Active cholesterol 20 years on

This review considers the following hypotheses, some well‐supported and some speculative. Almost all of the sterol molecules in plasma membranes are associated with bilayer phospholipids in complexes of varied strength and stoichiometry. These complexes underlie many of the material properties of the bilayer. The small fraction of cholesterol molecules exceeding the binding capacity of the phospholipids is thermodynamically active and serves diverse functions. It circulates briskly among the cell membranes, particularly through contact sites linking the organelles. Active cholesterol provides the upstream feedback signal to multiple mechanisms governing plasma membrane homeostasis, pegging the sterol level to a threshold set by its phospholipids. Active cholesterol could also be the cargo for various inter‐organelle transporters and the form excreted from cells by reverse transport. Furthermore, it is integral to the function of caveolae; a mediator of Hedgehog regulation; and a ligand for the binding of cytolytic toxins to membranes. Active cholesterol modulates a variety of plasma membrane proteins—receptors, channels and transporters—at least in vitro. Synopsis Sterols form complexes with bilayer phospholipids that tune the material properties of membranes. The cholesterol in excess of the stoichiometric binding capacity of the phospholipids is thermodynamically active. We consider here whether active cholesterol mediates plasma membrane homeostasis; is the substrate for intracellular transport; is the form exported from cells; manages caveolae; conveys Hedgehog signals; binds cytolysins and modulates the activity of several plasma membrane proteins.