Huuskonen Jarkko, Fielding Phoebe E, Fielding Christopher J
Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0130, USA.
Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):703-8. doi: 10.1161/01.ATV.0000121202.72593.da. Epub 2004 Feb 5.
Liver X receptor (LXR) is a member of a nuclear receptor family regulating the expression of several key proteins involved in lipid metabolism and inflammation. In contrast to several other nuclear receptors, very little is known about the coactivators needed for the agonist-mediated transactivation by LXR. In this study, we have investigated the role of p160 coactivator complex in the regulation of ATP-binding transporter A1 (ABCA1), a clinically important gene transcriptionally upregulated by LXR/RXR (retinoid X receptor) heterodimer.
Overexpression of LXRalpha, SRC-1, and p300, either alone or in combination, increased the luciferase activity driven by the wild-type ABCA1 promoter. The same coactivators bound to the ABCA1 promoter on oxysterol induction in chromatin immunoprecipitation assays. To the contrary, CARM-1 and P/CAF had no effect on ABCA1 transactivation, nor do they bind the promoter. When the DR-4 element was mutated from the ABCA1 promoter, only p300 was able to activate ABCA1 transcription in a ligand-independent manner.
The p160 coactivator complex members SRC-1 and p300, but not CARM-1 and P/CAF, coactivate LXR-mediated transcription of ABCA1 gene. In addition, p300 activates ABCA1 transcription independently of DR-4 element and LXR/RXR.
肝脏X受体（LXR）是核受体家族的成员，可调节参与脂质代谢和炎症的几种关键蛋白的表达。与其他几种核受体不同，对于LXR激动剂介导的反式激活所需的共激活因子知之甚少。在本研究中，我们研究了p160共激活因子复合物在ATP结合转运蛋白A1（ABCA1）调节中的作用，ABCA1是一种临床上重要的基因，由LXR/RXR（视黄酸X受体）异二聚体转录上调。
单独或联合过表达LXRα、SRC-1和p300均可增加野生型ABCA1启动子驱动的荧光素酶活性。在染色质免疫沉淀试验中，相同的共激活因子在氧化甾醇诱导下与ABCA1启动子结合。相反，CARM-1和P/CAF对ABCA1反式激活无影响，也不与启动子结合。当ABCA1启动子中的DR-4元件发生突变时，只有p300能够以不依赖配体的方式激活ABCA1转录。
p160共激活因子复合物成员SRC-1和p300可协同激活LXR介导的ABCA1基因转录，而CARM-1和P/CAF则不能。此外，p300可独立于DR-4元件和LXR/RXR激活ABCA1转录。
