Liver cancer (hepatocellular carcinoma or HCC) is the 2nd leading cause of death from cancer worldwide and it is the only cancer for which both the incidence and mortality are rising. Traditionally liver cancer was associated with cirrhosis due to chronic hepatitis B or C viruses, or alcohol consumption but more recently obesity or the metabolic syndrome accounts for the highest attributable fraction of HCC (37%) in the US. Approximately 80-90% of obese adults have nonalcoholic fatty liver disease and the metabolic syndrome, and a subset will go on to develop inflammation and NASH. Obesity is also a risk factor for HBV and HCV- related liver cancer and even alcoholic cirrhosis-related liver cancer. Furthermore, obesity reduces the efficacy of anti-HBV vaccination, and increases HCC in individuals treated for HCV. As obese individuals are at a higher risk of developing all types of HCC (non-viral, viral and alcoholic), there is a critical need to understand the changes that occur in the liver during obesity, which can guide both prevention efforts and the development of novel efficacious treatments for HCC. Alternative RNA splicing is generally thought to fine tune gene expression and cellular function in various tissues and contexts but there is also evidence that changes in RNA splicing may have dramatic effects on the pathogenesis of disease by switching expression of protein isoforms that may have opposing or antagonistic effects. In the liver, changes in RNA splicing have been documented during development and the maturation of hepatocytes as well as in HCC but most studies in early liver disease, NAFLD or NASH, have focused on total mRNA changes rather than changes in individual mRNA isoforms and alternative splicing. The idea that these changes may be causative for, rather than the result of, liver disease is supported by accumulating evidence from genetic manipulation of individual splicing factors in mice that contribute to liver disease. Lipid and glucose metabolism, fibrosis and inflammation are all processes that may be influenced by alternative splicing and they all may contribute to disease progression. Functional assessment of isoforms is essential however, as it is not possible a priori to predict the effect of a splice variant on protein activity. We propose to study two isoform switching events in the insulin receptor (IR) and Yes associated protein 1 (YAP1), which we have documented during early NAFLD in mice and humans, that may contribute to NASH and HCC.