Previously we have shown that conditional expression of an activated Notch mutant fused to Enhanced Green Fluorescent Protein in the intestine of adult mice PD 151746 results in a transient increase in goblet cells on the villus, within 24 hours of Notch activation, followed by crypt apoptosis and shedding of the recombinant epithelium. This conditional expression system also results in gene expression in the liver, where Notch has been shown to regulate bile duct formation in developing and early post-natal mice. Here we report that whereas ICD-E expression in the adult mouse liver alone has no detectable phenotype, induction of ICDE in the intestine and liver of adult mice results in fatty liver RBx-0597 disease associated with lipogranuloma formation and insulin resistance within four days. Further, we identify transcripts altered by ICD-E expression in the intestine, including rpL29 which has a role in innate immunity. These results provide further support for the role of the intestine in NAFLD and describe a new model of this disease. We therefore investigated the effects of increasing the dose of bNF to induce gene expression in the liver and small intestine simultaneously. mRNAs encoding ICD-E or EYFP were readily detectable in both the liver and in the intestine at 24 hours postinduction. In addition, immunohistochemistry revealed nuclear localized staining in the ICD-E animals and diffuse cytoplasmic staining in EYFP controls, consistent with in vitro results. Strikingly, small cytoplasmic vacuoles were visible in hepatocytes in experimental mice at 24 hours post-induction. By 96 hours the experimental livers had large fat filled vacoules, which was confirmed with the lipid stain Sudan III. Areas of leukocytic infiltration consistent with lipogranuloma formation were also seen. We undertook a systematic histological evaluation of the livers, scoring the severity of steatosis and lipogranuloma formation. There were statistically significant differences in both steatosis grade and the occurrence of lipogranuloma in experimental animals compared with controls at 96 hours postinduction.