Abstract
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.
Highlights
Previous work shows that the efflux of biosynthetic desmosterol from cells is three times more efficient than that of cholesterol
Our objectives were: 1) to distinguish whether greater efflux was due to more efficient delivery to the plasma membrane or to more rapid release from the plasma membrane; 2) to establish whether the selective partitioning of desmosterol into caveolae could account for the enhanced release of this sterol; and 3) to determine whether the faster release of desmosterol could be due to a difference in the association of sterols with the lipid bilayer, by comparing the abilities of cholesterol and desmosterol to transfer out of large unilamellar vesicles (LUV) to a variety of artificial and natural acceptors
The enhanced release of newly synthesized desmosterol in comparison to newly synthesized cholesterol could be due either to more efficient delivery to the plasma membrane or to more facile desorption from the plasma membrane to extracellular acceptors. To distinguish between these possibilities, we examined the newly synthesized sterols contained in the plasma membrane of CHOK1 cells in comparison to those in whole cells
Summary
Previous work shows that the efflux of biosynthetic desmosterol from cells is three times more efficient than that of 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. Our objectives were: 1) to distinguish whether greater efflux was due to more efficient delivery to the plasma membrane or to more rapid release from the plasma membrane; 2) to establish whether the selective partitioning of desmosterol into caveolae could account for the enhanced release of this sterol; and 3) to determine whether the faster release of desmosterol could be due to a difference in the association of sterols with the lipid bilayer, by comparing the abilities of cholesterol and desmosterol to transfer out of large unilamellar vesicles (LUV) to a variety of artificial and natural acceptors
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