Abstract
De novo phosphatidylcholine (PC) synthesis via CTP:phosphocholine cytidylyltransferase-α (CTα) is required for VLDL secretion. To determine the precise role of de novo PC synthesis in intestinal lipid metabolism, we deleted CTα exclusively in the intestinal epithelium of mice (CTαIKO mice). When fed a chow diet, CTαIKO mice showed normal fat absorption despite a ∼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, CTαIKO mice showed impaired passage of FAs and cholesterol from the intestinal lumen into enterocytes. Impaired intestinal lipid uptake in CTαIKO 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 CTαIKO 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 CTα under these conditions.
Highlights
De novo phosphatidylcholine (PC) synthesis via CTP:phosphocholine cytidylyltransferase- (CT ) is required for VLDL secretion
Despite the absence of intestinal CT activity and a dramatic decrease in the PC/PE ratio of intestinal membranes, TG appearance in plasma was comparable between CT IKO mice and control mice after an oral bolus of olive oil (Fig. 1J). This finding suggests that, in contrast to the liver where “new” PC synthesis is required for VLDL secretion [4], intestinal de novo PC synthesis is dispensable for chylomicron secretion in the setting of a low-fat diet
These results suggest that PC supplied to the intestine in bile is sufficient for chylomicron formation and secretion under these conditions
Summary
De novo phosphatidylcholine (PC) synthesis via CTP:phosphocholine cytidylyltransferase- (CT ) is required for VLDL secretion. When fed a chow diet, CT IKO mice showed normal fat absorption despite a 30% decrease in intestinal PC concentrations relative to control mice, suggesting that biliary PC can fully support chylomicron secretion under these conditions. Biliary bile acid and PC secretion was enhanced in CT 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 under these conditions.—Kennelly, J.
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