内质网应激感受器IRE1α在肝脏再生反应中的作用

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.

 

学科代码：消化病学　　　关键词：内质网；应激感受器；IRE1α；肝脏； ,中国作者重要发表 爱思唯尔医学网, Elseviermed
来源： Scopus