ABCA1-dependent but apoA-I-independent cholesterol efflux mediated by fatty acid-bile acid conjugates (FABACs).
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 (3beta-arachidylamido-7alpha,12alpha,5beta-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.
Goldiner
Ilana
I
AMC Liver Centre, Academic Medical Centre, Amsterdam, The Netherlands.
van der Velde
Astrid E
AE
Vandenberghe
Kristin E
KE
van Wijland
Michel A
MA
Halpern
Zamir
Z
Gilat
Tuvia
T
Konikoff
Fred M
FM
Veldman
Robert Jan
RJ
Groen
Albert K
AK
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D016632:Apolipoprotein A-I / Q000502:physiology*; D016718:Arachidonic Acid / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002499:Centrifugation, Density Gradient; D002784:Cholesterol / Q000378:metabolism*; D002793:Cholic Acids; D004268:DNA-Binding Proteins / Q000819:agonists; D005227:Fatty Acids / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010743:Phospholipids / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D013268:Stimulation, Chemical; D013449:Sulfonamides / Q000494:pharmacology; D013631:Tangier Disease / Q000503:physiopathology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D016718:Arachidonic Acid; D001647:Bile Acids and Salts; D002784:Cholesterol; D002793:Cholic Acids; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010743:Phospholipids; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C577836:ABCA1 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C455117:aramchol