Hypocholesterolemia, foam cell accumulation, but no atherosclerosis in mice lacking ABC-transporter A1 and scavenger receptor BI

Ying Zhao*, Marieke Pennings, Carlos L. J. Vrins, Laura Calpe-Berdiel, Menno Hoekstra, J. Kar Kruijt, Roelof Ottenhoff, Reeni B. Hildebrand, Ronald van der Sluis, Wendy Jessup, Wilfried Le Goff, M. John Chapman, Thierry Huby, Albert K. Groen, Theo J. C. Van Berkel, Miranda Van Eck

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

26 Citations (Scopus)

Abstract

High-density lipoprotein (HDL) mediated reverse cholesterol transport (RCT) is regarded to be crucial for prevention of foam cell formation and atherosclerosis. ABC-transporter A1 (ABCA1) and scavenger receptor BI (SR-BI) are involved in the biogenesis of HDL and the selective delivery of HDL cholesterol to the liver, respectively. In the present study, we phenotypically characterized mice lacking these two proteins essential for HDL metabolism. ABCA1 x SR-BI double knockout (dKO) mice showed severe hypocholesterolemia mainly due to HDL loss, despite a 90% reduction of HDL cholesterol uptake by liver. VLDL production was increased in dKO mice. However, non-HDL cholesterol levels were reduced, probably due to enhanced clearance via LRP1. Hepatobiliary cholesterol transport and fecal sterol excretion were not impaired in dKO mice. In contrast, the macrophage RCT in dKO mice was markedly impaired as compared to WT mice, associated with the accumulation of macrophage foam cells in the lung and Peyer's patches. Strikingly, no atherosclerotic lesion formation was observed in dKO mice. In conclusion, both ABCA1 and SR-BI are essential for maintaining a properly functioning HDL-mediated macrophage RCT, while the potential anti-atherosclerotic functions of ABCA1 and SR-BI are not evident in dKO mice due to the absence of pro-atherogenic lipoproteins. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)314-322
Number of pages9
JournalATHEROSCLEROSIS
Volume218
Issue number2
DOIs
Publication statusPublished - Oct-2011

Keywords

  • ABCA1
  • SR-BI
  • Reverse cholesterol transport
  • REVERSE CHOLESTEROL TRANSPORT
  • DENSITY-LIPOPROTEIN CHOLESTEROL
  • IN-VIVO
  • SR-BI
  • HDL-CHOLESTEROL
  • SELECTIVE UPTAKE
  • APOLIPOPROTEIN-E
  • DEFICIENT MICE
  • PLASMA
  • MACROPHAGE

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