How slow is the transbilayer diffusion (Flip-Flop) of cholesterol?

摘要

Garg et al. (1) recently used time-resolved small-angle neutron scattering to analyze the rate of passive transfer of cholesterol between phospholipid bilayer vesicles of l-palmitoyl-2-oleoyl-sw-glycero-3-phosphocholine made invisible by contrast matching. This elegant approach has the advantage of using the natural form of the sterol in a non-perturbing assay system. Their values for the half-time of intermembrane cholesterol transfer (namely, 88 min at 50°C) and its enthalpy of activation (101 kJ/mol) are in good agreement with earlier studies using other techniques. However, the surprising-indeed, newsworthy (2)-feature of this report was their inference that the transverse (i.e., transbilayer or intramembrane) diffusion (flip-flop) of cholesterol in the bilayer has a half-time of 200 min at 50°C. This value disagrees with those obtained by other techniques, where upper bounds for the half-time were on the order of minutes, seconds, and even milliseconds, estimates limited by the time-resolution of the experimental method (3-5). Molecular dynamics simulations also predict an upper bound of milliseconds (6). We therefore offer some thoughts as to why 200 min may not be an accurate estimate of the half-time of cholesterol flip-flop in phospholipid bilayers.