Does Complexation of Plasma Membrane Cholesterol with Phospholipids Determine its Transbilayer Distribution?

The transbilayer distribution of cholesterol in the plasma membrane is unresolved in that diverse analyses have yielded contradictory results. We now propose a model based on a novel mechanism. It assumes that (a) sterols associate stoichiometrically with phospholipids and (b) these complexes are filled to capacity in the plasma membrane. The sterol in each leaflet is then the product of the abundance of the leaflet phospholipids and their sterol stoichiometries. We applied the model to the bilayer of the human erythrocyte utilizing literature values for its cholesterol content, the abundance of phospholipids in the two leaflets and their cholesterol: phospholipid stoichiometries (1:1 mole/mole in the exofacial leaflet and 1:2 mole/mole in the endofacial leaflet). The model predicts that the outer leaflet contains about two thirds of the cholesterol in this membrane; i.e., twice that in the inner leaflet. Molecular dynamics simulations have delivered similar sidedness values for membranes in which the exofacial phospholipids have a higher sterol affinity. However, our mechanism holds that sterol affinity is irrelevant if the phospholipids are replete with sterol. Our results meet the requirement that the areas of the two leaflets be about equal. The model predicts that the sterol abundance in one leaflet of a bilayer will exceed that in the other when its phospholipids are fully complexed and have a higher sterol stoichiometry.