Molecular Mechanisms of Drug-Induced Liver Injury
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Project Summary/Drug-induced liver toxicity is a common cause of liver injury accounting for approximately one-half of the casesof acute liver failure. Currently there is no effective treatment for acute liver failure aside from livertransplantation, which remains a very difficult surgery with a multitude of possible complications and a highclinical and financial cost. Associated with acute liver failure are serious non-hepatic consequences, such asimpaired renal and brain function, which negatively impacts patient survival. Therefore, gaining greaterunderstanding into the molecular pathology contributing to the progression and complications from acute liverfailure could lead to an improvement in patient care, quality of life and a reduction in medical expenditures. Wehave previously shown that there is increased expression and secretion of transforming growth factor Î²1(TGFÎ²) from hepatocytes in a mouse model of acute liver failure and that this increase in circulating TGFÎ² canincrease blood brain barrier permeability and contribute to the resulting neurological complications. Theobjective of this proposal is to investigate the downstream consequences of aberrant TGFÎ² signaling on drug-induced hepatotoxicity and the development of hepatic encephalopathy with a specific emphasis on IGF1signaling. Based upon strong preliminary data, we propose the novel central hypothesis that during acute liverfailure, aberrant hepatic TGFÎ² signaling suppresses both circulating and central bioavailability of IGF1 viadifferential 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 TGFÎ² results inincreased IGF1 degradation and clearance from the periphery and contributes to hepatocyte cell death; and 2)Increased circulating TGFÎ² contributes to the development of hepatic encephalopathy by downregulation ofneuronal IGF1 expression and a subsequent increase in neuroinflammation. The completion of the proposedstudies will provide greater understanding into the molecular pathology contributing to acute liver failure and itscomplications, which would lead to the identification of novel therapeutic targets that could greatly benefit theUS healthcare system by improving patient morbidity and mortality, quality of life, and reducing medicalexpenditures.