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 ?1 (TGF?) from hepatocytes in a mouse model of acute liver failure and that this increase in circulating TGF? 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 TGF? 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 TGF? 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 TGF? results in increased IGF1 degradation and clearance from the periphery and contributes to hepatocyte cell death; and 2) Increased circulating TGF? 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.
The health relatedness of this grant proposal arises from the lack of effective treatments for drug-induced liver injury and its associated complications such as hepatic encephalopathy. Currently the only effective treatment option is liver transplantation, which is a costly and complicated procedure that requires lifelong immunosuppressive therapy. The goal for this research proposal is to provide greater understanding of the progressive molecular mechanisms of drug-induced liver injury and elucidate novel mechanisms by which acute liver failure leads to neurological complications, and the successful completion of this proposal will provide opportunities for the development of novel treatment paradigms for the management of acute liver failure and its complications.
|Grant, Stephanie; McMillin, Matthew; Frampton, Gabriel et al. (2018) Direct Comparison of the Thioacetamide and Azoxymethane Models of Type A Hepatic Encephalopathy in Mice. Gene Expr 18:171-185|