Abstract

Studies in animals support the human observation in that steatotic livers are more sensitive to liver damage following ischemia and reperfusion (I/R) than lean livers. Basal differences between lean and steatotic livers include increased hepatocyte fat content, alterations in hepatocyte substrate metabolism, ATP content, and up-regulation of mitochondrial uncoupling protein-2 (UCP2). Further, we have shown that toll-like receptor 4 (TLR4) expression is increased in steatotic livers. We believe these differences place steatotic livers in a compromised state that leads to liver dysfunction when an additional stress, such as I/R, is encountered. We have shown that 1) mice with steatotic livers have increased liver damage including hepatocyte necrosis and apoptosis compared to mice with lean livers following I/R;2) mice with steatotic livers are more susceptible to endotoxin-induced hepatocyte injury, which increases during I/R;3) neutralization of endotoxin partially blocks hepatocyte injury following I/R in mice with steatotic livers;4) UCP2 and TLR4 are upregulated in mice with steatotic livers;5) UCP2 knockout mice with steatotic livers exhibit less hepatocyte injury following I/R;and 6) mice with steatotic livers exhibit mitochondrial dysfunction and decreased ATP levels basally and following I/R. These studies have led us to the hypothesis that: the combination of UCP2 and TLR4 upregulation sensitizes steatotic hepatocytes to cell death following I/R. To gain a clear understanding of the significance of this in steatotic livers, we have developed the following three aims: 1) Define the role(s) of UCP2 in hepatocyte necrosis and apoptosis, and mitochondrial dysfunction in mice with steatotic livers subjected to I/R. 2) Elucidate the role of the endotoxin receptor, TLR4, in the increased sensitivity of steatotic livers to I/R. 3) Using isolated hepatocytes, determine the mechanism(s) by which UCP2 increases the sensitivity of steatotic hepatocytes to necrotic cell death and mitochondrial dysfunction following hypoxia/reoxygenation (H/R) injury.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069369-04
Application #
7663831
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Doo, Edward
Project Start
2006-09-05
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$284,808
Indirect Cost

  Institution

Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425

  Publications

Geng, Tuoyu; Sutter, Alton; Harland, Michael D et al. (2015) SphK1 mediates hepatic inflammation in a mouse model of NASH induced by high saturated fat feeding and initiates proinflammatory signaling in hepatocytes. J Lipid Res 56:2359-71
Palanisamy, Arun P; Taber, D J; Sutter, A G et al. (2015) Clinical outcomes and costs associated with in-hospital biliary complications after liver transplantation: a cross-sectional analysis. J Gastrointest Surg 19:282-9
Sutter, Alton G; Palanisamy, Arun P; Lench, Julie H et al. (2015) Development of steatohepatitis in Ob/Ob mice is dependent on Toll-like receptor 4. Ann Hepatol 14:735-43
Zhou, Shaotang; Palanisamy, Arun P; McGillicuddy, John W et al. (2014) New method of stent-facilitated arterial reconstruction for orthotopic mouse liver transplantation. J Surg Res 187:297-301
Palanisamy, Arun P; Cheng, Gang; Sutter, Alton G et al. (2014) Mitochondrial uncoupling protein 2 induces cell cycle arrest and necrotic cell death. Metab Syndr Relat Disord 12:132-42
Sutter, Alton G; Palanisamy, Arun P; Ellet, Justin D et al. (2014) Intereukin-10 and Kupffer cells protect steatotic mice livers from ischemia-reperfusion injury. Eur Cytokine Netw 25:69-76
Cheng, Gang; Palanisamy, Arun P; Evans, Zachary P et al. (2013) Cerulenin blockade of fatty acid synthase reverses hepatic steatosis in ob/ob mice. PLoS One 8:e75980
Brunetti-Pierri, N; Ng, Philip (2013) Adenoviral Vectors for Hemophilia Gene Therapy. J Genet Syndr Gene Ther 2:017
Evans, Zachary P; Palanisamy, Arun P; Sutter, Alton G et al. (2012) Mitochondrial uncoupling protein-2 deficiency protects steatotic mouse hepatocytes from hypoxia/reoxygenation. Am J Physiol Gastrointest Liver Physiol 302:G336-42
Ellett, Justin D; Atkinson, Carl; Evans, Zachary P et al. (2011) Toll-like receptor 4 knockout mice are protected from endothelial overactivation in the absence of Kupffer cells after total hepatic ischemia/reperfusion. Liver Transpl 17:1089-98

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