A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytes
A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytes
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DOI：
10.1111/j.1471-4159.2004.02183.x
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发表时间：
2004-02-01
影响因子：
4.7
通讯作者：
Paul, SM
中科院分区：
文献类型：
--
作者：
Liang, Y;Lin, SZ;Paul, SM
载脂蛋白E （apoE）是参与脂蛋白清除和胆固醇再分配的重要蛋白。ApoE在大脑星形胶质细胞中大量表达，与阿尔茨海默病（AD）的发病机制密切相关。我们在此报告了激活肝X受体（LXR）或类视黄醇X受体（RXR）的小分子配体导致人类星形细胞瘤细胞系（CCF-STTG1细胞）中apoE mRNA和蛋白表达以及apoE分泌的急剧增加。小鼠原代星形胶质细胞的检测也显示，在LXR/RXR激动剂孵育后，apoE mRNA和蛋白质的表达和分泌显著诱导。此外，用特异性合成LXR激动剂T0901317处理小鼠后，海马和大脑皮层的apoE mRNA和蛋白均上调，表明LXR激动剂在体内可上调脑内apoE的表达。随着ABCA1胆固醇转运蛋白表达的显著诱导，这些配体在载脂蛋白AI （apoAI）存在或不存在的情况下，都能有效地介导CCF-STTG1细胞和小鼠星形胶质细胞中的胆固醇外排。我们的研究提供了强有力的证据，证明小分子LXR/RXR激动剂可以有效地介导星形胶质细胞中apoE的合成和分泌以及胆固醇的稳态。LXR/RXR激动剂可能对包括AD在内的多种神经系统疾病的发病机制有重要影响。
Apolipoprotein E (apoE) is an important protein involved in lipoprotein clearance and cholesterol redistribution. ApoE is abundantly expressed in astrocytes in the brain and is closely linked to the pathogenesis of Alzheimer's disease (AD). We report here that small molecule ligands that activate either liver X receptors (LXR) or retinoid X receptor (RXR) lead to a dramatic increase in apoE mRNA and protein expression as well as secretion of apoE in a human astrocytoma cell line (CCF-STTG1 cells). Examination of primary mouse astrocytes also revealed significant induction of apoE mRNA, and protein expression and secretion following incubation with LXR/RXR agonists. Moreover, treatment of mice with a specific synthetic LXR agonist T0901317 resulted in up-regulation of apoE mRNA and protein in both hippocampus and cerebral cortex, indicating that apoE expression in brain can be up-regulated by LXR agonists in vivo. Along with a dramatic induction of ABCA1 cholesterol transporter expression, these ligands effectively mediate cholesterol efflux in both CCF-STTG1 cells and mouse astrocytes in the presence or absence of apolipoprotein AI (apoAI). Our studies provide strong evidence that small molecule LXR/RXR agonists can effectively mediate apoE synthesis and secretion as well as cholesterol homeostasis in astrocytes. LXR/RXR agonists may have significant impact on the pathogenesis of multiple neurological diseases, including AD.