - A possible novel mechanism of antiatherogenic activity of hydroxymethylglutaryl-coenzyme A reductase inhibitor: Atorvastatin and hepatic LRP1 expression

AU - Moon, Jae Hoon

AU - Kang, Saet Byol

AU - Park, Jong Suk

AU - Lee, Byung Wan

AU - Kang, Eun Seok

AU - Ahn, Chul Woo

AU - Lee, Hyun Chul

AU - Cha, Bong Soo

PY - 2011/7/1

Y1 - 2011/7/1

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