Yang Liu1, Mengle Shao1, Ying Wu1, Cheng Yan1, Shan Jiang2, Jingnan Liu1, Jianli Dai3, Liu Yang1, Jia Li4, Weiping Jia2, Liangyou Rui5, Yong Liu6. 1. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, China. 2. Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. 3. School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China. 4. National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. 5. Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA. 6. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China. Electronic address: liuy@sibs.ac.cn.
Abstract
BACKGROUND & AIMS: As the main detoxifying organ of the body, the liver possesses a remarkable ability to regenerate after toxic injury, tissue resection or viral infection. A growing number of cellular signaling pathways have been implicated in orchestrating the process of liver regeneration. Here we investigated the role of inositol-requiring enzyme-1α (IRE1α), a key signal transducer of the unfolded protein response (UPR), in liver regeneration. METHODS: Using mice with hepatocyte-specific deletion of IRE1α, we examined the role of IRE1α in liver regeneration after challenges with carbon tetrachloride (CCl4) or hepatic surgery. We also investigated if IRE1α deficiency could affect the activation state of signal transducer and activator of transcription 3 (STAT3) in hepatocytes. Using co-immunoprecipitation and glutathione S-transferase (GST) pull-down assays, we analyzed whether IRE1α could interact with STAT3 to regulate its phosphorylation. RESULTS: We found that in response to CCl4-induced liver damage or after two-thirds partial hepatectomy (PH), abrogation of IRE1α caused marked exacerbation of liver injury and impairment in regenerative proliferation of hepatocytes in mice. Furthermore, IRE1α deficiency resulted in dampened STAT3 activation, and restoration of IRE1α expression led to sustained phosphorylation of STAT3 in IRE1α-null hepatocytes. Additionally, IRE1α could directly and constitutively associate with STAT3, leading to elevated phosphorylation when stimulated by IL-6. CONCLUSIONS: These results suggest that IRE1α may promote liver regeneration through acting as a signaling platform to regulate the STAT3 pathway.
BACKGROUND & AIMS: As the main detoxifying organ of the body, the liver possesses a remarkable ability to regenerate after toxic injury, tissue resection or viral infection. A growing number of cellular signaling pathways have been implicated in orchestrating the process of liver regeneration. Here we investigated the role of inositol-requiring enzyme-1α (IRE1α), a key signal transducer of the unfolded protein response (UPR), in liver regeneration. METHODS: Using mice with hepatocyte-specific deletion of IRE1α, we examined the role of IRE1α in liver regeneration after challenges with carbon tetrachloride (CCl4) or hepatic surgery. We also investigated if IRE1α deficiency could affect the activation state of signal transducer and activator of transcription 3 (STAT3) in hepatocytes. Using co-immunoprecipitation and glutathione S-transferase (GST) pull-down assays, we analyzed whether IRE1α could interact with STAT3 to regulate its phosphorylation. RESULTS: We found that in response to CCl4-induced liver damage or after two-thirds partial hepatectomy (PH), abrogation of IRE1α caused marked exacerbation of liver injury and impairment in regenerative proliferation of hepatocytes in mice. Furthermore, IRE1α deficiency resulted in dampened STAT3 activation, and restoration of IRE1α expression led to sustained phosphorylation of STAT3 in IRE1α-null hepatocytes. Additionally, IRE1α could directly and constitutively associate with STAT3, leading to elevated phosphorylation when stimulated by IL-6. CONCLUSIONS: These results suggest that IRE1α may promote liver regeneration through acting as a signaling platform to regulate the STAT3 pathway.