Abstract This application is for the renewal of the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) clinical center at Saint Louis University and its pediatric component at Baylor University. The NASH Clinical Research Network (NASH CRN) has been sponsored by the NIDDK since 2002 with renewals in 2009, 2014 and 2019. Metabolic dysfunction associated steatotic liver disease (MASLD, previously called NAFLD) affects more than one out of three adults and one out of five children the U.S. MASLD, and especially its most severe subset, metabolic dysfunction associated steatohepatitis (MASH, previously called NASH), may lead to cirrhosis and primary liver cancer resulting in death or liver transplant which contributes to substantial health burdens and costs. The NASH CRN has been ideally and uniquely positioned to impact the growing public health significance of MASH that can only be addressed via a large research consortium. A primary objective of the NASH CRN has been to perform clinical trials of therapeutic agents for MASH in adults and children. A closely linked and high priority secondary objective is to conduct translational research in MASH and MASLD focusing on the pathogenesis that will provide the basis for understanding the natural history and developing better means of diagnosis, prevention, treatment, and clinical management. In this final phase of the NASH CRN, the adult vitamin E dosing trial (VEDS) initiated during the previous funding cycle will be completed. The longitudinal cohort Database-3 study of adults and children with MASLD will be wrapped up with closeout visits in year 1 to provide a unique repository of data and samples from a well-phenotyped cohort that can be used in future studies to prospectively define the natural history of the disease, the cardiovascular and metabolic risk factors, aid in biomarker discovery and validation to identify patients with at-risk MASH (MASH and at least stage 2 fibrosis) and identify factors affecting disease progression. The Saint Louis University Clinical Center of the NASH CRN will work collaboratively with the other clinical centers, SDCC and NIDDK to prioritize and conduct studies of existing datasets over the final three years of funding. Proposed in this application is a project for consideration that focuses on the role of the PNPLA3 I148M variant in sequestering and inactivating a protein called ABHD5 or CGI58. Human variants of this protein are associated with progressive liver disease and suppressed expression of this protein in rodents causes steatohepatitis. The underlying hypothesis is that basis for the PNPLA3 I148M variant contributing to progressive liver disease is its role of ABHD5/CGI-58 sequestration rather than its putative role in lipid droplet triglyceride turnover. Whether this project is pursued or other projects are given higher priority, the Saint Louis University clinical center will fully support the decision of the steering committee with inpu...