Biochem. J. (2006) 396
(529–536) (Printed in Great Britain)
ABCA1-dependent but apoA-I-independent cholesterol efflux mediated by fatty acid–bile acid conjugates (FABACs)
Ilana GOLDINER*†1, Astrid E. VAN DER VELDE*1, Kristin E. VANDENBERGHE*, Michel A. VAN WIJLAND*, Zamir HALPERN†, Tuvia GILAT†, Fred M. KONIKOFF†‡, Robert Jan VELDMAN§ and Albert K. GROEN*2
*AMC Liver Centre, Academic Medical Centre, Amsterdam, The Netherlands, †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, and §Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands
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 (3b-arachidylamido-7a,12a,5b-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.
Key words: ATP-binding cassette transporter A1 (ABCA1), Aramchol, atherosclerosis, cholesterol efflux, fatty acid–bile acid conjugate (FABAC), reverse cholesterol transport.
Abbreviations used: ABCA1, ATP-binding cassette transporter A1; apoA-I, apolipoprotein A-I; Aramchol, 3b-arachidylamido-7a,12a,5b-cholan-24-oic acid; BCA, bicinchoninic acid; DMEM, Dulbecco's modified Eagle's medium; FABAC, fatty acid–bile acid conjugate; HDL, high-density lipoprotein; LDH, lactate dehydrogenase; LXR, liver X receptor; NHS, N-hydroxysuccinimide; PBST, PBS containing 0.05% (w/v) Tween 20; RCT, reverse cholesterol transport.
1These authors contributed equally to this work.
2To whom correspondence should be addressed (email a.k.groen@amc.uva.nl).
Received 19 October 2005/1 March 2006; accepted 7 March 2006
Published as BJ Immediate Publication 7 March 2006, doi:10.1042/BJ20051694
The Biochemical Society, London ©2006
Editorial Advisory Panel
RSS feeds
Table of contents by email
My BJ toolbox
