Dynamic localization of hepatocellular transporters in health and disease

Figure 6 Endocytic internalization of canalicular transporters in E₂17G and in TLC-induced cholestasis. Protection from these cholestatic agents by the anticholestatic agents cAMP and TUDC is also shown. E₂17G and TLC induce endocytic internalization of canalicular transporters into the subapical compartment (SAC); this may lead to delivery to the lysosomal compartment, followed by degradation. E₂17G-induced activation of PKCα and TLC-induced, phosphatidylinositol 3-kinase (PI3K)-dependent activation of PKCε have been proposed to mediate this retrieval. Elevation of intracellular cAMP levels induced by administration of the permeant cAMP analogue DBcAMP, or by the phosphodiesterase inhibitor silibinin, prevents internalization, and accelerates re-insertion, via cytosolic Ca²⁺ elevations. On the other hand, TUDC prevents transporter endocytosis probably via co-stimulation of PKCα- and PKA-dependent pathways.