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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Kim, Kyu Min; Han, Chang Yeob; Kim, Ji Young et al. (2018) G?12 overexpression induced by miR-16 dysregulation contributes to liver fibrosis by promoting autophagy in hepatic stellate cells. J Hepatol 68:493-504
Picca, Anna; Mankowski, Robert T; Burman, Jonathon L et al. (2018) Mitochondrial quality control mechanisms as molecular targets in cardiac ageing. Nat Rev Cardiol 15:543-554
Kim, Do-Sung; Song, Lili; Wang, Jingjing et al. (2018) Carbon Monoxide Inhibits Islet Apoptosis via Induction of Autophagy. Antioxid Redox Signal 28:1309-1322
Chun, Sung Kook; Lee, Sooyeon; Flores-Toro, Joseph et al. (2018) Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers. Aging Cell :e12761
Cho, Joonseok; Zhang, Yujian; Park, Shi-Young et al. (2017) Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance. Nat Commun 8:14477
Chun, Sung Kook; Lee, Sooyeon; Yang, Ming-Jim et al. (2017) Exercise-Induced Autophagy in Fatty Liver Disease. Exerc Sport Sci Rev 45:181-186
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Biel, T G; Lee, S; Flores-Toro, J A et al. (2016) Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent manner. Cell Death Differ 23:279-90
Chun, Sung Kook; Go, Kristina; Yang, Ming-Jim et al. (2016) Autophagy in Ischemic Livers: A Critical Role of Sirtuin 1/Mitofusin 2 Axis in Autophagy Induction. Toxicol Res 32:35-46
Law, Mary E; Ferreira, Renan B; Davis, Bradley J et al. (2016) CUB domain-containing protein 1 and the epidermal growth factor receptor cooperate to induce cell detachment. Breast Cancer Res 18:80

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