Steatosis or lipid accumulation in non-adipocytes occurs in about 25 percent of cadaveric livers used for transplantation. Although usually asymptomatic, hepatic steatosis is a significant risk factor for postoperative liver failure, as fatty livers are much more sensitive to ischemia-reperfusion injury than normal """"""""lean"""""""" livers. Thus, fatty livers are often considered to be """"""""marginally acceptable"""""""" for transplantation. Our long-term goal is to develop a metabolic pre-conditioning regimen, which reduces hepatic lipid storage and increases the liver's ability to withstand ischemia-reperfusion injury. We hypothesize that metabolic pre-conditioning will reduce the risk of postoperative liver dysfunction to a level similar to that observed in non-steatotic livers.
Our specific aims are: (1) To characterize the metabolic and vascular homeostatic mechanisms in steatotic livers; (2) To intervene via metabolic conditioning techniques to reduce the sensitivity of hepatocytes and perfused livers to ischemia-reperfusion injury; (3) To optimize metabolic conditioning techniques for livers used in pre-clinical models of liver surgery. In the short-term, the proposed studies could (1) provide the rationale basis for increasing the liver donor pool size, as severely steatotic livers are usually discarded; (2) improve the outcome of patients which receive liver transplants with mild to moderate steatosis; and (3) provide new ways to prevent or limit hepatic fibrosis, as hepatic steatosis often precedes fibrosis in degenerative liver diseases. The long-term outcomes of this project are (1) scientific and technology bases to develop defatting methods for other organ systems affected by steatosis, such as pancreatic beta cells and cardiomyocytes in obese individuals; and (2) warm perfusion techniques with the potential to significantly increase organ storage time beyond the limits of current cold storage techniques.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK059766-01A1
Application #
6491296
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (02))
Program Officer
Serrano, Jose
Project Start
2002-09-15
Project End
2006-08-31
Budget Start
2002-09-15
Budget End
2003-08-31
Support Year
1
Fiscal Year
2002
Total Cost
$424,808
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Yarmush, Gabriel; Santos, Lucas; Yarmush, Joshua et al. (2016) Metabolic Flux Distribution during Defatting of Steatotic Human Hepatoma (HepG2) Cells. Metabolites 6:
Izamis, Maria-Louisa; Perk, Sinem; Calhoun, Candice et al. (2015) Machine perfusion enhances hepatocyte isolation yields from ischemic livers. Cryobiology 71:244-55
Nativ, Nir I; Yarmush, Gabriel; So, Ashley et al. (2014) Elevated sensitivity of macrosteatotic hepatocytes to hypoxia/reoxygenation stress is reversed by a novel defatting protocol. Liver Transpl 20:1000-11
Nativ, Nir I; Chen, Alvin I; Yarmush, Gabriel et al. (2014) Automated image analysis method for detecting and quantifying macrovesicular steatosis in hematoxylin and eosin-stained histology images of human livers. Liver Transpl 20:228-36
Liu, Qiang; Izamis, Maria-Louisa; Xu, Hongzhi et al. (2013) Strategies to rescue steatotic livers before transplantation in clinical and experimental studies. World J Gastroenterol 19:4638-50
Nativ, Nir I; Yarmush, Gabriel; Chen, Alvin et al. (2013) Rat hepatocyte culture model of macrosteatosis: effect of macrosteatosis induction and reversal on viability and liver-specific function. J Hepatol 59:1307-14
Patel, Suraj J; Milwid, Jack M; King, Kevin R et al. (2012) Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure. Nat Biotechnol 30:179-83
Tolboom, Herman; Izamis, Maria-Louisa; Sharma, Nripen et al. (2012) Subnormothermic machine perfusion at both 20°C and 30°C recovers ischemic rat livers for successful transplantation. J Surg Res 175:149-56
Parekkadan, Biju; Fletcher, Anne L; Li, Matthew et al. (2012) Aire controls mesenchymal stem cell-mediated suppression in chronic colitis. Mol Ther 20:178-86
Nativ, N I; Maguire, T J; Yarmush, G et al. (2012) Liver defatting: an alternative approach to enable steatotic liver transplantation. Am J Transplant 12:3176-83

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