Significance
Cholesterol is one of the most abundant of lipid molecules in the plasma membrane that surrounds all eukaryotic cells. It has several vital roles in the plasma membrane for example maintaining membrane integrity, modulating membrane fluidity over the range of physiological temperatures, and influencing the conformation and function of several key classes of membrane proteins including G-protein coupled receptors, and ion pumps. While the concentration of the cholesterol in the cell and different cellular membranes and proteins regulating its abundance has been well studied, its trans-bilayer distribution remains controversial and little is known about the collective activities maintaining the sterol at its physiological set point. Scientists have developed various computational and mathematical models to treat the different aspects of cholesterol metabolism but haven’t elucidated how cell cholesterol level is set.
In light of this, Rush University Medical Center researchers: Professor Theodore Steck, Dr. S. M. Ali Tabei, and Professor Yvonne Lange developed a basic model that sums up and combines crucial features of cholesterol homeostasis and tested it against experimental findings. They assumed that cholesterol regulates its level through the sterol-sensing proteins in the mitochondria and endoplasmic reticulum. Their research work was published in the journal, Traffic.
Most cell cholesterols associate with membrane phospholipids in simple stoichiometric complexes, while a small uncomplexed fraction has high chemical potential and is thermodynamically active. The uncomplexed cholesterol rapidly attains equilibrium in the organelles and regulates the activity of their homeostatic protein. The proposed model is built on the premise that the regulating elements keep cholesterol levels below the complexing potential of phospholipids.
Considering that plasma membrane phospholipids are carefully regulated, they are well-stocked with sterol. Therefore, plasma membrane sterol level matches plasma membrane phospholipids capacity. On the other hand, cytoplasmic membrane phospholipids don’t associate strongly with cholesterol and accumulate little of it until plasma membrane capacity is exceeded and excess cholesterol distributes throughout the cell. Therefore, the uncomplexed cholesterol increases significantly at this threshold and controls several plasma membrane activities and cholesterol homeostasis.
In the new proposed model, the authors considered cell membranes as two compartments. One was the plasma membrane, and the other contained intracellular organelles, which were treated as a single compartment, the endomembranes. For simplicity, they considered the membranes compartments to be homogenous laterally and transversely. Also, they assumed the uncomplexed cholesterol attained equilibrium rapidly in the membranes aided by various multiple transport proteins.
The authors assumed that the phospholipids were distributed equally in the two compartments as reported in the literature. They observed that all the membrane sterol molecules were complexed with polar phospholipids. The researchers also found that approximately 1-2% of the cholesterol in the plasma membrane was uncomplexed at the stoichiometric equivalence point of its phospholipids.
The proposed model helped the authors capture the importance of cellular cholesterol homeostasis. The circulation of the uncomplexed cholesterols sets the level in the cell via the negative feedback control of the regulatory elements. Consequently, the high-affinity phospholipids in the plasma membrane were kept near their equivalence point, while the less-dedicated endomembrane phospholipids were kept at low saturation. Therefore, the proposed data simulated the most relevant data the authors found; therefore, the model is robust.
Reference
Theodore L. Steck, S. M. Ali Tabei, and Yvonne Lange. A basic model for cell cholesterol homeostasis. Traffic. 2021; 22:471–481.