A basic model for cell cholesterol homeostasis

Abstract

Cells manage their cholesterol by negative feedback using a battery of sterol-responsive proteins. How these activities are coordinated so as to specify the abundance and distribution of the sterol is unclear. We present a simple mathematical model that addresses this question. It assumes that almost all of the cholesterol is associated with phospholipids in stoichiometric complexes. A small fraction of the sterol is uncomplexed and thermodynamically active. It equilibrates among the organelles, setting their sterol level according to the affinity of their phospholipids. The activity of the homeostatic proteins in the cytoplasmic membranes is then set by their fractional saturation with uncomplexed cholesterol in competition with the phospholipids. The high-affinity phospholipids in the plasma membrane (PM) are filled to near stoichiometric equivalence, giving it most of the cell sterol. Notably, the affinity of the phospholipids in the endomembranes (EMs) is lower by orders of magnitude than that of the phospholipids in the PM. Thus, the small amount of sterol in the EMs rests far below stoichiometric capacity. Simulations match a variety of experimental data. The model captures the essence of cell cholesterol homeostasis, makes coherent a diverse set of experimental findings, provides a surprising prediction and suggests new experiments.

A Method For Estimating The Cholesterol Affinity Of Integral Membrane Proteins From Experimental Data

“…We assumed that the cytoplasmic endomembranes, taken as a whole, have a very low cholesterol content (namely,  10 mol%) and phospholipids of very low cholesterol affinity. 24,25 It appears that proteins with modest cholesterol affinity (namely, those characterized in Figures 1-3) would be partially filled with cholesterol in such membranes while the oligomers with high affinity and cooperativity would for five of the transporters studied above and endomembranes that contained a 30/70 mixture of two phospholipids with stoichiometries of C:P = 1:1 and 1:2 and sterol association constants KP = 21 and 10, respectively. 24 The characteristics of the proteins are given in Table 8.…”

“…The bilayer was represented by a 1:1 mixture of two phospholipids with stoichiometries of C:P = 1:1 and 1:2 and sterol association constants of 5,000 and 2,500, respectively. 23 The values for the affinities of the proteins are given in Table 7. The cytoplasmic endomembranes, taken as a whole, appear to have a very low cholesterol content (namely,  10 mol%) and phospholipids of very low cholesterol affinity.…”

“…The cytoplasmic endomembranes, taken as a whole, appear to have a very low cholesterol content (namely,  10 mol%) and phospholipids of very low cholesterol affinity. 23,24 In Figure 8, we simulated the association of the sterol with five of the integral membrane Figure 8. Simulation of the association of cholesterol with proteins in membranes with the overall phospholipid characteristics of hypothetical endomembranes.…”

“…The bilayer was represented by a 1:1 mixture of two phospholipids with stoichiometries of C:P = 1:1 and 1:2 and sterol association constants of 5,000 and 2,500, respectively. 24 The values for the affinities of the proteins are given in Table 7. In Figure 8, we simulated the association of the sterol with five of the integral membrane proteins in a hypothetical intracellular compartment.…”

“…The model posits the formation of complexes between cholesterol and membrane phospholipids which, perforce, compete with the protein for the sterol. [22][23][24] Using published values for the sterol affinity and stoichiometry of the membrane phospholipids, the model delivers estimates of the sterol affinity and stoichiometry for the proteins.…”