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Papers In Press, published online ahead of print November 1, 2004
J. Lipid Res., doi:10.1194/jlr.M400199-JLR200
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Department of Biochemistry, Universite Paul Cezanne, Marseille, Cedex 20 13397
Corresponding Author: jacques.fantini{at}univ.u-3mrs.fr
Molecular associations beween sphingomyelin and cholesterol provide a molecular basis for the colocalization of these lipids in plasma membrane microdomains (lipid rafts) and for the inhibitory effect of sphingomyelin on the intestinal absorption of cholesterol. Using surface pressure measurements at the air-water interface, we showed that sphingosine, (the common sphingoid-backbone of most sphingolipids), formed condensed lipid complexes with cholesterol. Structure-activity relationship studies with long chain analogues of sphingosine, together with molecular mechanics simulations, were consistent with a specific interaction between sphingosine and the alpha face of cholesterol. The uptake of micellar cholesterol and the effect of sphingosine on cholesterol absorption were studied with two human model intestinal epithelial cell lines, Caco-2 and HT-29-D4. Real-time PCR quantitations of the putative cholesterol transporter Niemann-Pick C1 Like 1 (NPC1L1) mRNA revealed that, in these cell lines, the activity of cholesterol transport correlated with the level of NPC1L1 expression. In both cell lines, sphingosine induced a dose-dependent decrease of cholesterol absorption. Yet the effect of sphingosine was more dramatic in Caco-2 cells, which also displayed the highest expression of NPC1L1 mRNA. Altogether these data suggested that sphingosine interacts specifically with cholesterol and inhibits the intestinal NPC1L1-dependent transport of micellar cholesterol.
Revised on October 12, 2004
Accepted on October 19, 2004
Interaction of cholesterol with sphingosine: Physicochemical characterization and impact on intestinal absorption
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