Attenuation of the Lysosomal Death Pathway by Lysosomal Cholesterol Accumulation
Attenuation of the Lysosomal Death Pathway by Lysosomal Cholesterol Accumulation
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DOI：
10.1016/j.ajpath.2010.10.030
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发表时间：
2011-02-01
影响因子：
6
通讯作者：
Ollinger, Karin
中科院分区：
文献类型：
--
作者：
Appelqvist, Hanna;Nilsson, Cathrine;Ollinger, Karin
在过去的十年中，溶酶体膜透化（LMP）已成为细胞死亡信号的重要组成部分。调节溶酶体稳定性的机制尚未完全了解，但已表明涉及溶酶体膜脂质组成的变化。我们的目的是研究胆固醇在调节溶酶体膜通透性中的重要性及其对细胞凋亡的潜在影响。用U18666 A（一种抑制胆固醇转运并导致胆固醇在溶酶体中蓄积的两亲性药物）处理正常人成纤维细胞，可将细胞从由亲溶酶体去污剂0-甲基-丝氨酸十二烷酰胺盐酸盐（MSDH）、星形孢菌素（STS）或顺铂诱导的溶酶体依赖性细胞死亡中拯救出来。U18666 A预处理细胞可降低LMP，溶酶体胆固醇含量与其对MSDH诱导的透化的抵抗力呈线性关系。U18666 A没有诱导已知保护溶酶体膜的70 kDa热休克蛋白（Hsp 70）或抗凋亡Bcl-2蛋白的表达或定位的变化。自噬的诱导也被排除作为保护机制的贡献者。通过使用由于胆固醇转运蛋白Niemann-Pick C1型（NPC 1）突变而导致溶酶体胆固醇过载的中国仓鼠卵巢（CHO）细胞，证实了溶酶体胆固醇蓄积与防止溶酶体依赖性细胞死亡之间的关系。胆固醇在溶酶体中的积累通过增加溶酶体膜的稳定性来减弱细胞凋亡。(Am J Pathol 2011，178：629-639; DOI：10.1016/j.ajpath.2010.10.030）
In the past decade, lysosomal membrane permeabilization (LMP) has emerged as a significant component of cell death signaling. The mechanisms by which lysosomal stability is regulated are not yet fully understood, but changes in the lysosomal membrane lipid composition have been suggested to be involved. Our aim was to investigate the importance of cholesterol in the regulation of lysosomal membrane permeability and its potential impact on apoptosis. Treatment of normal human fibroblasts with U18666A, an amphiphilic drug that inhibits cholesterol transport and causes accumulation of cholesterol in lysosomes, rescued cells from lysosome-dependent cell death induced by the lysosomotropic detergent 0-methyl-serine dodecylamide hydrochloride (MSDH), staurosporine (STS), or cisplatin. LMP was decreased by pretreating cells with U18666A, and there was a linear relationship between the cholesterol content of lysosomes and their resistance to permeabilization induced by MSDH. U18666A did not induce changes in expression or localization of 70-kDa heat shock proteins (Hsp70) or antiapoptotic Bcl-2 proteins known to protect the lysosomal membrane. Induction of autophagy also was excluded as a contributor to the protective mechanism. By using Chinese hamster ovary (CHO) cells with lysosomal cholesterol overload due to a mutation in the cholesterol transporting protein Niemann-Pick type C1 (NPC1), the relationship between lysosomal cholesterol accumulation and protection from lysosome-dependent cell death was confirmed. Cholesterol accumulation in lysosomes attenuates apoptosis by increasing lysosomal membrane stability. (Am J Pathol 2011, 178:629-639; DOI: 10.1016/j.ajpath.2010.10.030)