ATP-Binding Cassette Transporter A1 Gene Transcription Is Downregulated by Activator Protein 2α

ATP-binding cassette transporter A1 (ABCA1) is a rate-limiting factor for high-density lipoprotein (HDL) biogenesis. The ABCA1 gene expression is known to be upregulated by various transcriptional factors. However, negative regulation factors would be better targets for pharmacological modulation of HDL biogenesis. Doxazosin, an α1-adrenoceptor blocker, increased ABCA1 mRNA, its protein, and apolipoprotein A-I–mediated HDL biogenesis in THP-1 macrophages and CHO-K1 cells, independent of α1-adrenoceptor blockade. Analysis of the human ABCA1 promoter indicated that the region between the positions −368 and −147 that contains an activator protein (AP)2-binding site responsible for the effects of doxazosin. Overexpression of AP2α inhibited ABCA1 transcription in a dose-dependent fashion. Mutation in the AP2-binding site caused increase of the basal promoter activity and canceling both the transactivation by doxazosin and the trans-repression by AP2α. Doxazosin had no effect on ABCA1 mRNA level in HepG2 cells,...