Molecular Pathogenesis of Cholestasis

Preface xiii 1. Mechanisms of Bile Formation: An Introduction 1(8) James L. Boyer Introduction 1(1) Historical Aspects 1(2) Overview of the Molecular Mechanisms of Bile Formation 3(6) 2. Hepatocellular Transport Systems: Basolateral Membrane 9(12) Bruno Hagenbuch and Peter J. Meier Summary 9(1) Introduction 9(1) The Na+/Taurocholate Cotransporting Polypeptide (Ntcp/NTCP) 9(2) The Organic Anion Transporting Polypeptides (Oates/OATPS) 11(5) The Multidrug Resistance Associated Protein 3 (Mrp3/MRP3) 16(5) 3. The ABC of Canalicular Transport 21(15) Guido J.E.J. Hooiveld and Michael Müller Summary 21(1) Introduction 21(1) ABC Transporter Proteins 22(1) The ABC-A Family 23(2) The ABC-B Family 25(3) The ABC-C Family 28(1) The ABC-G Family 29(1) Other Hepatic ABC-Transporter Proteins 30(6) 4. Gap Junctions in the Liver 36(12) Wihelma Echevarria and Michael H. Nathanson Summary 36(1) Introduction 36(1) Molecular Overview of the Gap Junction 36(2) The Role of Gap Junctions in Cell-to-Cell Signaling 38(2) Regulation of Liver Function by Gap Junctions 40(3) Conclusions 43(5) 5. Cholestasis: An Intracellular "Traffic Jam" 48(14) Helmut Kipp and Irwin M. Arias Summary 48(1) Introduction 48(1) Trafficking of Newly Synthesized ABC Transporters in Hepatocytes 49(3) Characteristics of Intrahepatic ABC Transporter Pools 52(3) Phosphatidyl 3-Kinase Regulates Intrahepatic Trafficking and Activity of Bile Canalicular ABC Transporters 55(1) The Effects of PI 3-K Modulators on CMV Function In Vitro 55(4) Results of Several Recent Studies Support the Thesis Presented in this Review 59(3) 6. The Pathobiology of Cholangiocytes 62(15) Gene LeSage, Shannon Glaser, Heather Francis, Marco Marzioni and Gianfranco Alpini Summary 62(1) Overview of Cholangiocyte Functions 62(1) Bile Duct Structure 63(1) Ductal Secretion 63(6) Cholangiocyte Proliferative Responses 69(1) Overview of Cholangiopathies 70(3) Future Perspectives 73(4) 7. Genetics, Mutations, and Polymorphisme 77(19) Laura Bull Summary 77(1) Introduction 77(1) Our DNA: The Basics 78(1) Steps in Genetic Mapping 79(12) Genetics of Cholestatic Disorders 91(1) Conclusions and Outlook 92(4) 8. Transcriptional Regulation of Hepatobiliary Transporters 96(16) Saul J. Karpen Summary 96(1) Introduction 96(1) Sinusoidal Transporters 97(4) Canalicular Transporters 101(2) Common Regulatory Themes 103(1) The Central Role of FXR in the Hepatic Response to Cholestasis 103(2) Conclusions 105(7) 9. Signal Transduction in Bile Formation and Cholestasis 112(14) M. SawkatAnwer and Cynthia R.L. Webster Summary 112(1) Introduction 112(2) Overview of Signal Transduction Pathways 114(1) Role of Cyclic AMP 114(2) Role of Calcium 116(3) Role of Protein Kinase C 119(1) Role of PISK Signaling Pathway 120(1) Role of MAPK Signaling Pathway 121(1) Role of Protein Phosphatases 121(5) 10. Bile Acid-Mediated Apoptosis in Cholestasis 126(9) Hajime Higuchi and Gregory J. Gores Summary 126(1) Bile Acids in the Pathophysiology of Cholestasis 126(1) Mechanisms of Bile Acid Cytotoxicity 127(2) Death Receptor-Mediated Activation as a Unifying Hypothesis for Bile Acid-Induced Apoptosis, Mitochondrial Dysfunction and Oxidative Stress 129(3) Inhibition of Fas Signaling as a Therapeutic Strategy for Attenuating Cholestatic Liver Injury 132(1) Conclusion 132(3) 11. Hepatic Drug Metabolism 135(14) Hiroshi Suzuki and Yuichi Sugiyama Summary 135(1) Introduction 135(1) Phase I Metabolism 135(5) Phase II Metabolism 140(5) Drug Metabolism under Cholestatic Conditions 145(1) Concluding Remarks 145(4) 12. Pathology of Cholestasis 149(21) James M. Crawford Summary 149(1) Introduction 149(1) Anatomic Considerations 150(3) The Morphology of Cholestasis 153(13) Conclusion 166(4) 13. Disorders of Bile Acid Transport 170(16) Peter L.M. Jansen, Ekkehard Sturm and Michael Müller Summary 170(1) Introduction 170(1) Hepatic Transport Proteins 171(3) Intestinal Reabsorption 174(1) Regulation of Bile Secretion 174(1) Genetic Transport Defects 175(1) Progressive Familial Intrahepatic Cholestasis Type 1 176(1) Benign Recurrent Intrahepatic Cholestasis 177(2) Progressive Familial Intrahepatic Cholestasis Type 2 179(1) Bile