Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat is stored in the liver in people who drink little or no alcohol. NAFLD is the most common cause of liver disease worldwide with an estimated global prevalence of 25.24%. The disease spectrum of NAFLD. L-R: Healthy liver, simple hepatosteatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Currently, there are no FDA-approved drugs for the treatment of NASH, which is becoming the leading cause of liver transplantation in the US. In recent decades, it has been suggested that changes in the lifestyles clearly drive the risk in the prevalence of NAFLD. However, hepatic fat content varies substantially among individuals with equivalent adiposity, indicating that genetic factors contribute to the development of NAFLD. To identify new mechanisms of NAFLD, we utilized a forward genetic screening platform to identify genes that affect hepatic fat content in mice. The screening and automated meiotic mapping detected mutations in many genes that were previously known or not known to regulate body weight, liver triglyceride, and other aspects of metabolism. Consistent with the concept that obesity is one of the major risk factors for NAFLD, we noticed a tight connection between body weight and liver triglyceride levels in most of the mutants identified. Nevertheless, the screen identified more than 20 genes in which mutations affect liver triglyceride with no change in body weight. We are currently working on these novel genes to identify new mechanisms of NAFLD.