The Selective Alzheimer's Disease Indicator-1 Gene (Seladin-1/DHCR24) Is a Liver X Receptor Target Gene
The Selective Alzheimer's Disease Indicator-1 Gene (Seladin-1/DHCR24) Is a Liver X Receptor Target Gene
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DOI：
10.1124/mol.108.048538
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发表时间：
2008-12-01
影响因子：
3.6
通讯作者：
Burris, Thomas P.
中科院分区：
文献类型：
--
作者：
Wang, Yongjun;Rogers, Pamela M.;Burris, Thomas P.
核激素受体肝X受体α（LXR α）和LXR β作为氧化胆固醇代谢物（氧化固醇）的生理受体发挥作用，并调节胆固醇和脂质代谢的几个方面。Seladin-1最初被鉴定为在与阿尔茨海默病相关的大脑区域中表达下调的基因。Seladin-1已被证明具有神经保护作用，后来被表征为3 β-羟基甾醇-Delta 24还原酶（DHCR 24），这是胆固醇生成途径中的关键酶。Seladin-1也被证明可以调节脂筏的形成。在直接LXR α靶基因的全基因组筛选中，我们在Seladin-1/DHCR 24基因的第二内含子内鉴定了LXR α占据位点。我们的特点是一个新的LXR反应元件内的第二内含子的这个基因，能够赋予LXR特异性配体的反应报告基因在HepG 2和人胚肾293细胞。此外，我们发现Seladin-1/DHCR 24基因表达在从LXR β-null小鼠分离的皮肤中显著降低。我们的数据表明，Seladin 1/DHCR 24是LXR的靶基因，LXR可能调节脂筏的形成。
The nuclear hormone receptors liver X receptor alpha (LXR alpha) and LXR beta function as physiological receptors for oxidized cholesterol metabolites (oxysterols) and regulate several aspects of cholesterol and lipid metabolism. Seladin-1 was originally identified as a gene whose expression was down-regulated in regions of the brain associated with Alzheimer's disease. Seladin-1 has been demonstrated to be neuroprotective and was later characterized as 3 beta-hydroxysterol-Delta 24 reductase (DHCR24), a key enzyme in the cholesterologenic pathway. Seladin-1 has also been shown to regulate lipid raft formation. In a whole genome screen for direct LXR alpha target genes, we identified an LXR alpha occupancy site within the second intron of the Seladin-1/DHCR24 gene. We characterized a novel LXR response element within the second intron of this gene that is able to confer LXR-specific ligand responsiveness to reporter gene in both HepG2 and human embryonic kidney 293 cells. Furthermore, we found that Seladin-1/DHCR24 gene expression is significantly decreased in skin isolated from LXR beta-null mice. Our data suggest that Seladin1/DHCR24 is an LXR target gene and that LXR may regulate lipid raft formation.