Project Summary/Abstract Drug-induced liver toxicity is a common cause of liver injury accounting for approximately one-half of the cases of acute liver failure. Currently there is no effective treatment for acute liver failure aside from liver transplantation, which remains a very difficult surgery with a multitude of possible complications and a high clinical and financial cost. Associated with acute liver failure are serious non-hepatic consequences, such as impaired renal and brain function, which negatively impacts patient survival. Therefore, gaining greater understanding into the molecular pathology contributing to the progression and complications from acute liver failure could lead to an improvement in patient care, quality of life and a reduction in medical expenditures. We have previously shown that there is increased expression and secretion of transforming growth factor β1 (TGFβ) from hepatocytes in a mouse model of acute liver failure and that this increase in circulating TGFβ can increase blood brain barrier permeability and contribute to the resulting neurological complications. The objective of this proposal is to investigate the downstream consequences of aberrant TGFβ signaling on drug- induced hepatotoxicity and the development of hepatic encephalopathy with a specific emphasis on IGF1 signaling. Based upon strong preliminary data, we propose the novel central hypothesis that during acute liver failure, aberrant hepatic TGFβ signaling suppresses both circulating and central bioavailability of IGF1 via differential mechanisms, and strategies to restore IGF1 levels can be hepatoprotective and neuroprotective. Two specific aims have been designed to test this working hypothesis: 1) Aberrant hepatic TGFβ results in increased IGF1 degradation and clearance from the periphery and contributes to hepatocyte cell death; and 2) Increased circulating TGFβ contributes to the development of hepatic encephalopathy by downregulation of neuronal IGF1 expression and a subsequent increase in neuroinflammation. The completion of the proposed studies will provide greater understanding into the molecular pathology contributing to acute liver failure and its complications, which would lead to the identification of novel therapeutic targets that could greatly benefit the US healthcare system by improving patient morbidity and mortality, quality of life, and reducing medical expenditures.