Dihydroartemisinin inhibits ER stress-mediated mitochondrial pathway to attenuate hepatocyte lipoapoptosis via blocking the activation of the PI3K/Akt pathway
Dihydroartemisinin inhibits ER stress-mediated mitochondrial pathway to attenuate hepatocyte lipoapoptosis via blocking the activation of the PI3K/Akt pathway
复制标题
双氢青蒿素通过阻断 PI3K/Akt 通路的激活，抑制 ER 应激介导的线粒体通路，从而减弱肝细胞脂肪凋亡
DOI：
10.1016/j.biopha.2017.11.010
复制
发表时间：
2018-01-01
影响因子：
7.5
通讯作者：
Zheng, Shizhong
中科院分区：
文献类型：
--
作者：
Chen, Xingran;Bian, Mianli;Zheng, Shizhong
酒精性肝病（ALD），其特征是脂肪酸在肝细胞中的积累，通常由慢性酒精消耗引起。我们以前的研究已经确定，DA通过减轻肝细胞脂肪变性来保护酒精性肝损伤。研究表明，饱和脂肪酸可引起肝细胞内质网应激和细胞凋亡。本研究旨在探讨DA对ALD的影响并进一步阐明其机制。结果表明，DA减轻小鼠酒精性肝损伤。我们的研究结果还表明，DA衰减暴露于乙醇的肝细胞中的脂质积累。DA减轻乙醇诱导的肝细胞凋亡。结果表明，DA剂量依赖性地改善线粒体途径的激活，这在归因于脂毒性的细胞凋亡中起着关键作用。此外，DA抑制JNK的激活和CHOP的表达，归因于ER应激的抑制。ER应激-JNK/CHOP-线粒体级联反应的激活被认为是肝细胞脂调亡的关键机制。此外，DA减弱肝细胞中的PI 3 K/Akt通路，与我们先前在HSC中的发现一致。DA的作用被PI 3 K特异性抑制剂LY 294002加强。总之，DA通过PI 3 K/Akt通路抑制依赖性机制显著保护肝细胞免受脂凋亡。
Alcoholic liver disease (ALD), characterized by accumulation of fatty acids in liver cells, is usually caused by Chronic alcohol consumption. Our previous study has identified that DA protects against alcoholic liver injury in alcohol-fed rats through alleviating hepatocyte steatosis. It has emerged that saturated fatty acids could provoke endoplasmic reticulum (ER) stress and apoptosis in hepatocytes. This study was aimed to explore the impact of DA on ALD and further elaborate the underlying mechanisms. Results demonstrated that DA attenuates alcoholic liver injury in mice. Our results also indicated that DA attenuated lipid accumulation in hepatocytes exposed to ethanol. DA attenuates ethanol-induced hepatocyte apoptosis. Results demonstrated that DA dose-dependently ameliorated activation of mitochondrial pathway activation, which plays a critical role in apoptosis attributed to lipotoxicity. Further, DA suppressed the activation of JNK and the expression of CHOP, attributed to the inhibition of ER stress. It has emerged that activation of ER stress-JNK/CHOP-mitochondria cascade is considered as the key mechanisms underlying hepatocyte lipoapoptosis. In addition, DA attenuates PI3K/Akt Pathway in hepatocytes, consistent with our previous finding in HSCs. DA effects were reinforced by PI3K specific inhibitor LY294002. In summary, DA significantly protected hepatocytes against lipoapoptosis via a PI3K/Akt Pathway inhibition-dependent mechanism.