ApoC-III is a critical cardiovascular risk factor, and humans expressing null mutations in apoC-III are robustly protected from cardiovascular disease. Because of its critical role in elevating plasma lipids and CVD risk, hepatic apoC-III regulation has been studied at length. Considerably less is known about the factors that regulate intestinal apoC-III. In this work, we use primary murine enteroids, Caco-2 cells, and dietary studies in wild-type mice to show that intestinal apoC-III expression does not change in response to fatty acids, glucose, or insulin administration, in contrast to hepatic apoC-III. Intestinal apoC-III is not sensitive to changes in FoxO1 expression (which is itself very low in the intestine, as is FoxO1 target IGFBP-1), nor is intestinal apoC-Ill responsive to western diet, a significant contrast to hepatic apoC-III stimulation during western diet. These data strongly suggest that intestinal apoC-III is not a FoxO1 target and support the idea that apoC-Ill is not regulated coordinately with hepatic apoC-III, and establishes another key aspect of apoC-III that is unique in the intestine from the liver. (C) 2017 Elsevier Inc. All rights reserved.