ABSTRACT This application is for the continuation of the Cleveland Clinic clinical site and its subsites of the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Nonalcoholic fatty liver disease (NAFLD) affects nearly a third of adults and a fifth of children in North America and is a major public health issue in the United States. NAFLD, and the more severe form, nonalcoholic steatohepatitis (NASH), lead to cirrhosis and primary liver cancer, as well as liver-, cardiovascular-, and cancer-related morbidity and mortality, resulting in major increases in health care burdens and costs. The NASH CRN is ideally and uniquely positioned to impact the continuing public health burden of NASH that can only be addressed through this large research consortium with a demonstrated track record of success in previous cycles. The primary objective of the NASH CRN is to perform high quality, reproducible clinical research on NASH and NAFLD in adults and children focusing on the pathogenesis that will provide the basis for understanding the natural history and developing means of better diagnosis, treatment, and clinical management. In this funding cycle of the NASH CRN, the adult and pediatric therapeutic trials initiated during the previous funding cycle will be completed, and new therapeutic trials, including phase 2a proof of mechanism and phase 2b clinical trials will be initiated to develop evidence-based treatment options that are safe, effective, and inexpensive. Specifically, we propose to repurpose vitamin D3 (cholecalciferol) as a treatment for NASH by proposing a network wide study comparing 5000 IU to 1000 IU daily for 24 months. The longitudinal cohort of adults and children with NAFLD will be extended, which will prospectively define the natural history of the disease, the cardiovascular and metabolic risk factors, and will aid in biomarker discovery and validation, and the development and validation of non-invasive techniques to evaluate and identify patients with NASH/NAFLD, responders to interventions and determine the rate of disease progression. We will include patients being evaluated for and undergoing bariatric surgery to this cohort. Finally, we will use a reverse translational approach to develop novel biomarkers and identify potential therapeutic targets in NASH. Specifically, we will evaluate a novel functional assay for high density cholesterol and a microRNA signature for NAFLD using the biorepository samples and resources from the previous funding cycles to complement the current studies for this aim. The Cleveland site has played a key role in both the clinical and translational research success of the NASH CRN since its inception. We have been a leading enrolling site in the PIVENS and FLINT trials in adults and TONIC and CynCh trials in children. The Cleveland site investigators are uniquely placed in improving the understanding of systemic abnormalities including cardiovascular and metabolic perturbations in NAFL...