Trehalose alleviates oxidative stress-mediated liver injury and Mallor-Denk body formation via activating autophagy in mice
Trehalose alleviates oxidative stress-mediated liver injury and Mallor-Denk body formation via activating autophagy in mice
复制标题
DOI：
10.1007/s00795-020-00258-2
复制
发表时间：
2020-06-25
影响因子：
1.8
通讯作者：
Harada, Masaru
中科院分区：
文献类型：
--
作者：
Honma, Yuichi;Sato-Morita, Miyuki;Harada, Masaru
自噬是长寿命的细胞质蛋白或受损细胞器的降解途径，也是许多易于聚集和致病的蛋白的降解途径。内质网应激和氧化应激与多种肝病的病理生理机制有关。这些应激可诱导肝细胞异常蛋白积聚、Mallory-Denk小体(MDB)形成和细胞凋亡。据报道，在神经退行性疾病模型中，一种二糖海藻糖可以诱导自噬，降低聚集倾向蛋白和细胞毒性。但海藻糖在肝细胞中的作用还不完全清楚。采用3，5-二乙氧基甲酰-1，4-二氢氯仿(DDC)处理3个月的小鼠模型，观察了海藻糖对肝细胞自噬、内质网应激和氧化应激介导的细胞毒性及MDB形成的影响。每隔一天腹腔注射含10%海藻糖的水(0.02 mg/g体重)，连续3个月。Western blotting和免疫染色分析表明，海藻糖可诱导DDC喂养小鼠肝细胞自噬，减少ER应激、氧化应激、MDB形成和肝细胞凋亡。电子显微镜显示海藻糖诱导自溶酶体形成，位于MDBS附近。因此，我们的发现表明，海藻糖可以通过激活自噬成为氧化应激相关肝病的治疗剂。
Autophagy is a degradation pathway for long-lived cytoplasmic proteins or damaged organelles and also for many aggregate-prone and disease-causing proteins. Endoplasmic reticulum (ER) stress and oxidative stress are associated with the pathophysiology of various liver diseases. These stresses induce the accumulation of abnormal proteins, Mallory-Denk body (MDB) formation and apoptosis in hepatocytes. A disaccharide trehalose had been reported to induce autophagy and decrease aggregate-prone proteins and cytotoxicity in neurodegenerative disease models. But the effects of trehalose in hepatocytes have not been fully understood. We examined the effect of trehalose on autophagy, ER stress and oxidative stress-mediated cytotoxicity and MDB formation in hepatocytes using mice model with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) treatment for 3 months. We administered trehalose by intraperitoneal injection of water containing 10% trehalose (0.02 mg/g body weight) every other day for 3 months. Our results demonstrated that trehalose induced autophagy and reduced ER stress, oxidative stress, MDB formation and apoptosis in hepatocytes of DDC-fed mice by Western blotting and immunostaining analyses. Electron microscopy revealed that trehalose induced autolysosome formation, which located is close to the MDBs. Thus, our findings suggest that trehalose can become a therapeutic agent for oxidative stress-related liver diseases via activating autophagy.