Currently, there are over 17,000 people on the UNOS waiting list for a liver transplant. Unfortunately, slightly over 5,000 livers are available yearly to satisfy this need. Exacerbating this problem, 25-30% of livers are routinely rejected for transplantation because of their increased intracellular fat content (steatosis). When transplanted, livers with high amounts of steatosis undergo a phenomenon called primary non-function (PNF), which is liver graft failure for reasons other than surgical error or rejection. There is massive hepatocyte necrosis, and ultimately, there is not enough remaining liver mass to sustain life. In our laboratory, we have identified two molecules which we believe are ultimately responsible for PNF in steatotic livers. The first, uncoupling protein-2 (UCP2), is upregulated in the mitochondria in situations of substrate excess, as in steatosis, and short-circuits the electron transport chain to deal with the excess reducing potential. However, during periods of stress, such as during liver transplantation, UCP2 prevents cells from being able to produce appropriate amounts of ATP and the cells die of necrosis because of energy deficit. The other molecule, toll-like receptor-4 (TLR4), is the main receptor for LPS. We have shown that removal of LPS with an antibody prior to steatotic liver ischemia/reperfusion dramatically improves the survival rate in steatotic animals. Therefore, we are investigating the surface receptor, TLR4, as a potential therapeutic target to improve the performance of steatotic livers after transplantation. We believe that pharmacological targeting of these two molecules will allow us to use steatotic livers in the future, thereby dramatically improving the liver donor pool.