The pathogenesis of NAFLD is complex and multiple processes are implicated in the accumulation of hepatic lipid. These include increased levels of plasma free fatty acids, due to increased lipolysis in adipose tissue or a high fat diet; increased de-novo lipogenesis within the liver; suppression of Very Low Density Lipoprotein secretion from the liver and decreased hepatic fatty acid oxidation. These processes may share a final common pathway in triggering endoplasmic reticulum stress and the unfolded protein response acting via the Indazole-Cl transcription factor XBP1, driving both steatosis and insulin resistance. There is increasing evidence that disruption of the gut-liver axis may be involved in the pathogenesis of fatty liver disease. Gut permeability is increased in NAFLD patients and levels of Carboxyamidotriazole circulating bacterial derived endotoxin rise in human subjects placed on a high fat diet. In mice, a continuous infusion of endotoxin results in fatty liver, weight gain, and hepatic insulin resistance. The microflora of the intestine may also have a role in NAFLD. Obese humans and mice have a distinctive gut microflora, which confers obesity when transferred from obese mice to germ free lean animals. Taken together these results support a role of disruption of the epithelial barrier and/or intestinal microflora in the development of NAFLD. In this study we investigate the hepatic phenotype produced by transgenic activation of Notch signaling in the intestine. Notch regulates many cell fate decisions in development and in adult life. Signal transduction occurs when the transmembrane Notch receptor is bound by ligands, such as Jagged, expressed on adjacent cells. The intracellular domain of the receptor is cleaved from the transmembrane domain by c secretase and translocates to the nucleus where it binds the transcription factor CBF1, leading to the recruitment of transcriptional coactivators and the expression of Notch target genes, such as members of the hairy-enhancer of split family of transcription factors. Notch signaling plays a key role specifying differentiation in the intestinal epithelium in developing and adult mice.