ABC transporter A1 (ABCA1) mediates and rate-limits biogenesis of high density lipoprotein (HDL), and hepatic ABCA1 plays a major role in regulating plasma HDL levels. HDL generation is also responsible for release of cellular cholesterol. In peripheral cells ABCA1 is up-regulated by the liver X receptor (LXR) system when cell cholesterol increases. However, cholesterol feeding has failed to show a significant increase in hepatic ABCA1 gene expression, and its expression is up-regulated by statins (3-hydroy-3-methylglutaryl-CoA reductase inhibitors), suggesting distinct regulation. In this study we investigated the mechanism of regulation of the rat hepatic ABCA1 gene and identified two major ABCA1 transcripts and two corresponding promoter regions. Compactin activated the novel liver-type promoter in rat hepatoma McARH7777 cells by binding the sterol regulatory element-binding protein-2 (SREBP-2). In contrast, compactin repressed the previously identified peripheral-type promoter in an LXR-responsive element-dependent but not E-box-dependent manner. Thus, compactin increased the liver-type transcript and decreased the peripheral-type transcript. The same two transcripts were also dominant in human and mouse livers, whereas the intestine contains only the peripheral-type transcript. Treatment of rats with pravastatin and a bile acid binding resin (colestimide), which is known to activate SREBP-2 in the liver, caused a reduction in the hepatic cholesterol level and the same differential responses in vivo, leading to increases in hepatic ABCA1 mRNA and protein and plasma HDL levels. We conclude that the dual promoter system driven by SREBP-2 and LXR regulates hepatic ABCA1 expression and may mediate the unique response of hepatic ABCA1 gene expression to cellular cholesterol status. High density lipoprotein (HDL)2 is thought to be antiatherogenic because plasma levels are negatively correlated with cardiovascular risk and because it removes cholesterol accumulated in cells in vitro (1, 2). HDL is assembled from a helical apolipoprotein and cellular cholesterol and phospholipid by a reaction mediated by ABC transporter A1 (ABCA1) (3, 4). The absence of functional ABCA1 in Tangier disease and in knock-out mice results in deficiency of plasma HDL, indicating the essential role of ABCA1 in HDL biogenesis (5, 6).Recent studies have shown the most important role of hepatic ABCA1 in maintaining plasma HDL levels. Selective knockdown of hepatic ABCA1 in mice causes a substantial (up to 80%) decrease in plasma HDL cholesterol (7,8), and overexpression of hepatic ABCA1 raises HDL cholesterol levels (9, 10).In peripheral cells, such as macrophages and fibroblasts, ABCA1 gene expression is up-regulated by loading cholesterol (11,12). This response is mediated by cholesterol-sensing nuclear receptor liver X receptor (LXR), which directly enhances ABCA1 gene expression, facilitating the release of excess cellular cholesterol by increasing the biogenesis of HDL particles (13, 14). In contrast, cholesterol feeding of mice or rats...
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