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J. Biol. Chem., Vol. 283, Issue 13, 8573-8579, March 28, 2008

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Mitochondrial Uncoupling Protein-2 Mediates Steatotic Liver Injury following Ischemia/Reperfusion^*

Zachary P. Evans, Justin D. Ellett, Michael G. Schmidt, Rick G. Schnellmann, and Kenneth D. Chavin^¶1

From the Departments of Microbiology and Immunology, Pharmaceutical Sciences, and ^¶Transplant Surgery, Medical University of South Carolina, Charleston, South Carolina 29425

Steatotic livers are not used for transplantation because they have a reduced tolerance for ischemic events with reduced ATP levels and greater levels of cellular necrosis, which ultimately result in total organ failure. Mitochondrial uncoupling protein-2 (UCP2) is highly expressed in steatotic livers and may be responsible for liver sensitivity to ischemia through mitochondrial and ATP regulation. To test this hypothesis, experiments were conducted in lean and steatotic (ob/ob), wild-type, and UCP2 knock-out mice subjected to total warm hepatic ischemi-a/reperfusion. Although ob/ob UCP2 knock-out mice and ob/ob mice have a similar initial phenotype, ob/ob UCP2 knock-out animal survival was 83% when compared with 30% in ob/ob mice 24 h after reperfusion. Serum alanine aminotransferase concentrations and hepatocellular necrosis were decreased in the ob/ob UCP2 knock-out mice when compared with ob/ob mice subjected to ischemia. Liver ATP levels were increased in the ob/ob UCP2 knock-out animals after reperfusion when compared with the ob/ob mice but remained below the concentrations from lean livers. Lipid peroxidation (thiobarbituric acid-reactive substances) increased after reperfusion most significantly in the steatotic groups, but the increase was not affected by UCP2 deficiency. These results reveal that UCP2 expression is a critical factor, which sensitizes steatotic livers to ischemic injury, regulating liver ATP levels after ischemia and reperfusion.

Received for publication, August 14, 2007 , and in revised form, November 21, 2007.

^* This work was supported by National Institutes of Health Grants 1R01DK069369 and 5P20RR017677-05. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Transplant, Dept. of Surgery, Medical University of South Carolina, 96 Jonathan Lucas St., CSB Suite 404, Charleston, SC 29425. Fax: 843-792-8596; E-mail: chavinkd{at}musc.edu.

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