24(S)-Hydroxycholesterol Induces Neuronal Cell Death through Necroptosis, a Form of Programmed Necrosis*
24(S)-Hydroxycholesterol Induces Neuronal Cell Death through Necroptosis, a Form of Programmed Necrosis*
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DOI：
10.1074/jbc.m111.236273
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发表时间：
2011-05
期刊：
影响因子：
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通讯作者：
Kazunori Yamanaka;Yoshiro Saito;T. Yamamori;Yasuomi Urano;N. Noguchi
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文献类型：
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作者：
Kazunori Yamanaka;Yoshiro Saito;T. Yamamori;Yasuomi Urano;N. Noguchi
24（S）-羟基胆固醇（24 S-OHC）由胆固醇24-羟化酶产生，主要在神经元中表达，在脑内具有重要的生理功能。相反，据报道，24 S-OHC具有强的细胞毒性。24 S-OHC诱导细胞死亡的分子机制尚未完全阐明。本研究以人神经母细胞瘤SH-SY 5 Y细胞和大鼠胚胎原代皮层神经细胞为材料，研究了24 S-OHC诱导细胞死亡的方式。24 S-OHC处理的SH-SY 5 Y细胞既没有出现细胞核碎裂，也没有出现caspase激活，这是凋亡的典型特征。24 S-OHC处理的细胞表现出坏死样的形态学变化，但不诱导ATP耗竭，这是坏死的特征之一。当细胞用坏死抑制素-1（坏死性凋亡所需的受体相互作用丝氨酸/苏氨酸激酶1（RIPK 1）抑制剂）处理时，24 S-OHC诱导的细胞死亡被显着抑制。通过转染RIPK 1的小干扰RNA来敲低RIPK 1有效地减弱了24 S-OHC诱导的细胞死亡。结果发现，无论是SH-SY 5 Y细胞还是原代皮层神经元细胞都不表达caspase-8，其受RIPK 1依赖性凋亡的调节。总的来说，这些结果表明，24 S-OHC通过坏死性凋亡（一种程序性坏死形式）诱导神经元细胞死亡。
24(S)-Hydroxycholesterol (24S-OHC) produced by cholesterol 24-hydroxylase expressed mainly in neurons plays an important physiological role in the brain. Conversely, it has been reported that 24S-OHC possesses potent cytotoxicity. The molecular mechanisms of 24S-OHC-induced cell death have not yet been fully elucidated. In this study, using human neuroblastoma SH-SY5Y cells and primary cortical neuronal cells derived from rat embryo, we characterized the form of cell death induced by 24S-OHC. SH-SY5Y cells treated with 24S-OHC exhibited neither fragmentation of the nucleus nor caspase activation, which are the typical characteristics of apoptosis. 24S-OHC-treated cells showed necrosis-like morphological changes but did not induce ATP depletion, one of the features of necrosis. When cells were treated with necrostatin-1, an inhibitor of receptor-interacting serine/threonine kinase 1 (RIPK1) required for necroptosis, 24S-OHC-induced cell death was significantly suppressed. The knockdown of RIPK1 by transfection of small interfering RNA of RIPK1 effectively attenuated 24S-OHC-induced cell death. It was found that neither SH-SY5Y cells nor primary cortical neuronal cells expressed caspase-8, which was regulated for RIPK1-dependent apoptosis. Collectively, these results suggest that 24S-OHC induces neuronal cell death by necroptosis, a form of programmed necrosis.