Cholesterol homeostasis and the escape tendency (activity) of plasma membrane cholesterol

Abstract

We review evidence that sterols can form stoichiometric complexes with certain bilayer phospholipids, and sphingomyelin in particular. These complexes appear to be the basis for the formation of condensed and ordered liquid phases, (micro)domains and/or rafts in both artificial and biological membranes. The sterol content of a membrane can exceed the complexing capacity of its phospholipids. The excess, uncomplexed membrane sterol molecules have a relatively high escape tendency, also referred to as fugacity or chemical activity (and, here, simply activity). Cholesterol is also activated when certain membrane intercalating amphipaths displace it from the phospholipid complexes. Active cholesterol projects from the bilayer and is therefore highly susceptible to attack by cholesterol oxidase. Similarly, active cholesterol rapidly exits the plasma membrane to extracellular acceptors such as cyclodextrin and high-density lipoproteins. For the same reason, the pool of cholesterol in the ER (endoplasmic reticulum) increases sharply when cell surface cholesterol is incremented above the physiological set-point; i.e., equivalence with the complexing phospholipids. As a result, the escape tendency of the excess cholesterol not only returns the plasma membrane bilayer to its set point but also serves as a feedback signal to intracellular homeostatic elements to down-regulate cholesterol accretion.

Influence of Cholesterol on Catecholamine Release from the Fusion Pore of Large Dense Core Chromaffin Granules

“…This finding indicates that the cholesterol molecules in the cytosolic leaflet of the plasma membrane or vesicular membrane are more critical for increasing the persistence of the semistable fusion pore. The ability of intracellular M␤CD to rapidly extract cholesterol at the cytosolic leaflets of the fusion pore is consistent with the notion that cholesterol in the cytosolic leaflet have a higher tendency to escape to an aqueous acceptor such as M␤CD (Lange and Steck, 2008). We found that acute cholesterol overload from the extracellular side also failed to affect the two types of foot signals.…”

Early steps in steroidogenesis: intracellular cholesterol trafficking

“…Cholesterol is essentially insoluble in water, having a critical micellar concentration of ‫ف‬ 25-40 M ( 6 ); hence, intracellular cholesterol is mainly found in membranes, with smaller amounts bound to proteins. The amount of cholesterol in human fi broblasts remains constant during months in culture ( 7 ), and the several pathways that regulate cell cholesterol have been studied extensively (8)(9)(10). How cells determine the amount of cholesterol they need and how they sense transient changes in the amount of cellular cholesterol is beginning to be understood.…”

Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol

“…On the other hand, the regulatory proteins that govern cholesterol homeostasis are mostly integral to the ER membrane ( 9,10 ). Cholesterol briskly circulates between the PM and ER and, presumably, other cellular membranes, by a mechanism (or mechanisms) the molecular basis of which is not well established ( 31,32 ). It may be the case that cholesterol partitions among available lipid compartments, including mitochondria, according to their relative sterol affi nities; these, in turn, would be dependent on their phospholipid compositions (32)(33)(34).…”

“…Similarly, it has been shown that incrementing resting fi broblast PM cholesterol or chemical activity, simply referred to here as activity. Increments in PM cholesterol above this sterol/pho spholipid equivalence point are not complexed and therefore have a greatly increased activity ( 31 ) [see also ( 40)] . The active cholesterol is thought to project from the bilayer surface more frequently and to escape to acceptors more readily.…”