The intestine plays a crucial role in regulating wholebody lipid homeostasis through dietary fat absorption and secretion, and through its endocrine secretions of incretin hormones and immune mediators. The intestine synthesizes a specialized lipoprotein, the chylomicron, which contains both dietary triglyceride (TAG) and cholesterol, in addition to both structural and functional apolipoprotein cargo. apoB-48 provides structure to the nascent chylomicron, while apoA-IV, apoA-I, and apoC-III function in the periphery to modify plasma lipid metabolism and clearance, interact with inflammatory apparatus for efficient clearance of dietary lipopolysaccharide and oxidized lipids, and modulate insulin signaling and glucose metabolism (1-3). Therefore, the intestine and its secreted chylomicron are critical regulators of metabolic disease.Despite the importance of the intestine in raising plasma TAG levels in the postprandial state and in apolipoprotein secretion, mechanistic studies are difficult to carry out. This is due to a lack of suitable ex vivo cell culture models that are nontransformed yet stable enough in culture for extended studies and genetic manipulations. The intestine is difficult to model ex vivo because enterocytes are in constant turnover, and are only replenished by intestinal stem cells

Apolipoprotein C-III (apoC-III) influences both plasma triglycerides and inflammation, and as such is a particularly important target for mediating cardiovascular disease (CVD). ApoC-III is an exchangeable apolipoprotein expressed in both liver and intestine; in humans, apoC-III levels in plasma are an independent predictor of CVD risk. ApoC-III is a potent regulator of plasma triglycerides through effects on intestinal lipid absorption, plasma triglyceride clearance, hepatic lipoprotein uptake, and VLDL secretion. ApoC-III also acts as a signaling molecule modulating vascular function. Hepatic apoC-III is regulated by insulin via the transcription factor, forkhead box protein O1 (FOXO1), and by glucose via carbohydrate-responsive element-binding protein (ChREBP). Though much is known about hepatic apoC-III, little is known about the regulation of intestinal apoC-III (including the primary stimulus for its expression). We have found that apoC-III is secreted from the intestine in response to dietary carbohydrate, and that a fish oil-enriched diet lowers intestinal apoC-III mRNA expression. Our findings suggest that ChREBP is the primary modulator of apoC-III expression in the intestine. While dietary fish oil lowers both hepatic and intestinal apoC-III mRNA levels, it appears to do so through distinctive mechanisms. This is a potentially important difference since apoC-III is a key regulator of post-prandial plasma lipid levels and inflammation.