IRE1α aggravates ischemia reperfusion injury of fatty liver by regulating phenotypic transformation of kupffer cells.

Abstract

Fatty liver is one of the widely accepted marginal donor for liver transplantation, but is also more sensitive to ischemia and reperfusion injury (IRI) and produces more reactive oxygen species (ROS). Moreover, so far, no effective method has been developed to alleviate it. Endoplasmic reticulum stress (ER-stress) of hepatocyte is associated with the occurrence of fatty liver disease, but ER-stress of kupffer cells (KCs) in fatty liver is not clear at all. This study evaluates whether ER-stress of KCs is activated in fatty liver and accelerate IRI of fatty livers. ER-stress of KCs was activated in fatty liver, especially the IRE1α signal pathway. KCs with activated ER-stress secreted more proinflammatory cytokine to induce its M1-phenotypic shift in fatty liver, resulting in more severe IRI. Also, activated ER-stress of BMDMs in vitro by tunicamycin can induce its pro-inflammatory shift and can be reduced by 4-PBA, an ER-stress inhibitor. Knockdown of IRE1α could regulate the STAT1 and STAT6 pathway of macrophage to inhibit the M1-type polarization and promote M2-phenotypic shift. Furthermore, transfusion of IRE1α-knockdown KCs significantly reduced the liver IRI as well as the ROS of HFD feeding mice. Altogether, these data demonstrated that IRE1α of KCs may be a potential target to reduce the fatty liver associated IRI in liver transplantation.

• Authors: Faji Yang, Shuai Wang, Yang Liu, Yuan Zhou, Longcheng Shang, Min Feng, Xianwen Yuan, Wei Zhu, Xiaolei Shi
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 124 Pg. 395-407 (08 20 2018) ISSN: 1873-4596 [Electronic] United States
• PMID: 29969718 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Ern1 protein, mouse
• Protein Serine-Threonine Kinases
• Endoribonucleases

Topics

• Animals
• Diet, High-Fat (adverse effects)
• Endoplasmic Reticulum Stress (physiology)
• Endoribonucleases (metabolism)
• Fatty Liver (metabolism, pathology)
• Kupffer Cells (metabolism)
• Liver Transplantation (methods)
• Male
• Mice
• Mice, Inbred C57BL
• Phenotype
• Protein Serine-Threonine Kinases (metabolism)
• Reperfusion Injury (metabolism, pathology)
• Warm Ischemia (adverse effects)