Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor.
Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor.
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DOI：
10.1074/jbc.m003337200
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发表时间：
2000-09
期刊：
影响因子：
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通讯作者：
P. Costet;Yi Luo;Nan Wang;A. Tall
中科院分区：
文献类型：
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作者：
P. Costet;Yi Luo;Nan Wang;A. Tall
丹吉尔病是一种以巨噬细胞中高密度脂蛋白和胆固醇积累水平低为特征的疾病，由atp结合盒转运体ABC1突变引起。在体外培养的巨噬细胞中，22(R)-羟基胆固醇和9-顺式维甲酸（9CRA）以加性方式诱导ABC1 mRNA，提示其受肝X受体（LXR）和类维甲酸X受体（RXR）家族核激素受体的诱导。我们从装载胆固醇的THP1巨噬细胞中克隆了人类ABC1转录物的5'端。转染RAW巨噬细胞后，上游启动子被22(R)-羟胆固醇诱导7倍，被9CRA诱导8倍，被9CRA和22(R)-羟胆固醇诱导37倍。此外，当与lxrα /RXR或lxrβ /RXR共转染时，启动子活性以甾醇响应的方式增加。进一步的实验确定了lxrα /RXR或lxrβ /RXR的结合位点，其直接重复序列间隔为4个核苷酸（从-70到-55碱基对）。该元件的突变消除了甾醇介导的启动子激活。结果显示LXR/RXR对ABC1启动子的甾醇依赖性转激活，提示LXR的小分子激动剂可能是逆转泡沫细胞形成和动脉粥样硬化的有用药物。
Tangier disease, a condition characterized by low levels of high density lipoprotein and cholesterol accumulation in macrophages, is caused by mutations in the ATP-binding cassette transporter ABC1. In cultured macrophages, ABC1 mRNA was induced in an additive fashion by 22(R)-hydroxycholesterol and 9-cis-retinoic acid (9CRA), suggesting induction by nuclear hormone receptors of the liver X receptor (LXR) and retinoid X receptor (RXR) family. We cloned the 5'-end of the human ABC1 transcript from cholesterol-loaded THP1 macrophages. When transfected into RAW macrophages, the upstream promoter was induced 7-fold by 22(R)-hydroxycholesterol, 8-fold by 9CRA, and 37-fold by 9CRA and 22(R)-hydroxycholesterol. Furthermore, promoter activity was increased in a sterol-responsive fashion when cotransfected with LXRalpha/RXR or LXRbeta/RXR. Further experiments identified a direct repeat spaced by four nucleotides (from -70 to -55 base pairs) as a binding site for LXRalpha/RXR or LXRbeta/RXR. Mutations in this element abolished the sterol-mediated activation of the promoter. The results show sterol-dependent transactivation of the ABC1 promoter by LXR/RXR and suggest that small molecule agonists of LXR could be useful drugs to reverse foam cell formation and atherogenesis.