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membrane contamination and thus could then be used to study transport function when pre pared as membrane vesicles. These approaches defined a number of transport functions in the plasma membranes of hepatocyres and ultimately led to the recognition that bile salts and 3 25 other solutes were transported into bile largely by ATP dependent transport mechanisms.2 - The advent ofmolecular cloning techniques and cellular expression systems rapidly acceler ated progress in this field and led to the molecular characterization ofmost ofthe major mem brane transport proteins that determine both the hepatic uptake of organic solutes as well as bile salt dependent and bile salt independent canalicular excretion. Overview of the Molecular Mechanisms of Bile Formation The major transporters that determine bile formation are illustrated in Figure 1 and are discussed in greater detail in the subsequent chapters. The enrerohepatic circulation ofbile salts maintains bile salt dependent bile flow. Bile salts are excreted into bile and are largely absorbed in the terminal ileum and then efficiently removed from the portal circulation at the basolateral plasma membrane of the heparocyte. Each of these steps is dependent on the function of bile salt transport proteins.
Contents
1. Mechanisms of Bile Formation: An Introduction.- 2. Hepatocellular Transport Systems: Basolateral Membrane.- 3. The ABC of Canalicular Transport.- 4. Gap Junctions in the Liver.- 5. Cholestasis• An Intracellular "Traffic Jam".- 6. The Pathobiology of Cholangiocytes.- 7. Genetics, Mutations, and Polymorphisms.- 8. Transcriptional Regulation of Hepatobiliary Transporters.- 9. Signal Transduction in Bile Formation and Cholestasis.- 10. Bile Acid-Mediated Apoptosis in Cholestasis.- 11. Hepatic Drug Metabolism.- 12. Pathology of Cholestasis.- 13. Disorders of Bile Acid Transport.- 14. Genetic Defects in Biliary Lipid Transport.- 15. Transport of Bilirubin Conjugates across Hepatocellular Membrane Domains and the Conjugated Hyperbilirubinemia of Dubin-Johnson Syndrome.- 16. Hepatic Copper Transport.- 17. Molecular Basis of Primary Biliary Cirrhosis.- 18. Primary Sclerosing Cholangitis.- 19. Drug-Induced Cholestatic Liver Disease.- 20. Acquired Alterations of Transporter Expression and Function in Cholestasis.- 21. Pathophysiological Basis of Pruritus and Fatigue in Cholestasis.- 22. Bone Disease in Chronic Cholestatic Liver Disease.- 23. Fat Absorption and Lipid Metabolism in Cholestasis.- 24. Medical Therapy of Cholestatic Liver Diseases.- 25. Hepatocyte Transplantation and Liver-Directed Gene Therapy.
