The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity
The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity
复制标题
DOI：
10.1002/hep.22183
复制
发表时间：
2008-05-01
期刊：
影响因子：
13.5
通讯作者：
Feldstein, Ariel E.
中科院分区：
文献类型：
--
作者：
Li, ZhengZheng;Berk, Michael;Feldstein, Ariel E.
线粒体功能受损在很大程度上被认为是导致非酒精性脂肪性肝病（NAFLD）疾病进展的核心异常。然而，导致NAFLD中线粒体功能障碍的分子机制仍然知之甚少。本研究检测了肝细胞中游离脂肪酸（FFA）过度积累对线粒体功能的影响以及溶酶体-线粒体轴在脂毒性中的作用。原代小鼠肝细胞，HepG 2和McNtcp.24细胞，用不同浓度的FFA处理，具有不同的饱和度，长达24小时。通过实时成像、细胞色素c再分布和活性氧（ROS）产生监测线粒体功能。建立了溶酶体和线粒体透化的时间关系。溶酶体蛋白酶组织蛋白酶B的活性受到遗传和药理学方法的抑制。将组织蛋白酶B敲除小鼠和野生型动物置于高碳水化合物饮食16周，并评估线粒体功能和肝损伤。暴露于饱和FFA的肝细胞导致线粒体去极化，细胞色素c的释放，并增加ROS的产生。溶酶体渗透和组织蛋白酶B重新分布到细胞质中发生几个小时前线粒体功能障碍。无论是药理学或遗传抑制组织蛋白酶B保存线粒体功能。最后，组织蛋白酶B失活保护线粒体，降低氧化应激，减轻体内肝损伤。结论：这些数据有力地表明饱和FFA在肝细胞中的过度积累直接诱导线粒体功能障碍和氧化应激。我们的数据进一步表明这一过程依赖于溶酶体的破坏和组织蛋白酶B的激活。
Impaired mitochondrial function is largely thought to be a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms resulting in mitochondrial dysfunction in NAFLD remain poorly understood. This study examined the effects of excessive accumulation of free fatty acids (FFAs) in liver cells on mitochondrial function and the role of the lysosomal-mitochondrial axis on lipotoxicity. Primary mouse hepatocytes, HepG2 and McNtcp.24 cells, were treated with varied concentrations of FFAs with different degrees of saturation for up to 24 hours. Mitochondrial function was monitored by real-time imaging, cytochrome c redistribution, and reactive oxygen species (ROS) production. The temporal relationship of lysosomal and mitochondrial permeabilization was established. Activity of the lysosomal protease cathepsin B was suppressed by genetic and pharmacological approaches. Cathepsin B-knockout mice and wild-type animals were place on a high-carbohydrate diet for 16 weeks, and mitochondrial function and liver damage were assessed. Exposure of liver cells to saturated FFAs resulted in mitochondrial depolarization, cytochrome c release, and increased ROS production. Lysosomal permeabilization and cathepsin B redistribution into the cytoplasm occurred several hours prior to mitochondrial dysfunction. Either pharmacological or genetic inhibition of cathepsin B preserved mitochondrial function. Finally, cathepsin B inactivation protected mitochondria, decreased oxidative stress, and attenuated hepatic injury in vivo. Conclusion: These data strongly suggest excessive accumulation of saturated FFAs in liver cells directly induce mitochondrial dysfunction and oxidative stress. Our data further suggest this process is dependent on lysosomal disruption and activation of cathepsin B.