CD36 is a multifunctional glycoprotein which binds nanomolar concentrations of long-chain fatty acids (LCFA) and is highly expressed on the luminal surface of enterocytes. Despite of its implication in oleoylethanolamide (OEA) and chylomicron synthesis, CD36 function in small intestine remains incompletely understood. Our in vivo data demonstrated that CD36 gene deletion in mice did not affect intestinal LCFA uptake. CD36 protein disappeared early from the luminal side of intestinal villi during the post-prandial period but only when the diet contained lipids. This drop was significant 1 h after a lipid supply and was associated with ubiquitination of CD36. Using CHO cells expressing CD36, it was shown that the digestion products, LCFA and diglycerides, trigger CD36 ubiquitination. In vivo treatment with a proteasome inhibitor prevented the lipid-mediated degradation of CD36. In vivo and ex vivo, CD36 was required for dietary-lipid activation of ERK1/2 which is associated ex vivo with an increase of ApoB48 and MTP, proteins involved in chylomicron formation. Therefore, intestinal CD36 through ERK1/2 mediated signaling displays features of a lipid sensor involved in the adaptation of intestinal metabolism to the postprandial lipid challenge by promoting the production of large chylomicrons rapidly cleared in the blood. Supported by: National Institute of Health and Medical Research (INSERM) and the National Institute of Agronomic Research (INRA) and by grants from the Research Program in Human Nutrition SensoFAT, French National.