Acid Synthesis Defects 179(1) Progressive Familial Intrahepatic Cholestasis Type 3 179(1) Therapy 179(1) Intrahepatic Cholestasis of Pregnancy Other Forms of Intrahepatic Cholestasis 180(6) 14. Genetic Defects in Biliary Lipid Transport 186(9) Ronald Oude Elferink Introduction 186(1) Hepatobiliary Lipid Secretion 186(1) Progressive Familial Intrahepatic Cholestasis (PFIC) 187(1) Progressive Familial Intrahepatic Cholestasis Type 1 (Formerly Called Byler's Disease) 188(1) Progressive Familial Intrahepatic Cholestasis Type 3 189(1) Adult Forms of MDR3 Deficiency 190(1) Serum Cholesterol Level in PFIC Patients 190(1) Sitosterolemia 191(4) 15. Transport of Bilirubin Conjugates across Hepatocellular Membrane Domains and the Conjugated Hyperbilirubinemie of Dubin-Johnson Syndrome 195(16) Anne T. Nies, Yunhai Gui, Jorg Kónig and Dietrich Keppler Summary 195(1) Introduction 195(1) Hepatocyte Uptake Transporters of the SLC21A Family 196(2) Uptake of Unconjugated Bilirubin by SLC21A6 198(1) Uptake of Bilirubin Conjugates by Members of the SLC21A Family 198(1) Members of the ABCO Subfamily Transporting Bilirubin Conjugates 199(1) Hereditary Deficiency of MRP2 in Dubin-Johnson Syndrome 200(3) Hereditary Mrp2 Deficiency in Animal Models 203(1) Polymorphisme in the Human ABCC2 Gene 204(1) Acquired MRP2 Deficiency in Cholestasis 204(7) 16. Hepatic Copper Transport 211(10) Iqbal Hamza and Jonathan D. Gitlin Summary 211(1) Introduction 211(1) Hepatic Copper Metabolism 212(4) Hepatic Copper Disorders 216(5) 17. Molecular Basis of Primary Biliary Cirrhosis 221(26) Margaret F. Bassendine Introduction 221(1) Tissue Damage 222(4) Autoreactivity 226(5) Genetic Factors 231(2) Non-Genetic Factors 233(3) Summary and Conclusions 236(11) 18. Primary Sclerosing Cholangitis 247(9) Einar Bjórnsson and Roger W. Chapman Introduction 247(1) Clinical, Biochemical and Serological Findings 247(1) Etiopathogenesis 248(1) Molecular Alterations and Defects in PSC 248(1) Role of Cystic Fibrosis-Mediated Chloride Channel Function 249(1) Animal Models of PSC 249(1) Role of Bacteria in Human Disease 250(1) Role of Autoimmunity 251(1) Summary and Conclusions 252(4) 19. Drug-Induced Cholestatic Liver Disease 256(10) Gerd A. Kullak-Ublick Summary 256(1) Introduction 256(1) Epidemiology and Taxonomy 257(1) Mechanisms of Cholestasis 257(5) Conclusions 262(4) 20. Acquired Alterations of Transporter Expression and Function in Cholestasis 266(23) Michael Trauner, Peter Fickert and Gernot Zollner Summary 266(1) Introduction 267(1) Insights from Experimental Animal Models of Cholestasis 267(11) Acquired Cholestatic Liver Diseases in Humans 278(1) Conclusions and Outlook 279(10) 21. Pathophysiological Basis of Pruritus and Fatigue in Cholestasis 289(12) Mark G. Swain Summary 289(1) Introduction 289(1) Pruritus in Cholestasis 289(3) Fatigue in Cholestasis 292(9) 22. Bone Disease in Chronic Cholestatic Liver Disease 301(13) Harald Dobnie and Astrid Fahrleitner Summary 301(1) Introduction 301(1) Physiology of Bone Metabolism 302(1) Presentation of Hepatic Osteodystrophy 303(1) Pathogenetic Factors 304(2) Bone Metabolism in the Posttransplantation Period 306(1) Recognition of Hepatic Osteodystrophy 307(1) Management of Osteoporosis in Cholestasis 308(1) Prevention of Bone Loss in the Early and Later Posttransplantation Period 309(1) Conclusions 310(4) 23. Fat Absorption and Lipid Metabolism in Cholestasis 314(15) Anniek Werner, Folkert Kuipers and Henkjan J. Verkade Introducton 314(1) Intestinal Lipid Absorption 315(5) Alterations in Lipid Homeostasis during Cholestasis 320(4) Nutritional Therapy in Cholestasis 324(1) Conclusions 324(5) 24. Medical Therapy of Cholestatic Liver Diseases 329(11) Christian Rust and Ulrich Beuers Summary 329(1) Introduction 329(1) Role of UDLA in Cholestatic Liver Diseases 330(1) Mechanisms of Action of UDLA 331(3) Role of Other Medical Therapies in Cholestatic Liver Diseases 334(6) 25. Hepatocyte Transplantation and Liver-Directed Gene Therapy 340(21) Chandan Guha, Siddhartha S. Ghosh, Sung W. Lee, Namita Roy-Chowdhury and Jayanta Roy-Chowdhury Introduction 340(1) Hepatocyte Transplantation 340(5) Liver-Directed Gene Therapy 345(16) Index 361