机构：[1]Division of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China四川大学华西医院[2]Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu, China四川大学华西医院[3]Department of Gastrointestinal Surgery, Laboratory of Bariatric and Metabolic Surgery, West China Hospital, Sichuan University, Chengdu, China四川大学华西医院[4]Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China- Liverpool Biomedical Research Centre, West China Hospital of Sichuan University, Chengdu, China四川大学华西医院[5]Department of Emergency, West China Hospital, Sichuan University, Chengdu, China四川大学华西医院[6]Institute of Translational Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China[7]State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China[8]Department of Diabetes Complications and Metabolism, Diabetes & Metabolism Research Institute of City of Hope, Beckman Research Institute of City of Hope, Duarte, CA[9]Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, China.四川大学华西医院
Endoplasmic reticulum (ER) stress is an adaptive response to excessive ER demand and contributes to the development of numerous diseases, including nonalcoholic fatty liver disease (NAFLD) that is hallmarked by the accumulation of lipid within hepatocytes. However, the underlying mechanisms remain elusive. MicroRNAs (miRNAs) play an indispensable role in various stress responses, but their implications in ER stress have not yet been systemically investigated. In this study, we identify a negative feedback loop comprising hepatic ER stress and miR-26a in NAFLD pathogenesis. Combining miRNA dot blot array and quantitative polymerase chain reaction, we find that miR-26a is specifically induced by ER stress in liver cells. This induction of miR-26a is critical for cells to cope with ER stress. In human hepatoma cells and murine primary hepatocytes, overexpression of miR-26a markedly alleviates chemical-induced ER stress, as well as palmitate-triggered ER stress and lipid accumulation. Conversely, deficiency of miR-26a exhibits opposite effects. Mechanistically, miR-26a directly targets the eukaryotic initiation factor 2α (eIF2α), a core ER stress effector controlling cellular translation. Intriguingly, miR-26a is reduced in the livers of NAFLD patients. Hepatocyte-specific restoration of miR-26a in mice significantly mitigates high-fat diet (HFD)-induced ER stress and hepatic steatosis. In contrast, deficiency of miR-26a in mice exacerbates HFD-induced ER stress, lipid accumulation, inflammation and hepatic steatosis. Conclusion: Our findings suggest ER stress-induced miR-26a upregulation as a regulator for hepatic ER stress resolution, and highlight the ER stress/miR-26a/eIF2α cascade as a promising therapeutic strategy for NAFLD.
This article is protected by copyright. All rights reserved.
基金：
Supported by the Ministry of Science and Technology of China (2018ZX09201018-005), the National Natural Science Foundation of China
(81570527, 81970561, 91540113, and 81502631), the National Cancer Institute of USA (NCI2R01CA139158), the 1.3.5 Project for Disciplines
of Excellence, West China Hospital, Sichuan University (ZYJC18049 and ZY2017308), and National Clinical Research Center for Geriatrics, West
China Hospital, Sichuan University (Z20191005 and Z20201003).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2021]版：
大类|1 区医学
小类|1 区胃肠肝病学
最新[2023]版：
大类|1 区医学
小类|1 区胃肠肝病学
第一作者：
第一作者机构：[1]Division of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
共同第一作者：
通讯作者：
通讯机构：[1]Division of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China[9]Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, China.[*1]Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China[*2]Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
医学