Hepatobiliary Transport in Health and Disease

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