Role for the endoplasmic reticulum stress sensor IRE1α in liver regenerative responses

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-1 alpha (IRE1 alpha), a key signal transducer of the unfolded protein response (UPR), in liver regeneration. Methods: Using mice with hepatocyte-specific deletion of IRE1 alpha, we examined the role of IRE1 alpha in liver regeneration after challenges with carbon tetrachloride (CCl4) or hepatic surgery. We also investigated if IRE1 alpha 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 IRE1 alpha 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 IRE1 alpha caused marked exacerbation of liver injury and impairment in regenerative proliferation of hepatocytes in mice. Furthermore, IRE1a deficiency resulted in dampened STAT3 activation, and restoration of IRE1 alpha expression led to sustained phosphorylation of STAT3 in IRE1 alpha-null hepatocytes. Additionally, IRE1 alpha could directly and constitutively associate with STAT3, leading to elevated phosphorylation when stimulated by IL-6. Conclusions: These results suggest that IRE1 alpha may promote liver regeneration through acting as a signaling platform to regulate the STAT3 pathway. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.