ABCA1-dependent but apoA-I-independent cholesterol efflux mediated by fatty acid-bile acid conjugates (FABACs)

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)529-536
Number of pages8
JournalBiochemical Journal
Volume396
Issue number3
DOIs
StatePublished - 15 Jun 2006

Keywords

  • ATP-binding cassette transporter A1 (ABCA1)
  • Aramchol
  • Atherosclerosis
  • Cholesterol efflux
  • Fatty acid-bile acid conjugate (FABAC)
  • Reverse cholesterol transport

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