Chapter category: Channels and Transporters
Cholestasis: An Intracellular "Traffic Jam"
Molecular Pathogenesis of Cholestasis
Edited by: Michael Trauner and Peter JansenISBN: 0-306-48240-1
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Mutations in the coding region of BSEP which result in its absence from the bile canalicular membrane are manifested by progressive cholestasis and liver damage. We have proposed that defects in intracellular trafficking and/or posttranslational regulation of BSEP may produce a similar phenotype. To test this hypothesis, it was necessary to determine the pathway utilized by BSEP and other canalicular ABC transporters and its regulation. Our studies reveal that BSEP traffics from Golgi to a subapical recycling endosomal compartment from which the transporter cycles to and from the canalicular membrane; the efflux compartment is cAMP-dependent. A second intracellular pool which responds to taurocholate was identified. Both intracellular sites contain at least six times more BSEP as is present in the canalicular membrane. Using pulse-chase and subcellular fractionation studies in rats and on-line image analysis of the movement of chimeric fluorescent BSEP in WIFb cells, we measured the trafficking rates and demonstrated the critical role of 3´ phosphoinositide products of phosphatidyl (PI) 3-kinase, microtubules and other intracellular components. In addition, the activity of BSEP in the canalicular membrane is regulated by PI 3-kinase products and by cAMP. All of these effects occur in the absence of new protein synthesis. Our studies indicate that the hepatocyte is protected from the detergent effects of retained bile acids by post-translationally mediated enhanced BSEP transcellular transport and activation within the canalicular membrane. Experimentally induced alterations in trafficking components impaired BSEP delivery to and/or activation in the canalicular membrane. The results suggest that intrahepatic cholestasis may result from an intracellular traffic jam and create exciting opportunities to investigate the interaction between inheritable defects in ABC transporters and acquired conditions in the pathogenesis of cholestasis associated with drugs, viruses, metals and other factors.
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