Nonalcoholic steatohepatitis is a common chronic liver disease but its pathogenesis is not well understood. Recent animal studies have suggested that microsomal enzymes may play a role in the pathogenesis of non-alcoholic steatohepatitis (NASH). In order to further understand the role of microsomal enzymes in the pathogenesis of NASH, we propose to conduct the following human studies. (1) We will conduct a study to test the hypothesis that microsomal enzymes play a role in the pathogenesis of NASH as a second hit. We will measure the activity of selected microsomal enzymes in obese with NASH as compared to fatty liver alone and normal liver histology. We also examine the relationship between the activity of selected microsomal enzymes and markers of oxidative stress, hepatic fibrosis and fibrogenesis, (2) We will conduct a study to test the hypothesis that insulin resistance plays a role in the pathogenesis of increased CYP2E1 activity, and its reversal by the administration of rosiglitazone will lower the CYP2E1 activity. In this study, we will measure the hepatic CYP2E1 activity and the levels of serum and urinary markers of lipid peroxidation before and after the administration of rosiglitazone for 16 wks., (3) We will test the hypothesis that microsomal enzymes are an important source of oxidative stress and lipid peroxidation in humans with NASH by measuring the levels of hepatic CYP2E1 activity and lipid peroxidation before and administering a selective mechanism-based CYP2E1 inhibitor, bis (diethylthiocarbamoyl) disulfide, (4) Studies have suggested that microsomal enzymes may play a role in the pathogenesis of NASH in adults, however, it is unknown if they play any role in the pathogenesis of NASH in children. We will conduct a study to characterize a microsomal enzyme known to generate oxidative stress in children with NASH and obese and lean controls. Additionally, we examine the relationship between this enzyme activity and the degree of insulin resistance and lipid peroxidation.
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