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The Journal of Lipid Research, Vol. 39, 2459-2470, December 1998
Copyright © 1998 by Lipid Research, Inc.

Original Article

Basis for rapid efflux of biosynthetic desmosterol from cells

^a Department of Biochemistry, Allegheny University of the Health Sciences, MCP Hahnemann School of Medicine, 2900 Queen Lane, Philadelphia, PA 19129

Correspondence to: William J. Johnson.

Previous work shows that the efflux of biosynthetic desmosterol from cells is three times more efficient than that of cholesterol. To explain this difference, we labeled CHO-K1 cells with [³H]acetate precursor and measured sterols in the whole cells, plasma membranes and caveolae, and those released to high density lipoprotein (HDL₃). The [³H]desmosterol-to-[³H]cholesterol ratio was similar in the plasma membrane and whole cells but was greater in HDL₃, suggesting that the more efficient efflux of desmosterol is due to more rapid desorption from the plasma membrane. The ratio in caveolae was similar to that in whole cells, arguing against selective delivery of desmosterol to caveolae as an explanation for the more rapid efflux of this sterol. Additionally, to demonstrate that the enhanced release of desmosterol was not due to enhanced intracellular cycling, we made vesicles from CHO-cell plasma membranes labeled with [³H]desmosterol or [¹⁴C]cholesterol, and the rapid release of desmosterol was demonstrated in this system. To characterize sterol efflux from a simple lipid bilayer system, we measured the transfer of cholesterol and desmosterol between large unilamellar vesicles (LUV), and found that desmosterol transferred two to three times more rapidly than cholesterol. A similar differential was seen when HDL₃ or low density lipoprotein (LDL) served as the acceptor.

These results show that the greater efflux efficiency of biosynthetic desmosterol can be attributed to more efficient desorption from the plasma membrane, and that this difference is a property of the sterols' association with the lipid bilayer. In vivo, the rapid efflux of biosynthetic sterol intermediates, followed by efficient delivery to the liver, may constitute an important mechanism for preventing various types of pathology associated with these materials.—Phillips, J. E., W. V. Rodrigueza, and W. J. Johnson. Basis for rapid efflux of biosynthetic desmosterol from cells. J. Lipid Res. 1998. 39: 2459–2470.

Supplementary key words: [³H]cholesteryl hexadecyl ether, [³H]cholesteryl methyl ether, plasma membrane, Dextran T-500, liposomes, reverse cholesterol transport, Smith-Lemli-Opitz syndrome, sonic hedgehog, sterol biosynthesis, sterol efflux, subcellular fractionation, Triparanol

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