Background and Aims: The small intestine plays an important role in cholesterol homeostasis. The aim of this study was to examine the regulation of cholesterol synthesis by lysophosphatidylcholine in intestinal cells. Methods: CaCo-2 cells cultured on semipermeable supports were incubated with taurocholate and lysophosphatidylcholine, and cholesterol synthesis rate, 3- hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity, mass, and messenger RNA abundance were estimated. Results: Lysophosphatidylcholine increased the rate of cholesterol synthesis as estimated by HMG-CoA reductase activity and acetate or water incorporation into sterols. Reductase was also increased by lysophosphatidylinositol or lysophosphatidylethanolamine but not by lysophophatidylserine. Lysophosphatidylcholine increased HMG-CoA reductase messenger RNA and mass, suggesting that lysophosphatidylcholine regulated reductase at the level of gene expression. The various lysophospholipids caused the efflux of cellular cholesterol into the apical medium, and the amount effluxed correlated with the observed increase in reductase activity. Adding cholesterol to micelles containing lysophosphatidylcholine prevented the increase in HMG-CoA reductase activity and mass. Conclusions: Lysophosphatidylcholine increased cholesterol synthesis by increasing the expression of HMG-CoA reductase at the level of the gene and protein. Efflux of cellular cholesterol and the need to replace this lost cholesterol account for the observed changes in cholesterol metabolism.
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