Tamehiro Norimasa, Shigemoto-Mogami Yukari, Kakeya Tomoshi, Okuhira Kei-Ichiro, Suzuki Kazuhiro, Sato Ryuichiro, Nagao Taku, Nishimaki-Mogami Tomoko
Division of Biosignaling, National Institute of Health Sciences, Tokyo 158-8501, Japan and Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
J Biol Chem. 2007 Jul 20;282(29):21090-9. doi: 10.1074/jbc.M701228200. Epub 2007 May 27.
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.
ABC转运蛋白A1（ABCA1）介导并限制高密度脂蛋白（HDL）的生物合成，肝脏中的ABCA1在调节血浆HDL水平中起主要作用。HDL的生成也负责细胞胆固醇的释放。在周围细胞中，当细胞胆固醇增加时，ABCA1会被肝脏X受体（LXR）系统上调。然而，胆固醇喂养未能使肝脏ABCA1基因表达显著增加，其表达却被他汀类药物（3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂）上调，提示存在不同的调节机制。在本研究中，我们研究了大鼠肝脏ABCA1基因的调节机制，鉴定出两种主要的ABCA1转录本和两个相应的启动子区域。康帕丁通过与固醇调节元件结合蛋白-2（SREBP-2）结合，激活了大鼠肝癌McARH7777细胞中的新型肝型启动子。相反，康帕丁以LXR反应元件依赖而非E盒依赖的方式抑制先前鉴定的外周型启动子。因此，康帕丁增加了肝型转录本并减少了外周型转录本。相同的两种转录本在人和小鼠肝脏中也占主导地位，而肠道仅含有外周型转录本。用普伐他汀和胆汁酸结合树脂（考来替胺）治疗大鼠，已知后者可激活肝脏中的SREBP-2，导致肝脏胆固醇水平降低以及体内相同的差异反应，从而使肝脏ABCA1 mRNA和蛋白以及血浆HDL水平升高。我们得出结论，由SREBP-2和LXR驱动的双启动子系统调节肝脏ABCA1的表达，并可能介导肝脏ABCA1基因表达对细胞胆固醇状态的独特反应。
