SR family RNA binding proteins regulate splicing of nascent RNAs in vitro but their physiological role in vivo is largely unexplored, as genetic deletion of many SR protein genes results in embryonic lethality. Here we show that SRSF1HKO mice ASF/SF2) have normal growth yet disrupted hepatocyte morphology. SRSF1HKO exhibit alterations in cell cycle regulation and lipid homeostasis characterized by heterogeneous hepatocyte populations, distorted glycogen storage, increased hepatic TG, and development of liver steatosis. The accumulation of lipids in the liver is associated with aging and is due to a decreased in triglyceride secretion but a normal rate of lipid synthesis. Our study provides the first evidence for a role of Srsf1 in morphological and functional differentiation of hepatocytes that may have relevance for human liver disease and metabolic dysregulation associated with a development of steatosis. SRSF1HKO is an essential mouse model in the pursuit of understanding the function of SR proteins in alternative splicing and its contribution to metabolic disease

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Serine-arginine rich splicing factor 3 (SRSF3) plays a critical role in hepatocyte function and its loss in mice promotes chronic liver damage and leads to HCC. Hepatocyte-specific SRSF3 knockout mice (SKO mice) also overexpress insulin-like growth factor 2 (IGF2). In the present study, double deletion of Igf2 and Srsf3 (DKO mice) prevents hepatic fibrosis and inflammation, and completely prevents tumor formation, and is associated with decreased proliferation, apoptosis and DNA damage, and restored DNA repair enzyme expression. This is confirmed in vitro, where IGF2 treatment of HepG2 hepatoma cells decreases DNA repair enzyme expression and causes DNA damage. Tumors from the SKO mice also show mutational signatures consistent with homologous recombination and mismatch repair defects. Analysis of frozen human samples shows that SRSF3 protein is decreased sixfold in HCC compared to normal liver tissue but SRSF3 mRNA is increased. Looking at public TCGA data, HCC patients having high SRSF3 mRNA expression show poor survival, as do patients with alterations in known SRSF3-dependent splicing events. The results indicate that IGF2 overexpression in conjunction with reduced SRSF3 splicing activity could be a major cause of DNA damage and driver of liver cancer.