ACAT1 regulates the dynamics of free cholesterols in plasma membrane which leads to the APP-α-processing alteration.
ACAT1 regulates the dynamics of free cholesterols in plasma membrane which leads to the APP-α-processing alteration.
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DOI：
10.1093/abbs/gmv101
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发表时间：
2015-12
影响因子：
3.7
通讯作者：
M. Zhu;Xiaonan Zhao;Jia Chen;Jiajia Xu;Guangjing Hu;Dongqing Guo;Qin Li;Xiaowei Zhang;C. Chang;B. Song;Ying Xiong;Ta-Yuan Chang;Bo-Liang Li
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文献类型：
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作者：
M. Zhu;Xiaonan Zhao;Jia Chen;Jiajia Xu;Guangjing Hu;Dongqing Guo;Qin Li;Xiaowei Zhang;C. Chang;B. Song;Ying Xiong;Ta-Yuan Chang;Bo-Liang Li
酰辅酶A：胆固醇酰基转移酶1(ACAT1)是细胞内唯一以游离胆固醇为底物的关键酶，参与细胞内胆固醇的稳态。在本研究中，我们以人神经母细胞瘤细胞系SK-N-SH为模型，首次观察到抑制ACAT1可以减少淀粉样前体蛋白(APP)的α加工。同时，用ACAT1的小干扰RNA和表达载体进行的转染实验表明，ACAT1可以依赖地影响APP-α的加工。此外，抑制ACAT1可以增加质膜中的游离胆固醇(PM-FC)，并且抑制ACAT1导致的PM-FC的增加可以导致APP-α加工的减少，这表明ACAT1调节PM-FC的动力学，从而导致APP-α加工的改变。更重要的是，进一步的结果表明，在ACAT1抑制下，PM-Fc和随后的APP-α-加工的变化不依赖于细胞总胆固醇水平，证实了ACAT1调节PM-Fc的动力学。最后，我们发现，即使当Niemann-Pick-C型依赖途径被阻断时，ACAT1抑制仍然明显导致PM-FC增加，表明ACAT1依赖的途径负责PM-FC向细胞内池的穿梭。我们的数据提供了一种新的见解，即ACAT1可能在人神经细胞中发挥重要作用，它在酶促调节PM-Fc的动态过程中可能发挥着重要作用。
Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) is a key enzyme exclusively using free cholesterols as the substrates in cell and is involved in the cellular cholesterol homeostasis. In this study, we used human neuroblastoma cell line SK-N-SH as a model and first observed that inhibiting ACAT1 can decrease the amyloid precursor protein (APP)-α-processing. Meanwhile, the transfection experiments using the small interfering RNA and expression plasmid of ACAT1 indicated that ACAT1 can dependently affect the APP-α-processing. Furthermore, inhibiting ACAT1 was found to increase the free cholesterols in plasma membrane (PM-FC), and the increased PM-FC caused by inhibiting ACAT1 can lead to the decrease of the APP-α-processing, indicating that ACAT1 regulates the dynamics of PM-FC, which leads to the alteration of the APP-α-processing. More importantly, further results showed that under the ACAT1 inhibition, the alterations of the PM-FC and the subsequent APP-α-processing are not dependent on the cellular total cholesterol level, confirming that ACAT1 regulates the dynamics of PM-FC. Finally, we revealed that even when the Niemann-Pick-Type C-dependent pathway is blocked, the ACAT1 inhibition still obviously results in the PM-FC increase, suggesting that the ACAT1-dependent pathway is responsible for the shuttling of PM-FC to the intracellular pool. Our data provide a novel insight that ACAT1 which enzymatically regulates the dynamics of PM-FC may play important roles in the human neuronal cells.