FABACs (fatty acid–bile acid conjugates) are synthetic molecules that are designed to treat a range of lipid disorders. The compounds prevent cholesterol gallstone formation and diet-induced fatty liver, and increase reverse cholesterol transport in rodents. The aim of the present study was to investigate the effect of FABACs on cholesterol efflux in human cells. Aramchol (3β-arachidylamido-7α,12α,5β-cholan-24-oic acid) increased cholesterol efflux from human skin fibroblasts in a dose-dependent manner in the absence of known efflux mediators such as apoA-I (apolipoprotein A-I), but had little effect on phospholipid efflux. An LXR (liver X receptor) agonist strongly increased Aramchol-induced cholesterol efflux; however, in ABCA1 (ATP-binding cassette transporter A1)-deficient cells from Tangier disease patients, the Aramchol effect was absent, indicating that activity of ABCA1 was required. Aramchol did not affect ABCA1 expression, but plasma membrane levels of the transporter increased 2-fold. Aramchol is the first small molecule that induces ABCA1-dependent cholesterol efflux without affecting transcriptional control. These findings may explain the beneficial effect of the compound on atherosclerosis.
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Research Article|
May 29 2006
ABCA1-dependent but apoA-I-independent cholesterol efflux mediated by fatty acid–bile acid conjugates (FABACs)
Ilana Goldiner;
Ilana Goldiner
1
*AMC Liver Centre, Academic Medical Centre, Amsterdam, The Netherlands
†Department of Gastroenterology, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel
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Astrid E. van der Velde;
Astrid E. van der Velde
1
*AMC Liver Centre, Academic Medical Centre, Amsterdam, The Netherlands
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Kristin E. Vandenberghe;
Kristin E. Vandenberghe
*AMC Liver Centre, Academic Medical Centre, Amsterdam, The Netherlands
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Michel A. van Wijland;
Michel A. van Wijland
*AMC Liver Centre, Academic Medical Centre, Amsterdam, The Netherlands
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Zamir Halpern;
Zamir Halpern
†Department of Gastroenterology, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel
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Tuvia Gilat;
Tuvia Gilat
†Department of Gastroenterology, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel
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Fred M. Konikoff;
Fred M. Konikoff
†Department of Gastroenterology, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel
‡The Minerva Centre for Cholesterol Gallstones and Lipid Metabolism in the Liver, Tel Aviv University, Tel Aviv, Israel
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Robert Jan Veldman;
Robert Jan Veldman
§Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands
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Albert K. Groen
Albert K. Groen
2
*AMC Liver Centre, Academic Medical Centre, Amsterdam, The Netherlands
2To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
October 19 2005
Revision Received:
March 01 2006
Accepted:
March 07 2006
Accepted Manuscript online:
March 07 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 396 (3): 529–536.
Article history
Received:
October 19 2005
Revision Received:
March 01 2006
Accepted:
March 07 2006
Accepted Manuscript online:
March 07 2006
Citation
Ilana Goldiner, Astrid E. van der Velde, Kristin E. Vandenberghe, Michel A. van Wijland, Zamir Halpern, Tuvia Gilat, Fred M. Konikoff, Robert Jan Veldman, Albert K. Groen; ABCA1-dependent but apoA-I-independent cholesterol efflux mediated by fatty acid–bile acid conjugates (FABACs). Biochem J 15 June 2006; 396 (3): 529–536. doi: https://doi.org/10.1042/BJ20051694
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