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©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
Steatotic livers are susceptible to normothermic ischemia-reperfusion injury from mitochondrial Complex-I dysfunction
Michael JJ Chu, Rakesh Premkumar, Anthony JR Hickey, Yannan Jiang, Brett Delahunt, Anthony RJ Phillips, Adam SJR Bartlett
Michael JJ Chu, Rakesh Premkumar, Anthony RJ Phillips, Adam SJR Bartlett, Department of Surgery, University of Auckland, Auckland 1142, New Zealand
Anthony JR Hickey, Anthony RJ Phillips, School of Biological Sciences, University of Auckland, Auckland 1142, New Zealand
Anthony JR Hickey, Anthony RJ Phillips, Adam SJR Bartlett, Maurice Wilkins Centre for Biodiscovery, University of Auckland, Auckland 1142, New Zealand
Yannan Jiang, Department of Statistics, University of Auckland, Auckland 1142, New Zealand
Brett Delahunt, Department of Pathology and Molecular Medicine, Wellington School of Medicine, University of Otago, Wellington 8140, New Zealand
Anthony RJ Phillips, Adam SJR Bartlett, New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland 1142, New Zealand
Author contributions: Chu MJJ, Premkumar R and Hickey AJR equally contributed to this paper; Chu MJJ designed the study, carried out experiments, performed data analysis, drafted manuscript, and revised the manuscript; Premkumar R designed the study, carried out animal surgery, and revised the manuscript; Hickey AJR designed the study, analyzed the data, and revised the manuscript; Jiang Y performed statistical analysis and revised the manuscript; Delahunt B performed histological analysis and revised the manuscript; Phillips ARJ designed the study, analyzed the data, and revised the manuscript; and Bartlett ASJR designed the study and revised the manuscript.
Supported by University of Auckland Faculty Research Development Fund.
Institutional animal care and use committee statement: All procedures were reviewed and approved by the University of Auckland Animal Ethics Committee (R965).
Conflict-of-interest statement: The authors do not have any conflict of interest to declare.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Michael JJ Chu, PhD, Candidate/General Surgical Resident, Department of Surgery, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
michaeljjc@gmail.com
Telephone: +64-2-1345320 Fax: +64-9-3779656
Received: January 23, 2016
Peer-review started: January 25, 2016
First decision: February 18, 2016
Revised: March 5, 2016
Accepted: March 18, 2016
Article in press: March 18, 2016
Published online: May 21, 2016
Processing time: 114 Days and 16.4 Hours
AIM: To assess the effects of ischemic preconditioning (IPC, 10-min ischemia/10-min reperfusion) on steatotic liver mitochondrial function after normothermic ischemia-reperfusion injury (IRI).
METHODS: Sixty male Sprague-Dawley rats were fed 8-wk with either control chow or high-fat/high-sucrose diet inducing > 60% mixed steatosis. Three groups (n = 10/group) for each dietary state were tested: (1) the IRI group underwent 60 min partial hepatic ischemia and 4 h reperfusion; (2) the IPC group underwent IPC prior to same standard IRI; and (3) sham underwent the same surgery without IRI or IPC. Hepatic mitochondrial function was analyzed by oxygraphs. Mitochondrial Complex-I, Complex-II enzyme activity, serum alanine aminotransferase (ALT), and histological injury were measured.
RESULTS: Steatotic-IRI livers had a greater increase in ALT (2476 ± 166 vs 1457 ± 103 IU/L, P < 0.01) and histological injury following IRI compared to the lean liver group. Steatotic-IRI demonstrated lower Complex-I activity at baseline [78.4 ± 2.5 vs 116.4 ± 6.0 nmol/(min.mg protein), P < 0.001] and following IRI [28.0 ± 6.2 vs 104.3 ± 12.6 nmol/(min.mg protein), P < 0.001]. Steatotic-IRI also demonstrated impaired Complex-I function post-IRI compared to the lean liver IRI group. Complex-II activity was unaffected by hepatic steatosis or IRI. Lean liver mitochondrial function was unchanged following IRI. IPC normalized ALT and histological injury in steatotic livers but had no effect on overall steatotic liver mitochondrial function or individual mitochondrial complex enzyme activities.
CONCLUSION: Warm IRI impairs steatotic liver Complex-I activity and function. The protective effects of IPC in steatotic livers may not be mediated through mitochondria.
Core tip: We report a detailed mitochondrial function analysis of dietary-induced hepatic steatosis, which was not choline-deficient, during warm ischemia and after ischemia-reperfusion injury. We evaluated mitochondrial complex I and II activities as well as the impact of ischemic preconditioning on mitochondrial function. This study demonstrates that steatotic livers have decreased Complex-I activity at baseline and that Complex-I function is further impaired after warm ischemia-reperfusion injury. Ischemic preconditioning was unable to attenuate the harmful effect of ischemia-reperfusion on mitochondrial function.
