Intestinal de novo phosphatidylcholine synthesis is required for dietary lipid absorption and metabolic homeostasis

De novo phosphatidylcholine (PC) synthesis via CTP:phosphocholine cytidylyltransferase-alpha (CT alpha) is required for VLDL secretion. To determine the precise role of de novo PC synthesis in intestinal lipid metabolism, we deleted CT alpha exclusively in the intestinal epithelium of mice (CT alpha(IKO) mice). When fed a chow diet, CT alpha(IKO) mice showed normal fat absorption despite a similar to 30% decrease in intestinal PC concentrations relative to control mice, suggesting that biliary PC can fully support chylomicron secretion under these conditions. However, when fed a high-fat diet, CT alpha(IKO) mice showed impaired passage of FAs and cholesterol from the intestinal lumen into enterocytes. Impaired intestinal lipid uptake in CT alpha(IKO) mice was associated with lower plasma triglyceride concentrations, higher plasma glucagon-like peptide 1 and peptide YY, and disruption of intestinal membrane lipid transporters after a high-fat meal relative to control mice. Unexpectedly, biliary bile acid and PC secretion was enhanced in CT alpha(IKO) mice due to a shift in expression of bile-acid transporters to the proximal intestine, indicative of accelerated enterohepatic cycling. These data show that intestinal de novo PC synthesis is required for dietary lipid absorption during high-fat feeding and that the reacylation of biliary lyso-PC cannot compensate for loss of CT alpha under these conditions.