Localization status of hepatocellular transporters in cholestasis

Vectorial transport of osmotically active solutes from blood into bile is essential for bile flow generation. Therefore, the localization status of hepatocellular transporters involved in this function is critical. These transporters are localized either in the plasma membrane or in an endosomal, submembranous compartment, from where they undergo recycling to the plasma membrane. The balance between exocytic targeting/endocytic internalization from/to this recycling compartment is therefore a chief determinant of the liver capability to secrete bile. Furthermore, its impairment may lead to sustained endocytic internalization, eventually resulting in transporter degradation. Exacerbated internalization of hepatocellular transporters occurs in several experimental models of cholestasis, and also in most human cholestatic liver diseases. This review outlines the possible mechanisms explaining this alteration (e.g., alteration of the organization of actin or actin-transporter linking proteins), and the mediators involved (e.g., activation of "cholestatic" signaling pathways). Finally, several experimental therapeutic approaches based upon the administration of compounds that stimulate exocytic targeting of canalicular transporters (e.g., cAMP, tauroursodeoxycholate) are described with regard to their capability to prevent cholestatic alterations resulting from transporter internalization.