Abildayeva Karlygash, Jansen Paula J, Hirsch-Reinshagen Veronica, Bloks Vincent W, Bakker Arjen H F, Ramaekers Frans C S, de Vente Jan, Groen Albert K, Wellington Cheryl L, Kuipers Folkert, Mulder Monique
Department of Molecular Cell Biology, Institute of Brain and Behavior (European Graduate School of Neuroscience, EURON), University of Maastricht, 6200 MD Maastricht, The Netherlands.
J Biol Chem. 2006 May 5;281(18):12799-808. doi: 10.1074/jbc.M601019200. Epub 2006 Mar 8.
Both apolipoprotein E (apoE) and 24(S)-hydroxycholesterol are involved in the pathogenesis of Alzheimer disease (AD). It has been hypothesized that apoE affects AD development via isoform-specific effects on lipid trafficking between astrocytes and neurons. However, the regulation of the cholesterol supply of neurons via apoE-containing high density lipoproteins remains to be clarified. We show for the first time that the brain-specific metabolite of cholesterol produced by neurons, i.e. 24(S)-hydroxycholesterol, induces apoE transcription, protein synthesis, and secretion in a dose- and time-dependent manner in cells of astrocytic but not of neuronal origin. Moreover, 24(S)-hydroxycholesterol primes astrocytoma, but not neuroblastoma cells, to mediate cholesterol efflux to apoE. Similar results were obtained using the synthetic liver X receptor (LXR) agonist GW683965A, suggesting involvement of an LXR-controlled signaling pathway. A 10-20-fold higher basal LXRalpha and -beta expression level in astrocytoma compared with neuroblastoma cells may underlie these differential effects. Furthermore, apoE-mediated cholesterol efflux from astrocytoma cells may be controlled by the ATP binding cassette transporters ABCA1 and ABCG1, since their expression was also up-regulated by both compounds. In contrast, ABCG4 seems not to be involved, because its expression was induced only in neuronal cells. The expression of sterol regulatory element-binding protein (SREBP-2), low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and SREBP-1c was transiently up-regulated by GW683965A in astrocytes but down-regulated by 24(S)-hydroxycholesterol, suggesting that cholesterol efflux and synthesis are regulated independently. In conclusion, evidence is provided that 24(S)-hydroxycholesterol induces apoE-mediated efflux of cholesterol in astrocytes via an LXR-controlled pathway, which may be relevant for chronic and acute neurological diseases.
载脂蛋白E（apoE）和24（S）-羟基胆固醇均参与阿尔茨海默病（AD）的发病机制。据推测，apoE通过对星形胶质细胞和神经元之间脂质转运的亚型特异性作用影响AD的发展。然而，通过含apoE的高密度脂蛋白对神经元胆固醇供应的调节仍有待阐明。我们首次表明，神经元产生的胆固醇脑特异性代谢物，即24（S）-羟基胆固醇，以剂量和时间依赖性方式诱导星形胶质细胞而非神经元来源的细胞中的apoE转录、蛋白质合成和分泌。此外，24（S）-羟基胆固醇使星形细胞瘤而非神经母细胞瘤细胞引发胆固醇外流至apoE。使用合成肝X受体（LXR）激动剂GW683965A获得了类似结果，表明涉及LXR控制的信号通路。与神经母细胞瘤细胞相比，星形细胞瘤中基础LXRα和-β表达水平高10至20倍可能是这些差异效应的基础。此外，apoE介导的星形细胞瘤细胞胆固醇外流可能受ATP结合盒转运蛋白ABCA1和ABCG1控制，因为它们的表达也被这两种化合物上调。相比之下，ABCG4似乎不参与，因为其表达仅在神经元细胞中被诱导。固醇调节元件结合蛋白（SREBP-2）、低密度脂蛋白受体、3-羟基-3-甲基戊二酰辅酶A还原酶和SREBP-1c的表达在星形胶质细胞中被GW683965A短暂上调，但被24（S）-羟基胆固醇下调，表明胆固醇外流和合成是独立调节的。总之，有证据表明24（S）-羟基胆固醇通过LXR控制的途径诱导星形胶质细胞中apoE介导的胆固醇外流，这可能与慢性和急性神经疾病有关。
