17: Chemical Activity of Cholesterol in Membranes
A (hypothetical) equilibrium constant between cholesterol dissolved in water, and in a lipid bilayer membrane, is a measure of the chemical activity of cholesterol in the membrane. This is obviously a difficult quantity to measure. In 2000 Arun Radhakrishnan and I attempted to obtain a measure of this activity for cholesterol in mixtures with phospholipids by measuring the loss rate from the monolayer to cyclodextrin in the aqueous sub phase (448). The purpose of the experiment was to look for an expected correlation between the loss rate and separate theoretical calculations we had made of the chemical activity. We were encouraged by the correlations we found. At the end of the paper we made some theoretical speculations concerning the possible relation between cholesterol chemical activity and the regulation of the biosynthesis of cholesterol in cells. At the time of this paper Brown and Goldstein had already described a number of ER proteins and a transcription factor involved in this regulation, with the promise of more complications to come. The key novel ingredient to our proposal is that it is a property of the lipid bilayer alone that is a key regulatory element, in spite of the involvement of many proteins in the regulatory process. Arun has pursued this general problem since this 2000 paper. As I understand it, he has found a protein (X) which is normally water soluble, and that binds cholesterol I. The binding reaction takes place in the aqueous phase at the water-membrane interface. When cholesterol is bound to X, forming XC, then XC is membrane bound. The thermodynamic cycle for forming XC clearly involves the chemical activity of cholesterol, and this could dominate the reaction even if the binding of XC to the membrane is not reversible, and/or involves XC oligomerization. The progress that Arun has made in this area is remarkable and the reader is referred to papers by him in J. Biol. Chem. for details.