Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
Exp Neurol. 2012 Jun;235(2):476-83. doi: 10.1016/j.expneurol.2011.11.010. Epub 2011 Nov 18.
ATP-binding cassette transporter A1 (ABCA1) is a cholesterol transporter that transfers excess cellular cholesterol onto lipid-poor apolipoproteins. Given its critical role in cholesterol homeostasis, ABCA1 has been studied as a therapeutic target for Alzheimer's disease. Transcriptional regulation of ABCA1 by liver X receptor has been well characterized. However, whether ABCA1 expression is regulated at the posttranscriptional level is largely unknown. Identification of a novel pathway that regulates ABCA1 expression may provide new strategy for regulating cholesterol metabolism and amyloid β (Aβ) levels. Since ABCA1 has an unusually long 3' untranslated region, we investigated whether microRNAs could regulate ABCA1 expression. We identified miR-106b as a novel regulator of ABCA1 expression and Aβ metabolism. miR-106b significantly decreased ABCA1 levels and impaired cellular cholesterol efflux in neuronal cells. Furthermore, miR-106b dramatically increased levels of secreted Aβ by increasing Aβ production and preventing Aβ clearance. Alterations in Aβ production and clearance were rescued by expression of miR-106b-resistant ABCA1. Taken together, our data suggest that miR-106b affects Aβ metabolism by suppressing ABCA1 expression.
三磷酸腺苷结合盒转运体 A1（ABCA1）是一种胆固醇转运蛋白，可将细胞内多余的胆固醇转移到脂质缺乏的载脂蛋白上。鉴于其在胆固醇稳态中的关键作用，ABCA1 已被研究作为阿尔茨海默病的治疗靶点。肝 X 受体对 ABCA1 的转录调控已得到很好的描述。然而，ABCA1 的表达是否在转录后水平受到调节在很大程度上尚不清楚。鉴定出调节 ABCA1 表达的新途径可能为调节胆固醇代谢和淀粉样蛋白 β（Aβ）水平提供新策略。由于 ABCA1 具有异常长的 3'非翻译区，我们研究了 microRNAs 是否可以调节 ABCA1 的表达。我们确定 miR-106b 是 ABCA1 表达和 Aβ代谢的新型调节因子。miR-106b 可显著降低神经元细胞中的 ABCA1 水平并损害细胞胆固醇外排。此外，miR-106b 通过增加 Aβ产生和阻止 Aβ清除来显著增加分泌型 Aβ的水平。ABCA1 的表达可挽救 Aβ 产生和清除的改变。综上所述，我们的数据表明，miR-106b 通过抑制 ABCA1 的表达来影响 Aβ 的代谢。
