Using a non-invasive cell-based system to evaluate disease activity, determine molecular mechanism and target new therapeutics with particular emphasis on fibrosis in obesity

Obesity is a major risk factor for the development of Nonalcoholic steatohepatitis (NASH). Hepatic fibrosis leading to cirrhosis is amajor health problem in patients infected with NASH. In the western countries 60% of obese people have simple steatosis, 20-25% have NASH and 2-3% have cirrhosis. Obesity remains a risk factor for cirrhosis-related death. The current therapeutic options for NASH are few. The fibrogenic stimulation index (FSI) has the potential to stage NASH. The proposed studies are designed to use the FSI to assess fibrosis in the obese mouse model of NASH, determine the molecular events occurring in the obese mouse model of NASH, assess potential new drug therapy and to determine if antisense will alter fibrotic indices including FSI. We have previously reported that pentoxifylline is antifibrotic in an experimental model of hepatic fibrosis and the FSI predicted its beneficial effect. Knowledge translation is an important aspect of this study as we will translate complex molecular information into screening tests and potential new therapy and critical information for obese patients with NASH. This study will likely identify the tremendous benefit of novel antifibrotic drugs and assess current drugs used to treat NASH in the obese population in reducing the fibrotic indices in NASH.