Transcriptional regulatory networks in lipid metabolism control ABCA1 expression

The ATP-binding cassette transporters, ABCA1 and ABCG1, are major players in mediating cellular efflux of phospholipids and cholesterol to apoA-I containing lipoproteins including prebeta-HDL and alphaHDL and thereby exert important antiatherogenic properties. Although the exact mechanisms how ABC transporters mediate lipid transport are not completely resolved, recent evidence from several laboratories including ours suggests that vesicular transport processes involving different interactive proteins like beta2-syntrophin, alpha1-syntrophin, Lin7, and cdc42 are critically involved in cellular lipid homeostasis controlled by ABCA1 and ABCG1. Besides sterols and fatty acids as known physiological modulators of the LXR/RXR and SREBP pathways, a growing list of natural and synthetic substances and metabolic regulators such as retinoids, PPAR-ligands, hormones, cytokines, and drugs are particularly effective in modulating ABCA1 and ABCG1 gene expression. Although ABCA1 protein amounts are regulated at the level of stability, the majority of potent activating and repressing mechanisms on ABCA1 function directly act on the ABCA1 gene promoter. Among the inducing factors, liver-X-receptors (LXR), retinoic acid receptors (RAR) and peroxisome proliferator-activated receptors (PPARs) along with their coactivators provide an amplification loop for ABCA1 and ABCG1 expression. The ABCA1 promoter is further stimulated by the ubiquitous factor Sp1 and the hypoxia-induced factor 1 (HIF1), which bind to GC-boxes and the E-box, respectively. Shutdown of ABCA1 expression in the absence of sterols or in certain tissues is mediated by corepressor complexes involving unliganded LXR, sterol-regulatory element binding protein 2 (SREBP2), Sp3, and the SCAN-domain protein ZNF202, which also impacts nuclear receptor signaling. Thus, a highly sophisticated transcriptional network controls the balanced expression of ABCA1.