Häussinger / Keitel / Kubitz Hepatobiliary Transport in Health and Disease

1. Auflage 2012
ISBN: 978-3-11-027934-4
Verlag: De Gruyter
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 312 Seiten

One major function of the liver is the uptake of endo- and xenobiotics from the bloodstream and their excretion into bile. The transport systems involved in hepatobiliary transport have been recently cloned and characterized at the molecular level and it is becoming clear that mutations and polymorphisms of individual transporter molecules underlie a variety of liver diseases. Furthermore, new research has shown that bile acids, whose function in digestion is long known, also behave as signal molecules in a variety of organs, including the intestinal and biliary epithelia, sinusoidal endothelial and immune cells. This book provides indepth surveys on the structure and function of transport molecules involved in hepatobiliary transport, on the role of different bile acids receptors in various organs and their function in health and disease, the mechanisms of bile salt-induced apoptosis and hepatocyte protection, and the role of transporter mutations as causes and modifiers of liver diseases. The book will be of interest not only for biochemists, structural chemists and biologists, but also for clinicians.

Zielgruppe

Researchers and advanced students in biochemistry, molecular biology, structural biology, clinical medicine

Autoren/Hrsg.

Häussinger, Dieter

Keitel, Verena

Kubitz, Ralf

Fachgebiete

• Medizin | Veterinärmedizin Medizin | Public Health | Pharmazie | Zahnmedizin Vorklinische Medizin: Grundlagenfächer Biochemie (med.)
• Medizin | Veterinärmedizin Medizin | Public Health | Pharmazie | Zahnmedizin Vorklinische Medizin: Grundlagenfächer Molekulare Medizin, Zellbiologie
• Naturwissenschaften Biowissenschaften Molekularbiologie
• Medizin | Veterinärmedizin Medizin | Public Health | Pharmazie | Zahnmedizin Klinische und Innere Medizin Hepatologie
• Naturwissenschaften Biowissenschaften Biochemie (nichtmedizinisch)
• Naturwissenschaften Chemie Organische Chemie Biochemie

