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Journal of Lipid Research, Vol. 47, 2781-2788, December 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Ceramide structural features required to stimulate ABCA1-mediated cholesterol efflux to apolipoprotein A-I

Amy B. Ghering and W. Sean Davidson¹

Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45237-0507

Published, JLR Papers in Press, September 21, 2006.

¹ To whom correspondence should be addressed. e-mail: sean.davidson{at}uc.edu

Ceramide is a component of the sphingomyelin cycle and a well-established lipid signaling molecule. We recently reported that ceramide specifically increased ABCA1-mediated cholesterol efflux to apolipoprotein A-I (apoA-I), a critical process that leads to the formation of cardioprotective HDL. In this report, we characterize the structural features of ceramide required for this effect. C2 dihydroceramide, which contains a fully saturated acyl chain and is commonly used as a negative control for ceramide apoptotic signaling, stimulated a 2- to 5-fold increase in ABCA1-mediated cholesterol efflux to apoA-I over a 0–60 µM concentration range without the cell toxicity apparent with native C2 ceramide. Compared with C2 ceramide, C6 and C8 ceramides with medium-length N-acyl chains showed a similar extent of efflux stimulation (a 2- to 5-fold increase) but at a higher onset concentration than the less hydrophobic C2 ceramide. In contrast, the reduced and methylated ceramide analogs, N,N-dimethyl sphingosine and N,N,N-trimethyl sphingosine, failed to stimulate cholesterol efflux. We found that changes in the native spatial orientation at either of two chiral carbon centers (or both) resulted in an 50% decrease compared with native ceramide-stimulated cholesterol efflux. These data show that the overall ceramide shape and the amide bond are critical for the cholesterol efflux effect and suggest that ceramide acts through a protein-mediated pathway to affect ABCA1 activity.

Supplementary key words chemical structure • stereochemistry • ATP binding cassette type A1

Abbreviations: apoA-I, apolipoprotein A-I; CAPK, ceramide-activated protein kinase; CAPP, ceramide-activated protein phosphatase; DMS, N,N-dimethyl sphingosine; PVDF, polyvinylidene difluoride; TMS, N,N,N-trimethyl sphingosine

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