Fig. 7.

Schematic model of cholesterol enrichment in the PM. The PM has at least three distinct pools of cholesterol (see the text): i) distributed to non-raft phospholipid matrix; ii) distributed to SM/cholesterol-rafts; and iii) immobilized with transmembrane proteins. Cholesterol is exchangeable between pools i and ii. In contrast, once cholesterol enters pool iii (i.e., firmly associates with membrane proteins), it is not free to be exchanged with other pools. In normal cells, the inter-organelle bulk flow of cholesterol synthesized in the ER may proceed with the aid of various sterol-transfer proteins in the downhill direction. Cholesterol can be more concentrated in pool ii than in pool i, although the chemical activity of cholesterol in the two pools is equal. Note that biological energy is required for the delivery of SM to the PM. Sterol/PI4P-coexchanging transfer systems, which can mediate the uphill movement of cholesterol from the ER to the PM at MCSs, may be responsible for a quantitatively smaller cholesterol flux, although this energy-consuming flux presumably plays an important role in the homeostasis of the minimum requirement of PM cholesterol. Provided that the chemical activity of cholesterol in PM pools i and ii is also similar to the activity in the ER, the elimination of SM from the PM makes the chemical activity of the bulk cholesterol in the PM higher than that in the ER and, consequently, drives PM cholesterol to move to the ER. Here, inter-membrane transfer of cholesterol may be mediated by sterol-transfer proteins along with chemical activity.