Unsaturated fatty acids suppress the expression of the ATP-binding cassette transporter G1 (ABCG1) and ABCA1 genes via an LXR/RXR responsive element

Abstract 

ATP-binding cassette transporters (ABC) G1 and ABCA1 are membrane cholesterol transporters and have been implicated to mediate cholesterol efflux from cells in the presence of high density lipoproteins and its major protein constituent apolipoprotein A-I, respectively. We previously demonstrated that unsaturated fatty acids suppress the stimulatory effects of oxysterols and retinoids on ABCA1 gene transcription. We here demonstrate that unsaturated fatty acids significantly suppress the stimulatory effects of oxysterols and retinoids on the expression of ABCG1 mRNA and protein and the activity of the wild-type human ABCG1 promoter as well as ABCA1. Mutation or deletion of the DR4 element within the ABCG1 or ABCA1 promoters, to which the transcriptional inducers LXR and RXR bind, abolished the suppressive effects of unsaturated fatty acids. Our observations provide the first evidence that unsaturated fatty acids suppress ABCG1 gene expression by a mechanism which involves the binding of LXR/RXR to the promoters. Suppression of both the ABCA1 and ABCG1 genes may indicate that unsaturated fatty acids suppress not only cholesterol efflux to apoA-I and thereby nascent HDL formation but also HDL-dependent cholesterol efflux from vascular cells.

Abbreviations: ABC, ATP-binding cassette transporter, apo, apolipoprotein, ATP, adenosine triphosphate, BSA, bovine serum albumin, CETP, cholesterol ester transfer protein, CYP7A, 7α-hydroxylase, DR4, direct repeat 4, EPA, eicosapentaenoic acid, LA, linoleic acid, AraA, arachidonic acid, OA, oleic acid, PA, palmitic acid, SA, stearic acid, HDL, high density lipoprotein, LXRα, liver-X-receptor alpha, LXRβ, liver-X-receptor beta, RXRα, retinoid-X-receptor alpha, USFA, unsaturated fatty acid, TG, triglyceride, 9-cis-RA, 9-cis retinoic acid, 22R-HC, 22(R)-hydroxycholesterol

Keywords: ATP-binding cassette transporter, Cholesterol transport, Diabetes, Unsaturated fatty acid, Highdensity lipoprotein, LXR, RXR, Direct repeat 4