caa a22 4500 605543097 CHVBK 20210128100924.0 cr unu---uuuuu 210128e20150901xx s 000 0 eng 10.1007/s00109-015-1282-2 doi (NATIONALLICENCE)springer-10.1007/s00109-015-1282-2 miR-26a enhances autophagy to protect against ethanol-induced acute liver injury [Elektronische Daten] [Weidong Han, Xianghui Fu, Jiansheng Xie, Zhipeng Meng, Ying Gu, Xichun Wang, Ling Li, Hongming Pan, Wendong Huang] Autophagy is a process for the turnover of intracellular organelles and molecules during stress responses. microRNAs (miRNAs) are small, non-coding endogenous RNAs that may regulate almost every cellular process. However, the roles of miRNAs in autophagy are still poorly understood. In this study, we show that miR-26a enhances autophagy in both culture cells and the mouse liver. Hepatic overexpression of miR-26a in mice alleviated ethanol-induced hepatic steatosis and liver injury. Overexpression of miR-26a increased the expression of the autophagy mediator Beclin-1, which is regulated by mitogen-activated protein kinases (MAPKs). We identified DUSP4 and DUSP5, two MAPKs inhibitors, as direct targets of miR-26a. We further demonstrated that miR-26a targeted the 3′-UTRs of several other negative regulators of autophagy. Our results thus identify a novel miRNA-mediated mechanism that enhances cytoprotective autophagy in the liver. Key messages: • miR-26a enhances autophagy in liver cells. • Hepatic overexpression of miR-26a in mice alleviates ethanol-induced liver injury. • Overexpression of miR-26a increases the expression of autophagy mediator Beclin-1. • DUSP4 and DUSP5, two MAPKs inhibitors, were identified as direct targets of miR-26a. The Author(s), 2015 miR-26a nationallicence Autophagy nationallicence Hepatic steatosis nationallicence Mitogen-activated protein kinases nationallicence Ethanol binge nationallicence 3′-UTR : 3′ untranslated region nationallicence miRNAs : MicroRNAs nationallicence miR-26a : MicroRNA 26a nationallicence MAPKs : Mitogen-activated protein kinases nationallicence LDs : Lipid droplets nationallicence mRNAs : Messenger RNAs nationallicence CQ : Chloroquine nationallicence tf-LC3 : Tandem fluorescent-tagged LC3 nationallicence PCR : Real-time polymerase chain reaction nationallicence ALT : Alanine aminotransferase nationallicence TEM : Transmission electron microscopy nationallicence Han Weidong Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, 3 East Qingchun Road, 310016, Hangzhou, Zhejiang, China aut Fu Xianghui Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, 91010, Duarte, CA, USA aut Xie Jiansheng Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, 3 East Qingchun Road, 310016, Hangzhou, Zhejiang, China aut Meng Zhipeng Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, 91010, Duarte, CA, USA aut Gu Ying Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, 91010, Duarte, CA, USA aut Wang Xichun Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, 91010, Duarte, CA, USA aut Li Ling Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, 91010, Duarte, CA, USA aut Pan Hongming Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, 3 East Qingchun Road, 310016, Hangzhou, Zhejiang, China aut Huang Wendong Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, 91010, Duarte, CA, USA aut Journal of Molecular Medicine Springer Berlin Heidelberg 93/9(2015-09-01), 1045-1055 0946-2716 93:9<1045 2015 93 109 https://doi.org/10.1007/s00109-015-1282-2 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00109-015-1282-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Han Weidong Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, 3 East Qingchun Road, 310016, Hangzhou, Zhejiang, China aut NATIONALLICENCE 700 1- Fu Xianghui Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, 91010, Duarte, CA, USA aut NATIONALLICENCE 700 1- Xie Jiansheng Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, 3 East Qingchun Road, 310016, Hangzhou, Zhejiang, China aut NATIONALLICENCE 700 1- Meng Zhipeng Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, 91010, Duarte, CA, USA aut NATIONALLICENCE 700 1- Gu Ying Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, 91010, Duarte, CA, USA aut NATIONALLICENCE 700 1- Wang Xichun Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, 91010, Duarte, CA, USA aut NATIONALLICENCE 700 1- Li Ling Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, 91010, Duarte, CA, USA aut NATIONALLICENCE 700 1- Pan Hongming Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, 3 East Qingchun Road, 310016, Hangzhou, Zhejiang, China aut NATIONALLICENCE 700 1- Huang Wendong Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, 91010, Duarte, CA, USA aut NATIONALLICENCE 773 0- Journal of Molecular Medicine Springer Berlin Heidelberg 93/9(2015-09-01), 1045-1055 0946-2716 93:9<1045 2015 93 109