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Upregulation of Carbonyl Reductase 1 by Nrf2 as a Potential Therapeutic Intervention for Ischemia/ Reperfusion Injury during Liver Transplantation

Molecules and Cells 2019년 42권 9호 p.672 ~ 685
 ( Kwon Jae-Hyun ) - University of Ulsan College of Medicine Asan Medical Center Department of Surgery

 ( Lee Joo-Young ) - University of Ulsan College of Medicine Asan Medical Center Department of Convergence Medicine
 ( Kim Ji-Ye ) - University of Ulsan College of Medicine Asan Medical Center Department of Convergence Medicine
 ( Kirchner Varvara A. ) - University of Minnesota Department of Surgery
 ( Jo Yong-Hwa ) - Kyung Hee University School of Medicine Department of Biochemistry and Molecular Biology
 ( Miura Takeshi ) - Osaka Ohtani University Faculty of Pharmacy
 ( Kim Na-Young ) - University of Ulsan College of Medicine Asan Medical Center Department of Convergence Medicine
 ( Song Gi-Won ) - University of Ulsan College of Medicine Asan Medical Center Department of Surgery
 ( Hwang Shin ) - University of Ulsan College of Medicine Asan Medical Center Department of Surgery
 ( Lee Sung-Gyu ) - University of Ulsan College of Medicine Asan Medical Center Department of Surgery
 ( Yoon Young-In ) - University of Ulsan College of Medicine Asan Medical Center Department of Surgery
 ( Tak Eun-Young ) - University of Ulsan College of Medicine Asan Medical Center Department of Convergence Medicine

Abstract


Currently, liver transplantation is the only available remedy for patients with end-stage liver disease. Conservation of transplanted liver graft is the most important issue as it directly related to patient survival. Carbonyl reductase 1 (CBR1) protects cells against oxidative stress and cell death by inactivating cellular membrane-derived lipid aldehydes. Ischemia-reperfusion (I/R) injury during living-donor liver transplantation is known to form reactive oxygen species. Thus, the objective of this study was to investigate whether CBR1 transcription might be increased during liver I/R injury and whether such increase might protect liver against I/R injury. Our results revealed that transcription factor Nrf2 could induce CBR1 transcription in liver of mice during I/R. Pre-treatment with sulforaphane, an activator of Nrf2, increased CBR1 expression, decreased liver enzymes such as aspartate aminotransferase and alanine transaminase, and reduced I/R-related pathological changes. Using oxygenglucose deprivation and recovery model of human normal liver cell line, it was found that oxidative stress markers and lipid peroxidation products were significantly lowered in cells overexpressing CBR1. Conversely, CBR1 knockdown cells expressed elevated levels of oxidative stress proteins compared to the parental cell line. We also observed that Nrf2 and CBR1 were overexpressed during liver transplantation in clinical samples. These results suggest that CBR1 expression during liver I/R injury is regulated by transcription factor Nrf2. In addition, CBR1 can reduce free radicals and prevent lipid peroxidation. Taken together, CBR1 induction might be a therapeutic strategy for relieving liver I/R injury during liver transplantation.

키워드

carbonyl reductase 1; ischemia-reperfusion injury; lipid peroxidation; living-donor liver transplantation; Nrf2; oxidative stress
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