Project Summary Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) ranks as one of the most important causes of chronic liver disease in the United States, with 1 of every 3 adults and 1 of every 5 children affected. NAFLD, especially NASH, is associated with increased liver, cardiovascular and cancer-related mortality. The NASH Clinical Research Network (NASH CRN) was established in 2002 to conduct research related to its clinical features, risk factors, pathogenesis, natural history and treatment in children and adults. Over the last funding cycle, the CRN has accrued a comprehensive database of 4,544 patients from five studies during the current funding period (to 1 Oct 18). Two clinical trials were completed (FLINT and CyNCh) and The Losartan for Pediatric NAFLD (STOP-NAFLD) trial is underway with first patient randomized in Oct 2018. Additionally, the NASH CRN has archived a total of 504,685 biospecimens (serum, plasma, liver tissue, DNA ad cDNA) in the NIDDK Biorepository, and 28,436 samples have been withdrawn for translational research using the Ancillary Studies mechanism. Since 2004, a total of 31 publications have resulted from the 104 approved Ancillary Studies. Building on the success of the last funding cycle, the NIDDK has issued RFA- DK-08-505 with the objectives of continue the NASH CRN for an additional 5 years. The objectives of the NASH CRN during this next funding period are: (a) to complete the network-wide studies initiated during the last funding period. These are two observational longitudinal cohort studies (the Adult and Pediatric NAFLD Database 2 studies) and a randomized double blind controlled therapeutic trial of losartan for NAFLD in children (STOP-CO, n=110). The NAFLD database may be amended to meet additional outcome goals during the next funding period. These modifications may include extending the length of follow-up of those enrolled, consideration of a follow-up liver biopsy in a subset of patients, and expansion to include greater focus on cardiovascular, diabetes and cancer-related outcomes; (b) to conduct new translational studies based on the clinical material and archived biospecimens from previous funding periods including novel markers of autophagy, an important means of controlling cellular lipids that is understudied relative to other lipid-regulating pathways in the liver and potential role in NAFLD disease severity; and (c) to conduct additional novel therapeutic studies in adults and children with NASH, such as the proposed phase 2 study of amlodipine, as pro-autophagic therapy, in children and adults with NASH (AMPAT Trial). Ancillary studies will leverage new collaborations (e.g. immunology, microbiome) to develop a comprehensive model of NAFLD/NASH which will allow identification of adults and children at risk and establish effective preventive and treatment strategies against NASH.