Protective role of autophagy in methionine-choline deficient diet-induced advanced nonalcoholic steatohepatitis in mice
Protective role of autophagy in methionine-choline deficient diet-induced advanced nonalcoholic steatohepatitis in mice
复制标题
DOI：
10.1016/j.ejphar.2015.11.012
复制
发表时间：
2016-01-05
影响因子：
5
通讯作者：
Gao, Xiaogang
中科院分区：
文献类型：
--
作者：
Chen, Rui;Wang, Quanxing;Gao, Xiaogang
蛋氨酸胆碱缺乏(MCD)饮食导致严重的肝损伤，类似于人类非酒精性脂肪性肝炎(NASH)。自噬已经成为一种关键的溶酶体途径，通过细胞器和蛋白质等细胞成分的降解来维持细胞的功能和生存。这项研究的目的是阐明自噬在MCD诱导的小鼠脂肪变性、纤维化、炎症、线粒体功能障碍和内质网(ER)应激中的作用。用MCD饲料喂养小鼠，并用雷帕霉素(自噬增强剂)或氯喹(自噬抑制剂)治疗10周。生化和组织学检查结合肝组织基因表达分析评价肝损伤程度。饲喂MCD饲料的小鼠肝脏自噬通量受损，表现为Lc3-II/Lc3-I比值降低和p62蛋白表达增加。研究发现，雷帕霉素激活自噬可以减轻MCD诱导的脂肪变性、纤维化、炎症、线粒体功能障碍和内质网应激。相比之下，接受氯喹治疗的MCD小鼠出现了更多的肝脏损伤。综上所述，自噬途径在MCD诱导的晚期NASH中起着重要的保护作用。因此，药物促进自噬可能为NASH的治疗提供一种新的治疗策略。(C)到2015年爱思唯尔。版权所有。
The methionine choline-deficient (MCD) diet leads to severe liver injury similar to human nonalcoholic steatohepatitis (NASH). Autophagy has emerged as a critical lysosomal pathway that maintains cell function and survival through the degradation of cellular components such as organelles and proteins. The goal of this study was to elucidate the role of autophagy in MCD-induced steatosis, fibrosis, inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in mice. Mice were fed with MCD diet and treated with rapamycin (an autophagy enhancer) or chloroquine (an autophagy inhibitor) for 10 weeks. Liver injury was evaluated biochemically and histologically together with hepatic gene expression analysis. Autophagic flux was impaired in livers of mice fed with MCD diet, evidenced by reduced ratio of LC3-II/LC3-I and increased protein expression of p62. It was found that autophagy activation by rapamycin attenuated MCD-induced steatosis, fibrosis, inflammation, mitochondrial dysfunction, and ER stress. By contrast, MCD mice treated with chloroquine developed more liver injury. In conclusions, the autophagic pathway plays an important protective role in MCD-induced advanced NASH. Thus, pharmacological promotion of autophagy may provide a novel therapeutic strategy for treatment of NASH. (C) 2015 Elsevier By. All rights reserved.