Here we investigate the effects of expressing an activated mutant of Notch (ICD-E) in an inducible transgenic mouse model. Hepatic expression of ICD-E in adult animals has no detectable phenotype, but simultaneous induction of ICD-E in both the liver and small intestine results in hepatic steatosis, lipogranuloma formation and mild insulin resistance within 96 hours. This supports work that suggests that fatty liver disease may result from disruption of the gut-liver axis. In the intestine, ICD-E expression is known to produce a transient change in the proportion of goblet cells followed by shedding of the recombinant epithelium. We report additional intestinal transcriptional changes following ICD-E expression, finding significant transcriptional down-regulation of rpL29 (ribosomal protein L29), which is implicated in the regulation of intestinal flora. These results provide further evidence of a gut-liver axis in the development of fatty liver disease and insulin resistance and validate a new model for future studies of hepatic steatosis.