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

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43 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

Bibliographical note

Funding Information:
This work was supported by a National Research Foundation grant funded by the Korea government (MEST) ( 2009-0091380 ).

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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