Regulation of the angiopoietin-like protein 3 gene by LXR
Regulation of the angiopoietin-like protein 3 gene by LXR
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DOI：
10.1194/jlr.m200367-jlr200
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发表时间：
2003-01-01
影响因子：
6.5
通讯作者：
Cai, TQ
中科院分区：
文献类型：
--
作者：
Kaplan, R;Zhang, T;Cai, TQ
血管生成素是血管内皮生长因子家族的成员之一，最近发现血管生成素样蛋白3(Angptl3)主要在肝脏表达，在调节脂质代谢中发挥重要作用。在这项研究中，我们证明了Angptl3基因是肝脏X受体(LXR)的直接靶点。喂食高胆固醇饮食的小鼠肝脏中Angptl3的表达显著增加。给小鼠口服T0901317，一种合成的LXR选择性激动剂，可以提高血脂水平和肝脏中Angptl3的mRNA水平。用LXR选择性激动剂处理HepG2细胞后，Angptl3mRNA的表达呈剂量依赖性增加。对Angptl3转录起始点5‘端DNA序列的分析表明，存在几个潜在的转录因子结合位点，包括LXR的结合位点。当将Angptl3基因导入HepG2细胞后，其启动子活性可被LXR或维甲酸X受体选择性激动剂显著诱导。预测的LXR结合位点(DR4元件)的突变完全取消了LXR激动剂介导的启动子的激活。综上所述，这些研究表明，Angptl3受LXR转录调控，并揭示了LXR调节脂代谢的新机制。
Angiopoietins are members of the vascular endothelial growth factor family: One family member, angiopoietin-like protein 3 (Angptl3), was recently shown to be predominantly expressed in the liver and to play an important role in regulating lipid metabolism. In this study, we show that the Angptl3 gene is a direct target of the liver X receptor (LXR). Mice fed a high cholesterol diet exhibited a significant increase in Angptl3 expression in the liver. Oral administration to mice of T0901317, a synthetic LXR-selective agonist, increases levels of plasma lipids and Angptl3 mRNA in the liver. Treatment of HepG2 cells with LXR selective agonists led to a dose-dependent increase of Angptl3 mRNA. Analysis of the DNA sequence just 5' of the Angptl3 transcriptional start site revealed the presence of several potential transcription factor binding sites, including that for LXR. When transfected into HepG2 cells, the promoter activity of Angptl3 was significantly induced by LXR- or retinoid X receptor-selective agonists. Mutation of the predicted LXR binding site (DR4 element) completely abolished the LXR agonist-mediated activation of the promoter. EN Together, these studies show that Angptl3 is transcriptionally regulated by LXR, and reveals a novel mechanism by which LXR may regulate lipid metabolism.