On the puzzling distribution of cholesterol in the plasma membrane

• Cholesterol was expected to be mostly in the outer leaflet of the plasma membrane.
• Cholesterol is not found to be mostly in the outer leaflet.
• We propose it is drawn to the inner leaflet by phosphatidylethanolamine (PE).
• Cholesterol relieves the bending energy due to the PE in the inner leaflet.
• Cholesterol dilutes the PE and also reduces its spontaneous curvature.

The distribution of cholesterol between the two leaves of the plasma membrane in mammalian cells presents a conundrum; given cholesterol's known affinity for sphingomyelin, which resides predominantly in the exoplasmic leaf, why is it that experiment finds a majority of the cholesterol in the cytoplasmic leaf? This article reviews a recently proposed solution to this puzzle.