Abstract
ATP-binding cassette transporter A1 (ABCA1) is a pivotal regulator of cholesterol efflux from cells to apolipoproteins, whereas sterol-responsive element-binding protein 2 (SREBP2) is the key protein regulating cholesterol synthesis and uptake. We investigated the regulation of ABCA1 by SREBP2 in vascular endothelial cells (ECs). Our results showed that sterol depletion activated SREBP2 and increased its target, low density lipoprotein receptor mRNA, with a concurrent decrease in the ABCA1 mRNA. Transient transfection analysis revealed that sterol depletion decreased the ABCA1 promoter activity by 50%, but low density lipoprotein receptor promoter- and the sterol-responsive element-driven luciferase activities were increased. Overexpression of the N terminus of SREBP2 (SREBP2(N)), an active form of SREBP2, also inhibited the ABCA1 promoter activity. Functionally adenovirus-mediated SREBP2(N) expression increased cholesterol accumulation and decreased apoA-I-mediated cholesterol efflux. The conserved E-box motif was responsible for the SREBP2(N)-mediated inhibition since mutation of the E-box increased the basal activity of the ABCA1 promoter and abolished the inhibitory effect of SREBP2(N). Furthermore sterol depletion and SREBP2(N) overexpression induced the binding of SREBP2(N) to both consensus and ABCA1-specific E-box. Chromatin immunoprecipitation assay demonstrated that serum starvation enhanced the association of SREBP2 and the ABCA1 promoter in ECs. To correlate this mechanism pathophysiologically, we found that oscillatory flow caused the activation of SREBP2 and therefore attenuated ABCA1 promoter activity in ECs. Thus, this SREBP-regulated mechanism may control the efflux of cholesterol, which is a newly defined function of SREBP2 in ECs in addition to its role in cholesterol uptake and biosynthesis.
Highlights
ATP-binding cassette transporter A1 (ABCA1) is a pivotal regulator of cholesterol efflux from cells to apolipoproteins, whereas sterol-responsive element-binding protein 2 (SREBP2) is the key protein regulating cholesterol synthesis and uptake
Results from transient transfection assays showed that SFM decreased the luciferase reporter driven by the ABCA1 promoter by 49 Ϯ 6% compared with cells under 20% fetal bovine serum (FBS) (Fig. 1C)
In the present study we reported that the binding of SREBP2(N) to E-box motif within the hABCA1 promoter is responsible for the repressive effect of serum deprivation and oscillatory flow on the expression of ABCA1 in endothelial cells (ECs)
Summary
ATP-binding cassette transporter A1 (ABCA1) is a pivotal regulator of cholesterol efflux from cells to apolipoproteins, whereas sterol-responsive element-binding protein 2 (SREBP2) is the key protein regulating cholesterol synthesis and uptake. Our results showed that sterol depletion activated SREBP2 and increased its target, low density lipoprotein receptor mRNA, with a concurrent decrease in the ABCA1 mRNA. Sterol-responsive element-binding proteins (SREBPs), including SREBP1a, -1c, and -2, modulate the transcription of a number of genes involved in the synthesis and receptor-mediated uptake of cholesterol and fatty acids [13,14,15]. Given the important role of SREBP2 and ABCA1 in cholesterol homeostasis and the significance of cholesterol traffic in the vessel wall, we investigated the regulation of ABCA1 by SREBP2 in ECs. Our results showed that, by binding to the E-box, SREBP2 could inhibit ABCA1 transcription. This SREBP-regulated mechanism controlling cholesterol efflux is a newly defined function of SREBP2 in the vascular wall
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