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Mol Cells. 2019 Sep 5. doi: 10.14348/molcells.2019.0003. [Epub ahead of print]

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

Kwon JH1,2,3, Lee J4,2,3, Kim J4,2, Kirchner VA5, Jo YH6, Miura T7, Kim N4, Song GW1,2, Hwang S1,2, Lee SG1,2, Yoon YI#1,2, Tak E#4,2.

Author information

1
Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
2
Asan-Minnesota Institute for Innovating Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
3
These authors contributed equally to this work.
4
Department of Convergence Medicine, Asan Medical Institute of Convergence Science and Technology; and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
5
Division of Transplantation, Department of Surgery and Asan-Minnesota Institute for Innovating Transplantation, University of Minnesota, Minneapolis, MN 55455, USA
6
Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea
7
Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka 584-8540, Japan
#
Contributed equally

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.

KEYWORDS:

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

PMID:
31486328
DOI:
10.14348/molcells.2019.0003
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