Bile flow generation is driven by the vectorial transfer of osmotically active
compounds from sinusoidal blood into a confined space, the bile canaliculus. Hence, localization
of hepatocellular transporters relevant to bile formation is crucial for bile secretion.
Hepatocellular transporters are localized either in the plasma membrane or in recycling
endosomes, from where they can be relocated to the plasma membrane on demand, or
endocytosed when the demand decreases. The balance between endocytic internalization/
exocytic targeting to/from this recycling compartment is therefore the main determinant
of the hepatic capability to generate bile, and to dispose endo- and xenobiotics. Furthermore,
the exacerbated endocytic internalization is a common pathomechanisms in both experimental
and human cholestasis; this results in bile secretory failure and, eventually, posttranslational
transporter downregulation by increased degradation. This review summarizes
the proposed structural mechanisms accounting for this pathological condition (e.g., alteration
of function, localization or expression of F-actin or F-actin/transporter cross-linking
proteins, and switch to membrane microdomains where they can be readily endocytosed),
and the mediators implicated (e.g., triggering of “cholestatic” signaling transduction pathways).
Lastly, we discussed the efficacy to counteract the cholestatic failure induced by
transporter internalization of a number of therapeutic experimental approaches based upon
the use of compounds that trigger exocytic targetting of canalicular transporters (e.g.,
cAMP, tauroursodeoxycholate). This therapeutics may complement treatments aimed to
transcriptionally improve transporter expression, by affording proper localization and
membrane stability to the de novo synthesized transporters.
Keywords: Bile salts, cAMP, cholestasis, endocytosis, hepatocellular transporters, signaling pathways, ursodeoxycholate,
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