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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069369-03
Application #
7477046
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
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$284,808
Indirect Cost
Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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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
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