Bile Secretion and Cholestasis

Textbook of Gastroenterology, Fifth Edition

Volumn 1, Issue , 2009, Pages 401-428

  Weinman, Steven A ^a   Jalil, Sajid ^b  

^a UNIVERSITY OF TEXAS MEDICAL BRANCH   (United States)

^b UNIVERSITY OF NORTH DAKOTA   (United States)

Author keywords

Anatomy and physiology of bile secretion and enterohepatic circulation; Bile duct secretion regulation; Bile formation and mechanisms of regulation; Bile secretion and cholestasis; Cholestasis; Mechanisms of canalicular bile formation; Organic solute transport; Pharmacotherapy prospects

Indexed keywords

EID: 84862586579     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9781444303254.ch16     Document Type: Chapter

References (344)

1. Wheeler HO. Secretion of bile acids by the liver and their role in the formation of hepatic bile. Arch Intern Med 1972; 130: 533.
2. Forker EL. Mechanisms of hepatic bile formation. Annu Rev Physiol 1977; 39: 323.
3. Paumgartner G, Paumgartner D. Current concepts of bile formation. Prog Liver Dis 1982; 7: 207.
4. Boyer JL. New concepts of mechanisms of hepatocyte bile formation. Physiol Rev 1980; 60: 303.
5. Glickman RM. Fat absorption and malabsorption. Clin Gastroenterol 1983; 12: 323.
6. Stieger B, Meier PJ. Bile acid and xenobiotic transporters in liver. Curr Opin Cell Biol 1998; 10: 462.
7. Suzuki H, Sugiyama Y. Transport of drugs across the hepatic sinusoidal membrane: sinusoidal drug influx and efflux in the liver. Semin Liver Dis 2000; 20: 251.
8. Oude Elferink RPJ, Groen AK. Mechanisms of biliary lipid secretion and their role in lipid homeostasis. Semin Liver Dis 2000; 20: 293.
9. Oude Elferink RP, Paulusma CC, Groen AK. Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases. Gastroenterology 2006; 130: 908.
10. Trauner M, Wagner M, Fickert P, Zollner G. Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis. J Clin Gastroenterol 2005; 39: S111.
11. Pauli-Magnus C, Meier PJ. Hepatocellular transporters and cholestasis. J Clin Gastroenterol 2005; 39: S103.
12. Kullak-Ublick GA, Stieger B, Meier PJ. Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 2004; 126: 322.
13. Anthony PP, Ishak KG, Nayak NC et al. The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization. J Clin Pathol 1978; 31: 395.
14. Pratt DS. Cholestasis and cholestatic syndromes. Curr Opin Gastroenterol 2005; 21: 270.
15. Geier A, Fickert P, Trauner M. Mechanisms of disease: mechanisms and clinical implications of cholestasis in sepsis. Nat Clin Pract Gastroenterol Hepatol 2006; 3: 574.
16. Zollner G, Marschall HU, Wagner M, Trauner M. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol Pharm 2006; 3: 231.
17. Wagner M, Trauner M. Transcriptional regulation of hepatobiliary transport systems in health and disease: implications for a rationale approach to the treatment of intrahepatic cholestasis. Ann Hepatol 2005; 4: 77.
18. Forker EL. Two sites of bile formation as determined by mannitol and erythritol clearance in the guinea pig. J Clin Invest 1967; 46: 1189.
19. Klaassen CD, Watkins IJB. Mechanisms of bile formation, hepatic uptake, and biliary excretion. Pharmacol Rev 1984; 36: 1.
20. Weibel RR, Staubli W, Gnagi HR, Hess FH. Correlated morphometric and biochemical studies of the liver cell. I. Morphometric model, stereologic methods and normal morphometric data for rat liver. J Cell Biol 1969; 42: 68.
21. Mitic LL, Anderson JM. Molecular architecture of tight junctions. Annu Rev Physiol 1998; 60: 121.
