Hepatobiliary Transport in Health and Disease (eBook)

Dieter Häussinger, Verena Keitel, Ralf Kubitz (Herausgeber)

eBook Download: PDF

2012
312 Seiten
De Gruyter (Verlag)
978-3-11-027934-4 (ISBN)

Infos

The transport systems involved in hepatobiliary transport have been 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. This book provides 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 book will be of interest for biochemists, structural chemists, biologists and clinicians.

 

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

Autoren

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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, Germany.
Ralf Kubitz, Heinrich-Heine Universität, Düsseldorf, Germany.
Verena Keitel, Heinrich-Heine Universität, Düsseldorf, Germany.

Inhalt

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

Produkt-Details

• Erscheint lt. Verlag: 29.5.2012
• Zusatzinfo: 17 b/w and 21 col. ill., 10 b/w tbl.
• Verlagsort: Berlin/Boston
• Sprache: englisch
• Themenwelt: Medizinische Fachgebiete ► Innere Medizin ► Gastroenterologie
• Themenwelt: Naturwissenschaften ► Biologie ► Biochemie
• Themenwelt: Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie
• Themenwelt: Technik
• Schlagworte: Biochemie • Gastroenterologie • Leber • Molekularbiologie
• ISBN-10: 3-11-027934-7 / 3110279347
• ISBN-13: 978-3-11-027934-4 / 9783110279344