Lipotoxicity-mediated cell dysfunction and death involve lysosomal membrane permeabilization and cathepsin L activity.
Lipotoxicity-mediated cell dysfunction and death involve lysosomal membrane permeabilization and cathepsin L activity.
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DOI：
10.1016/j.brainres.2009.12.038
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发表时间：
2010-03-08
期刊：
影响因子：
2.9
通讯作者：
De Leon, Marino
中科院分区：
文献类型：
--
作者：
Almaguel, Frankis G.;Liu, Jo-Wen;Pacheco, Fabio J.;De Leon, Daisy;Casiano, Carlos A.;De Leon, Marino
当细胞暴露于升高水平的游离脂肪酸时触发的脂毒性涉及细胞功能障碍和细胞凋亡，并且正在成为促成包括中枢神经系统病症和糖尿病在内的各种病理状况的潜在因素。我们已经表明，棕榈酸（PA）诱导的脂毒性（PA-LTx）在神经生长因子分化的PC 12（NGFDPC 12）细胞与细胞氧化应激（ASCOS）和细胞凋亡的增强状态，这些事件被二十二碳六烯酸（DHA）抑制。PA-LTx在神经细胞中的机制还不清楚，但我们以前的研究结果表明，它涉及ROS的产生，线粒体膜透化（MMP）和caspase激活。本研究使用神经生长因子分化的PC 12细胞（NGFDPC 12细胞），发现溶酶体膜透化（LMP）是PA诱导的脂毒性的早期事件，先于MMP和凋亡。组织蛋白酶L而不是组织蛋白酶B是该过程中的重要贡献者，因为其药理学抑制显著减弱LMP、MMP和细胞凋亡。此外，经历脂毒性的NGFDPC 12细胞与DHA的共处理显著降低了LMP，表明DHA通过拮抗导致溶酶体功能障碍的上游信号起作用。这些结果表明，LMP是脂毒性的关键早期介质，并强调了针对导致LMP的上游信号的干预对于治疗与脂毒性相关的病理状况的价值。
Lipotoxicity, which is triggered when cells are exposed to elevated levels of free fatty acids, involves cell dysfunction and apoptosis and is emerging as an underlying factor contributing to various pathological conditions including disorders of the central nervous system and diabetes. We have shown that palmitic acid (PA)-induced lipotoxicity (PA-LTx) in nerve growth factor-differentiated PC12 (NGFDPC12) cells is linked to an augmented state of cellular oxidative stress (ASCOS) and apoptosis, and that these events are inhibited by docosahexanoic acid (DHA). The mechanisms of PA-LTx in nerve cells are not well understood, but our previous findings indicate that it involves ROS generation, mitochondrial membrane permeabilization (MMP), and caspase activation. The present study used nerve growth factor differentiated PC12 cells (NGFDPC12 cells) and found that lysosomal membrane permeabilization (LMP) is an early event during PA-induced lipotoxicity that precedes MMP and apoptosis. Cathepsin L, but not cathepsin B, is an important contributor in this process since its pharmacological inhibition significantly attenuated LMP, MMP, and apoptosis. In addition, co-treatment of NGFDPC12 cells undergoing lipotoxicity with DHA significantly reduced LMP, suggesting that DHA acts by antagonizing upstream signals leading to lysosomal dysfunction. These results suggest that LMP is a key early mediator of lipotoxicity, and underscore the value of interventions targeting upstream signals leading to LMP for the treatment of pathological conditions associated with lipotoxicity.
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影响因子：
5.3
作者：
Ghavami S;Asoodeh A;Klonisch T;Halayko AJ;Kadkhoda K;Kroczak TJ;Gibson SB;Booy EP;Naderi-Manesh H;Los M
通讯作者：
Los M
影响因子：
4.8
作者：
Cirman, T;Oresic, K;Turk, B
通讯作者：
Turk, B
影响因子：
4.1
作者：
Antunes, F;Cadenas, E;Brunk, UT
通讯作者：
Brunk, UT
影响因子：
4.2
作者：
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通讯作者：
Yagmurca, Murat
影响因子：
4.8
作者：
Droga-Mazovec, Gabriela;Bojic, Lea;Turk, Boris
通讯作者：
Turk, Boris