This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. While biochemically normal at rest, steatotic livers have an intrinsically impaired ability to manage energy deficit (decreased ATP) associated with ischemia/reperfusion (I/R) and are more susceptible to damage from circulating factors (especially endotoxin). The specific research objectives of this project are addressing our underlying hypothesis that steatotic hepatocytes are more susceptible to I/R injury due to an upregulation of uncoupling protein-2 (UCP2), have increased sensitivity to endotoxin, and have altered biochemical pathways secondary to substrate excess. We believe that through the coordinated manipulation of these parameters, it will be possible to transiently protect the steatotic liver and thereby decrease the damage incurred from I/R. To investigate this, first, we are investigating the associated mechanisms of protecting steatotic livers from irreversible damage from endotoxin in vivo in the setting of I/R. Second, we are inhibiting fatty acid synthase in an effort to protect steatotic hepatocytes from steatosis. Finally, we will determine the effectiveness of transient attenuation of UCP2 expression in vitro and in vivo to decrease the global sensitivity of steatotic hepatocytes to I/R injury. Our goals are being accomplished in vitro, using freshly isolated and culture hepatocytes. In addition, we are using both our warm ischemia and liver transplant mouse models. We anticipate that the results from this work will facilitate a better understanding of the hepatocyte dysfunction that occurs when steatotic livers are transplanted. Thus far, we have made progress in defining the biochemical status of the steatotic liver in relation to I/R, specifically in relation to the effects of UCP2 expression. This is giving us more insight into the future design of therapeutic mediators. It is ultimately hoped that the results from this project will lead to increased success of steatotic livers after transplantation thus expanding the pool of available donor livers.
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