PROJECT ABSTRACT Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) represent a major cause of liver disease morbidity and mortality. The NASH Clinical Research Network (NASH CRN) has been sponsored by the NIDDK since 2002 and is an international leader in clinical studies of NASH. The overarching objective of this application is to pursue clinical and translational research in NASH that will ultimately lead to improvement in the management of patients with NAFLD and NASH. There remains a need to understand the burden of liver disease and other causes of morbidity and mortality in NASH. New medications for adults with NASH are currently in clinical trials but no therapies are currently in development for children. Thus there is a need for the NASH CRN to continue our leadership in clinical trials for NASH. This application is for the Continuation of the Seattle Clinical Center of the NASH CRN, which has been part of the NASH CRN since 2002 and represents a large geographic area with a unique patient population. Several specific aims are proposed that will advance the objectives of the NASH CRN during the next period of funding. We will continue enrollment and longitudinal follow-up of NAFLD and NASH patients in the adult and pediatric Database studies, which include over 3,000 adults and children with biopsy-proven NASH. Detailed information about recruitment and retention plans are provided. The STOP-NAFLD clinical trial has begun enrollment and will examine the safety and efficacy of losartan for pediatric NASH. We will actively contribute to this study through our collaboration with Seattle Childrens Hospital. We will also actively participate in adult NASH trials and make these studies a priority at our clinical center. A translational aim has been proposed that will utilize the biospecimens and clinical data of patients in the Database studies to examine the role of hepatic iron deposition on innate immunity and relationship to NASH progression. We also describe new transcriptomic studies in NASH via a new collaboration with the Institute for Systems Biology that will provide mechanistic insights and a systems approach for the study of NASH. Finally we propose a clinical trial of low- dose vitamin E in patients with and without type 2 diabetes. Although vitamin E was shown to be effective in the PIVENS trial, safety concerns have been raised with higher doses and there are few controlled trials examining its efficacy in patients with diabetes. The PI and Seattle Clinical Center have been leaders in the NASH CRN since its inception and we remain fully committed to ensuring the success and impact of this network in improving liver health and advancing the mission of the NIDDK.