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

J Hepatol. 2015 Mar;62(3):590-8. doi: 10.1016/j.jhep.2014.10.022. Epub 2014 Oct 22.

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.

Keywords: Hepatocyte proliferation; IRE1α; Liver regeneration; STAT3; Unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Tetrachloride / toxicity
  • Cell Proliferation / physiology
  • Chemical and Drug Induced Liver Injury / pathology
  • Chemical and Drug Induced Liver Injury / physiopathology
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum Stress / physiology*
  • Endoribonucleases / deficiency
  • Endoribonucleases / genetics
  • Endoribonucleases / physiology*
  • Female
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Liver Regeneration / drug effects
  • Liver Regeneration / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Regulatory Factor X Transcription Factors
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Transcription Factors / metabolism

Substances

  • DNA-Binding Proteins
  • Regulatory Factor X Transcription Factors
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Transcription Factors
  • Carbon Tetrachloride
  • Ern1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases