Basis for rapid efflux of biosynthetic desmosterol from cells

Previous work shows that the efflux of biosynthetic desmosterol from cells is three times more efficient than that of cholesterol. To explain this dif ference, we labeled CHO-K1 cells with [H-3]acetate precursor and measured s terols in the whole cells, plasma membranes and caveolae, and those release d to high density lipoprotein (HDL3), The [H-3]desmosterol-to-[H-3] cholest erol ratio was similar in the plasma membrane and whole cells but was great er in HDL3, suggesting that the more efficient efflux of desmosterol is due to more rapid desorption from the plasma membrane. The ratio in caveolae w as similar to that in whole cells, arguing against selective delivery of de smosterol to caveolae as an explanation for the more rapid efflux of this s terol, Additionally, to demonstrate that the enhanced release of desmostero l was not due to enhanced intracellular cycling, we made vesicles from CHO- cell plasma membranes labeled with [3H]desmosterol or [C-14]cholesterol, an d the rapid release of desmosterol was demonstrated in this system. To char acterize 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 rapid ly than cholesterol, A similar differential was seen when HDL3 or low densi ty lipoprotein (LDL) served as the acceptor. These results show that the gr eater efflux efficiency of biosynthetic desmosterol can be attributed to mo re 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 efficien t delivery to the liver, may constitute an important mechanism for preventi ng various types of pathology associated with these materials.