MiR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression.
MiR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression.
复制标题
DOI：
10.1016/j.expneurol.2011.11.010
复制
发表时间：
2012-06
影响因子：
5.3
通讯作者：
Kim, Jungsu
中科院分区：
文献类型：
--
作者：
Kim, Jaekwang;Yoon, Hyejin;Ramirez, Cristina M.;Lee, Sang-Mi;Hoe, Hyang-Sook;Fernandez-Hernando, Carlos;Kim, Jungsu
atp结合盒转运蛋白A1 （ABCA1）是一种胆固醇转运蛋白，可将多余的细胞胆固醇转移到脂质贫乏的载脂蛋白上。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。肝脏X受体对ABCA1的转录调控已被很好地表征。然而，ABCA1表达是否在转录后水平受到调控在很大程度上是未知的。ABCA1表达调控新途径的发现可能为调节胆固醇代谢和β淀粉样蛋白（a β）水平提供新的策略。由于ABCA1具有异常长的3 '非翻译区，我们研究了microrna是否可以调节ABCA1的表达。我们发现miR-106b是ABCA1表达和a β代谢的一种新的调节因子。miR-106b显著降低ABCA1水平和神经元细胞胆固醇外排受损。此外，miR-106b通过增加Aβ产生和阻止Aβ清除显著增加分泌的Aβ水平。通过mir -106b耐药ABCA1的表达挽救了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表达来影响Aβ代谢。
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.
登录
查看更多内容
影响因子：
16.2
作者：
Kim, Jungsu;Basak, Jacob M.;Holtzman, David M.
通讯作者：
Holtzman, David M.
DOI：
10.1523/jneurosci.5491-10.2011
发表时间：
2011-02-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kanekiyo T;Zhang J;Liu Q;Liu CC;Zhang L;Bu G
通讯作者：
Bu G
DOI：
10.1073/pnas.0710263105
发表时间：
2008-04-29
影响因子：
11.1
作者：
Hebert, Sebastien S.;Horre, Katrien;De Strooper, Bart
通讯作者：
De Strooper, Bart
DOI：
10.1073/pnas.1017576108
发表时间：
2011-07-12
影响因子：
11.1
作者：
Cohen, Jonathan E.;Lee, Philip R.;Fields, R. Douglas
通讯作者：
Fields, R. Douglas
影响因子：
14.9
作者：
Betel D;Wilson M;Gabow A;Marks DS;Sander C
通讯作者：
Sander C