Sterol regulatory element-binding protein-2-and liver X receptor-driven dual promoter regulation of hepatic ABC transporter A1 gene expression - Mechanism underlying the unique response to cellular cholesterol status
Sterol regulatory element-binding protein-2-and liver X receptor-driven dual promoter regulation of hepatic ABC transporter A1 gene expression - Mechanism underlying the unique response to cellular cholesterol status
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DOI：
10.1074/jbc.m701228200
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发表时间：
2007-07-20
影响因子：
4.8
通讯作者：
Nishimaki-Mogami, Tomoko
中科院分区：
文献类型：
--
作者：
Tamehiro, Norimasa;Shigemoto-Mogami, Yukari;Nishimaki-Mogami, Tomoko
ABC转运蛋白A1 （ABCA1）介导高密度脂蛋白（HDL）的生物生成并限制其速率，而肝脏ABCA1在调节血浆HDL水平中起主要作用。高密度脂蛋白的生成也负责细胞胆固醇的释放。在外周细胞中，当细胞胆固醇升高时，ABCA1被肝X受体（LXR）系统上调。然而，胆固醇喂养并未显示出肝脏ABCA1基因表达的显著增加，而他汀类药物（3-羟基-3-甲基戊二酰辅酶a还原酶抑制剂）上调了ABCA1基因的表达，表明其有明显的调控作用。在本研究中，我们研究了大鼠肝脏ABCA1基因的调控机制，并鉴定了两个主要的ABCA1转录本和两个相应的启动子区域。Compactin通过结合甾醇调节元件结合蛋白-2 （SREBP-2）激活大鼠肝癌McARH7777细胞中的新型肝型启动子。相比之下，紧实蛋白以lxr响应元件依赖而不是e -box依赖的方式抑制先前确定的外设型启动子。因此，紧致蛋白增加了肝型转录物，减少了外周型转录物。这两种转录本在人和小鼠的肝脏中也占主导地位，而在肠道中只含有外周型转录本。用普伐他汀和胆汁酸结合树脂（已知可激活肝脏中的SREBP-2）治疗大鼠，导致肝脏胆固醇水平降低，体内也有相同的差异反应，导致肝脏ABCA1 mRNA和蛋白质以及血浆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。
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.