Nonalcoholic fatty liver disease (NAFLD) is characterized by an abnormal accumulation of lipids in the hepatocytes and affects 25% of the world population. NAFLD can progress to NASH, liver fibrosis, cirrhosis and hepatocellular carcinoma. NASH is now the second indication for liver transplantation and will likely become the primary indication for liver transplantation by 2020. Despite the high prevalence, our understanding of the disease is still very limited and there is no therapy for the treatment of NASH. With this proposal we will: (1) Identify the mouse model that better reproduces the human disease, and will allow to test new drugs and drug targets; (2) identify a novel set of genes that characterize NASH/NAFLD in mice, with the goal to translate these findings to humans.