Inhaltsverzeichnis

1;Preface;5
2;List of Contributors;7
3;Abbreviations;17
4;1 Physiology of bile formation: Hepatocellular bile salt transporters;21
4.1;1.1 Introduction;21
4.2;1.2 Sodium-dependent bile salt uptake into hepatocytes;23
4.3;1.3 Sodium-independent bile salt uptake into hepatocytes;27
4.4;1.4 Bile salt export across the canalicular membrane;28
4.5;1.5 Bile salt salvage systems;32
4.6;1.6 Concluding remarks;32
4.7;1.7 References;33
5;2 Structure and function of hepatic ABC transporters;43
5.1;2.1 Introduction to human ABC transporters expressed in the liver;43
5.2;2.2 Structure and function of the bile salt export pump (ABCB11; BSEP);45
5.3;2.3 Structure and function of the multidrug resistance protein 3 (ABCB4; MDR3);52
5.4;2.4 Structure and function of the breast cancer resistance protein (ABCG2; BCRP);57
5.5;2.5 Concluding remarks;60
5.6;2.6 References;61
6;3 Short- and long-term regulation of hepatobiliary transport;69
6.1;3.1 Introduction;69
6.2;3.2 Short-term regulation of sinusoidal transport systems;69
6.3;3.3 Long-term regulation of sinusoidal transport systems;71
6.4;3.4 Short-term regulation of canalicular secretion;74
6.5;3.5 Long-term regulation of canalicular transport systems;76
6.6;3.6 Methods of studying subcellular transporter distribution;78
6.7;3.7 Summary;79
6.8;3.8 References;80
7;4 Nuclear bile acid receptor FXR and hepatobiliary transport systems;91
7.1;4.1 Introduction;91
7.2;4.2 Nuclear receptors;91
7.3;4.3 Bile acids and the enterohepatic circulation;94
7.4;4.4 Bile acid homeostasis, enterohepatic circulation, and FXR;95
7.5;4.5 The role of FXR in the pathogenesis of biliary diseases;99
7.6;4.6 Concluding remarks;100
7.7;4.7 References;101
8;5 Bile acid signaling in the liver and the biliary tree;105
8.1;5.1 Introduction;105
8.2;5.2 Bile acid signaling in liver parenchymal cells (hepatocytes);105
8.3;5.3 Bile acid signaling in sinusoidal endothelial cells;109
8.4;5.4 Bile acid signaling in Kupffer cells;110
8.5;5.5 Bile acid signaling in hepatic stellate cells;111
8.6;5.6 Bile acid signaling in the biliary tree;113
8.7;5.7 References;116
9;6 Modulation of innate immunity and inflammation by bile acids and their receptors;123
9.1;6.1 Introduction;123
9.2;6.2 Impact of FXR deletion on immunity and inflammation - lessons from FXR knockout mice;126
9.3;6.3 Role of TGR5 in the modulation of immune function;128
9.4;6.4 Effects of bile acids on immunological function independently of bile acid receptors;129
9.5;6.5 Obstructive jaundice and its impact on immune function;130
9.6;6.6 Role of bile acids and FXR in viral infections;131
9.7;6.7 Concluding remarks;131
9.8;6.8 References;132
10;7 Bile acids as extrahepatic and interorgan signaling molecules;137
10.1;7.1 Introduction;137
10.2;7.2 Bile acid-dependent modulation of glucose homeostasis;138
10.3;7.3 Impact of bile acids on energy expenditure;140
10.4;7.4 Bile acid receptors and immune response;140
10.5;7.5 Role of bile acid receptors in the cardiovascular system;141
10.6;7.6 Role of bile acid receptors in the kidney;142
10.7;7.7 Bile acid receptors in the central and peripheral nervous system;144
10.8;7.8 Summary and future perspectives;144
10.9;7.9 References;145
11;8 Disorders of bile duct development;151
11.1;8.1 Introduction;151
11.2;8.2 Morphogenesis of the intrahepatic bile duct epithelium: molecular players involved and their relationship with arterial morphogenesis;151
11.3;8.3 Ductal plate malformation (DPM): definition, clinical heterogeneity, and classification based on animal models;156
11.4;8.4 Cilia in cholangiocytes: a multifunctional transducing system;156
11.5;8.5 DPM-related cholangiopathies;158
11.6;8.6 Alagille's syndrome (AGS);165
11.7;8.7 References;166
12;9 Mutations of the bile salt export pump (BSEP) and multidrug-resistance protein 3 (MDR3);171
12.1;9.1 Introduction;171
12.2;9.2 BSEP-related liver diseases;171
12.3;9.3 MDR3-related liver diseases;178
12.4;9.4 Treatment of BSEP- and MDR3-associated liver diseases;182
12.5;9.5 Concluding remarks;182
12.6;9.6 References;183
13;10 MRP2 (ABCC2) and disorders of bilirubin handling in liver;191
13.1;10.1 Introduction;191
