title: The Dichotomy of Endoplasmic Reticulum Stress Response in Liver Ischemia-Reperfusion Injury.
abstract: Endoplasmic reticulum (ER) stress plays critical roles in the pathogenesis of liver ischemia-reperfusion injury (IRI). As ER stress triggers an adaptive cellular response, the question of what determines its functional outcome in liver IRI remains to be defined. In a murine liver partial warm ischemia model, we studied how transient (30 minutes) or prolonged (90 minutes) liver ischemia regulated local ER stress response and autophagy activities and their relationship with liver IRI. Effects of chemical chaperon 4-phenylbutyrate (4-PBA) or autophagy inhibitor 3-methyladenine (3-MA) were evaluated. Our results showed that although the activating transcription factor 6 branch of ER stress response was induced in livers by both types of ischemia, liver autophagy was activated by transient, but inhibited by prolonged, ischemia. Although 3-MA had no effects on liver IRI after prolonged ischemia, it significantly increased liver IRI after transient ischemia. The 4-PBA treatment protected livers from IRI after prolonged ischemia by restoring autophagy flux, and the adjunctive 3-MA treatment abrogated its liver protective effect. The same 4-PBA treatment, however, increased liver IRI and disrupted autophagy flux after transient ischemia. Although both types of ischemia activated 5' adenosine monophosphate-activated protein kinase and inactivated protein kinase B (Akt), prolonged ischemia also resulted in downregulations of autophagy-related gene 3 and autophagy-related gene 5 in ischemic livers. These results indicate a functional dichotomy of ER stress response in liver IRI via its regulation of autophagy. Transient ischemia activates autophagy to protect livers from IRI, whereas prolonged ischemia inhibits autophagy to promote the development of liver IRI.
authors.affiliation: 1 Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China. 2 Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA. 3 Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Haomming
authors.initials: H
authors.lastname: Zhou
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhu
authors.forename: Shi
authors.initials: S
authors.lastname: Yue
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
authors.forename: Xuehao
authors.initials: X
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhai
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D051696:Activating Transcription Factors / Q000378:metabolism; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D015398:Signal Transduction; D013997:Time Factors; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D052096:Warm Ischemia
chemical_list: D051696:Activating Transcription Factors; C471855:Atf5 protein, mouse; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D008869:Microtubule-Associated Proteins; D010654:Phenylbutyrates; C025946:3-methyladenine; C075773:4-phenylbutyric acid; D044763:Ubiquitin-Conjugating Enzymes; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; C568853:Atg3 protein, mouse; D000225:Adenine