Basic mechanisms of cholesterol transport between two membranes. (a) Vesicular transport. This process requires ATP but does not require a change in the transversal distribution of cholesterol in the donor membrane. (b) Diffusion through the cytoplasm either bound to a carrier protein (upper arrows) or by free diffusion (lower arrows). Cholesterol in the donor membrane must desorb from the cytoplasmic leaflet, so the transbilayer distribution of cholesterol can affect this process. (c) Transport across membrane contacts. Adjacent donor and acceptor membranes come into close contact, resulting in cholesterol shuttling across the intermembrane space. This process requires cholesterol in the cytosolic leaflet of the donor membrane and may be facilitated by transport proteins.

Cholesterol transport in nonpolarized cells. LDL carrying cholesterol and CE (esterified cholesterol) is transported (a) from sorting endosomes (SE) to late endosomes (LE) and lysosomes (Ly), from which cholesterol can efflux and reach the plasma membrane or the ER, where it gets esterified (b). Efflux from LE and Ly is poorly characterized, as indicated by dashed lines. Cholesterol can move from the plasma membrane to the ERC by a nonvesicular, ATP-independent process (c). In contrast, recycling of cholesterol occurs almost exclusively in vesicles also carrying other recycling markers (d). De novo synthesized cholesterol is mostly transported from the ER directly to the plasma membrane, bypassing the Golgi apparatus (f), but some follows the biosynthetic secretory pathway from the ER to the TGN (e). Excess cholesterol (Ch) in the ER becomes esterified (CE) and stored in cytoplasmic lipid droplets (D).

Cholesterol transport in polarized cells. Polarized cells form distinct apical (red) and basolateral (blue) membrane compartments, which are separated by tight junctions (TJ). Proteins and lipids are sorted along the biosynthetic and endocytic pathways indicated by blue (basolateral) and red (apical) vesicles. Plasma membrane cholesterol is transported in vesicles between the basolateral and apical membrane via a subapical compartment or apical recycling compartment (SAC/ARC). Recycling to the basolateral membrane can also occur from this compartment (a). LDL cholesterol has the same fate as in nonpolarized cells (b). A fraction of de novo synthesized cholesterol is transported along the biosynthetic pathway as in nonpolarized cells. In the TGN, cholesterol might form microdomains or rafts along with sphingolipids that segregate from the remaining TGN membrane and carry apically destined proteins and lipids to the apical membrane shown in red (c). Basolaterally destined vesicles (blue) bud off of the TGN but should contain less cholesterol (d). Plasma membrane cholesterol can shuttle rapidly between the plasma membrane domains by nonvesicular transport. This process involves fast transbilayer migration of cholesterol to circumvent the lateral diffusion barrier created by the TJ in the exoplasmic leaflet of the plasma membrane. Transport through the cytoplasm bound to a protein carrier (e), and/or diffusion along the inner monolayer (f) result in rapid exchange of cholesterol between the apical and basolateral plasma membrane domain. CE formation occurs as in nonpolarized cells but is omitted for clarity.