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.