Mitochondrial dysfunction is the major mechanism precipitating I/R injury which commonly occurs during liver surgery, trauma, hemorrhagic shock and liver transplantation. Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase that induces longevity, stress resistance and tumor suppression. The role of SIRT1 in ischemia/reperfusion-mediated liver injury is unknown. The goal of this study is to investigate the role of SIRT1 in I/R injury to liver and to develop therapeutic strategies to improve liver function after I/R. Our principal hypothesis is that calpain-dependent SIRT1 loss causes a sequential chain of defective mitophagy, mitochondrial permeability transition (MPT) onset and hepatocyte death after I/R. Accordingly, we propose that restoration or enhancement of hepatic SIRT1 will promote mitophagy and consequently ameliorate mitochondrial failure and liver dysfunction after reperfusion. To test our hypothesis, we will use hepatocytes isolated from SIRT1 wild type (WT) and knockout (KO) mice for characterization of cellular mechanisms causing SIRT1 depletion, defective mitophagy, and onset of the MPT and cell death after I/R. In addition, we will use anesthetized WT and KO SIRT1 mice to confirm and extend our in vitro findings to an in vivo model of hepatic I/R. Finally, we will extend and translate our findings from mice into human liver biopsies. These studies provide critical mechanistic insights into lethal I/R injury to the lver, and will establish novel therapeutic approaches for improving I/R-mediated liver failure.

Public Health Relevance

Impairment of blood flow causes a tissue ischemia and recovery of blood flow causes reperfusion injury to liver. Ischemia/reperfusion (I/R) injury is a causative factor of morbidity and mortality during liver resection, hemorrhagic shock, trauma, and transplantation. I/R injury remains a fundamental complication of hepatic surgery, and patients with preexisting liver diseases that often require inflow occlusion are more likely to develop severe postoperative I/R injury. Better understanding of the mechanisms underlying ischemia/reperfusion injury would establish novel therapeutic approaches for improving liver function after liver surgery.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Sherker, Averell H
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University of Florida
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Akin, Debra; Wang, S Keisin; Habibzadegah-Tari, Pouran et al. (2014) A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy 10:
Fischer, Trevan D; Wang, Jin-Hee; Vlada, Adrian et al. (2014) Role of autophagy in differential sensitivity of hepatocarcinoma cells to sorafenib. World J Hepatol 6:752-8
Czaja, Mark J; Ding, Wen-Xing; Donohue Jr, Terrence M et al. (2013) Functions of autophagy in normal and diseased liver. Autophagy 9:1131-58
Kim, Jae-Sung; Wang, Jin-Hee; Biel, Thomas G et al. (2013) Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers. Toxicol Appl Pharmacol 273:600-10
Dutta, Debapriya; Xu, Jinze; Kim, Jae-Sung et al. (2013) Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity. Autophagy 9:328-44
Park, Bonggoo; Lee, Yong-Moon; Kim, Jae-Sung et al. (2013) Neutral sphingomyelinase 2 modulates cytotoxic effects of protopanaxadiol on different human cancer cells. BMC Complement Altern Med 13:194
Law, M E; Corsino, P E; Jahn, S C et al. (2013) Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms. Oncogene 32:1316-29
Wang, Jin-Hee; Behrns, Kevin E; Leeuwenburgh, Christiaan et al. (2012) Critical role of autophage in ischemia/reperfusion injury to aged livers. Autophagy 8:140-1
Kim, Jae-Sung; Wang, Jin-Hee; Lemasters, John J (2012) Mitochondrial permeability transition in rat hepatocytes after anoxia/reoxygenation: role of Ca2+-dependent mitochondrial formation of reactive oxygen species. Am J Physiol Gastrointest Liver Physiol 302:G723-31
Wang, Jin-Hee; Ahn, In-Sook; Fischer, Trevan D et al. (2011) Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice. Gastroenterology 141:2188-2199.e6

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