13.2;10.2 The conjugate efflux pump MRP2 in the hepatocyte canalicular membrane;191
13.3;10.3 Formation of unconjugated bilirubin and its uptake into hepatocytes;193
13.4;10.4 Formation of bilirubin glucuronides and their transport into bile by MRP2;194
13.5;10.5 Uptake of bilirubin glucuronides into hepatocytes;194
13.6;10.6 MRP3, a basolateral efflux pump, contributes to conjugated hyperbilirubinemia;195
13.7;10.7 Genetic disorders and drug-induced inhibition of bilirubin uptake into hepatocytes;195
13.8;10.8 Genetic variants of the MRP2 (ABCC2) gene and MRP2 deficiency in Dubin-Johnson syndrome;196
13.9;10.9 Impairment of MRP2 localization in the hepatocyte canalicular membrane;197
13.10;10.10 References;197
14;11 Hepatobiliary transport during pregnancy: Cross talk between transporters and hormones;203
14.1;11.1 Introduction;203
14.2;11.2 Estrogens as cholestatic agents;203
14.3;11.3 Cholestatic activity of progesterone;205
14.4;11.4 Biochemical observations in symptom-free pregnant women;206
14.5;11.5 Genetic lessons from congenital cholestasis;206
14.6;11.6 Transporter variants and cholestasis of pregnancy;207
14.7;11.7 Nuclear receptors and cholestasis of pregnancy;209
14.8;11.8 Gallstones and pregnancy;209
14.9;11.9 Concluding remarks;210
14.10;11.10 References;210
15;12 Hepatobiliary transport and gallstone formation;215
15.1;12.1 Introduction;215
15.2;12.2 Epidemiology and risk factors of cholelithiasis;215
15.3;12.3 Hepatobiliary transporters and the pathophysiology of gallstone formation;216
15.4;12.4 Genetic variation in hepatobiliary transporter genes and gallstone susceptibility;219
15.5;12.5 Concluding remarks;222
15.6;12.6 References;223
16;13 Molecular basis of primary biliary cirrhosis;227
16.1;13.1 Introduction;227
16.2;13.2 Pathogenesis of PBC;230
16.3;13.3 Concluding remarks;234
16.4;13.4 References;235
17;14 The molecular basis of primary sclerosing cholangitis;243
17.1;14.1 Introduction;243
17.2;14.2 Immune-mediated bile duct injury;247
17.3;14.3 Toxic bile duct injury;251
17.4;14.4 Fibrosis and cirrhosis;252
17.5;14.5 Cancer development;253
17.6;14.6 Concluding remarks;253
17.7;14.7 References;255
18;15 Drug-induced cholestatic liver injury;261
18.1;15.1 Introduction;261
18.2;15.2 Diagnostic criteria of drug-induced cholestasis;261
18.3;15.3 Hepatocellular drug concentration;262
18.4;15.4 Hepatic bile salt accumulation;264
18.5;15.5 Susceptibility to drug-induced cholestasis;265
18.6;15.6 Concluding remarks;267
18.7;15.7 References;267
19;16 Bile acids and receptors: Therapeutic relevance;273
19.1;16.1 Introduction;273
19.2;16.2 Nuclear and membrane BA receptors: general concepts;273
19.3;16.3 Therapeutic potential of BAs;274
19.4;16.4 Role of BA receptors in BA homeostasis and bile production: therapeutic implications in cholestasis;274
19.5;16.5 Role of BA receptors for targeting hepatic inflammation and fibrosis;277
19.6;16.6 Role of BA receptors in the pathogenesis and treatment of gallstone disease;278
19.7;16.7 BA receptors in intestine: therapeutic implications for the gut-liver axis and inflammatory bowel disease;279
19.8;16.8 Role of BAs in lipid metabolism: therapeutic implications for atherosclerosis and nonalcoholic fatty liver disease (NAFLD);280
19.9;16.9 Role of BAs in hepatic glucose metabolism and beyond;282
19.10;16.10 BA receptors in hepatobiliary and colorectal cancer;284
19.11;16.11 BA receptors beyond the liver and gastrointestinal tract;285
19.12;16.12 Concluding remarks;285
19.13;16.13 References;286
20;17 Analysis of bile acids by tandem mass spectrometry;297
20.1;17.1 Introduction;297
20.2;17.2 Experimental procedures;298
20.3;17.3 Applications;301
20.4;17.4 Summary;306
20.5;17.5 References;307
21;Index;309

Über Autor(innen)

Dieter Häussinger, Heinrich-Heine Universität, Düsseldorf, Deutschland. Verena Keitel, Heinrich-Heine Universität, Düsseldorf, Deutschland. Ralf Kubitz, Heinrich-Heine Universität, Düsseldorf, Deutschland.

Dieter Häussinger, Heinrich-Heine Universität, Düsseldorf, Deutschland.
Verena Keitel, Heinrich-Heine Universität, Düsseldorf, Deutschland. Ralf Kubitz, Heinrich-Heine Universität, Düsseldorf, Deutschland.