Chapter category: Channels and Transporters
Signal Transduction in Bile Formation and Cholestasis
Molecular Pathogenesis of Cholestasis
Edited by: Michael Trauner and Peter JansenISBN: 0-306-48240-1
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Chapter authors:
Bile formation involves vectorial transport of solutes from blood to bile and is dependent on coordinated activities of various solute transporters located at the basolateral and apical membranes of hepatocytes and cholangiocytes. Cholestasis results when the vectorial transport of solutes destined for bile is compromised. Our understanding of various transporters, their substrates and locations has increased steadily as is the cellular mechanism regulating these transporters. It is becoming more evident that choleretic and cholestatic agents modify the function of these transporters through various signal tranduction pathways. Cyclic AMP, acting via PKA and the PI3K signaling pathway, stimulate transhepatic transport of bile acids by translocating Ntcp and Bsep to the sinusoidal and the canalicular membrane, respectively. Cell swelling induced by hypo-osmotic media stimulates hepatic uptake and biliary excretion of bile acids via the PI3K and the ERK signaling pathway, respectively. TUDC and cell swelling also stimulate biliary bile acid excretion via the p38 MAPK signaling pathway. TUDC reverses TLC cholestasis by stimulating PKC-mediated translocation of Mrp2 to the canalicular membrane. Calcium, acting via Ca2+/calmodulin-dependent kinases/phosphatases, augments cAMP-mediated translocation of Ntcp, increases tight-junctional permeability by phosphorylating myosin light-chain and stimulates sinusoidal Na+/H+ exchange. PKC stimulates bile acid secretion, most likely by phosphorylating Bsep, and Na+/H+ exchange. However, our understanding of the role of specific PKC isoforms involved in bile formation is still lacking. Molecular mechanisms by which PI3K and MAPK signaling pathways stimulate transporter translocation along the cytoskeleton have not been elucidated. Our knowledge of the role of protein phosphatases in bile formation is rather limited. It is, however, anticipated that further understanding in these areas will be forthcoming in the near future.
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