22. Bradley SE, Herz R. Permselectivity of biliary canalicular membrane in rats: clearance probe analysis. Am J Physiol 1978; 235: E570.
23. Hardison WGM, Dalle-Molle E, Gosink E et al. Function of rat hepatocyte tight junctions: studies with bile acid infusions. Am J Physiol 1991; 260: G167.
24. Sperber I. Secretion of organic anions in the formation of urine and bile flow. Pharmacol Rev 1959; 11: 109.
25. Alpini G, Lenzi R, Zhai W et al. Bile secretory function of intrahepatic biliary epithelium in the rat. Am J Physiol 1989; 257: G124.
26. Tavoloni N. The intrahepatic biliary epithelium: an area of growing interest in hepatology. Sem Liver Dis 1987; 7: 280.
27. Erlinger S. Physiology of bile secretion and enterohepatic circulation. In: Johnson LR (ed). Physiology of the Gastrointestinal Tract, 2nd edn. New York: Raven Press, 1987: 1557.
28. Wong MH, Oelkers P, Craddock AL, Dawson PA. Expression cloning and characterization of the hamster ileal sodium-dependent bile acid transporter. J Biol Chem 1994; 269: 1340.
29. Gong YZ, Everett ET, Schwartz DA et al. Molecular cloning, tissue distribution, and expression of a 14-kDa bile acid-binding protein from rat ileal cytosol. Proc Natl Acad Sci USA 1994; 91: 4741.
30. Kramer W, Girbig F, Gutjahr U, Kowalewski S. Radiation-inactivation analysis of the Na+/bile acid co-transport system from rabbit ileum. Biochem J 1995; 306: 241.
31. Dawson PA, Hubbert M, Haywood J et al. The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. J Biol Chem 2005; 280: 6960.
32. Kullak-Ublick GA, Stieger B, Hagenbuch B, Meier PJ. Hepatic transport of bile salts. Semin Liver Dis 2000; 20: 273.
33. Groothuis GM, Hardonk MJ, Keulemans KP et al. Autoradiographic and kinetic demonstration of acinar heterogeneity of taurocholate transport. Am J Physiol 1982; 243: G455.
34. Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med 1999; 159: 2647.
35. Sodeman T, Bronk SF, Roberts PJ et al. Bile salts mediate hepatocyte apoptosis by increasing cell surface trafficking of Fas. Am J Physiol 2000; 278: G992.
36. Pauli-Magnus C, Stieger B, Meier Y et al. Enterohepatic transport of bile salts and genetics of cholestasis. J Hepatol 2005; 43: 342.
37. Trauner M, Boyer JL. Cholestatic syndromes. Curr Opin Gastroenterol 2004; 20: 220.
38. Kullak-Ublick GA, Paumgartner G, Berr F. Long-term effects of cholecystectomy on bile acid metabolism. Hepatology 1995; 21: 41.
39. Truong AT, Ballatori N. Glutathione as a primary osmotic driving force in hepatic bile formation. Am J Physiol 1992; 263: G617.
40. Boyer JL. Bile duct epithelium: frontiers in transport physiology. Am J Physiol 1996; 270: G1.
41. Hofmann AF. Current concepts of biliary secretion. Dig Dis Sci 1989; 34: 16S.
42. Lazaridis KN, Pham L, Tietz P et al. Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium-dependent bile acid transporter. J Clin Invest 1997; 100: 2714.
43. Chignard N, Mergey M, Veissiere D et al. Bile acid transport and regulating functions in the human biliary epithelium. Hepatology 2001; 33: 496.
44. Blitzer BL, Boyer JL. Cytochemical localization of Na+, K+-ATPase in the rat hepatocyte. J Clin Invest 1978; 62: 1104.
45. Graf J, Henderson RM, Krumpholz B, Boyer JL. Cell membrane and transepithelial voltages and resistances in isolated rat hepatocyte couplets. J Membr Biol 1987; 95: 241.
46. Henderson RM, Graf J, Boyer JL. Inward-rectifying potassium channels in rat hepatocytes. Am J Physiol 1989; 256: G1028.
47. Li X-H, Weinman SA. Chloride channels and hepatocellular function. Prospects for molecular identification. Annu Rev Physiol 2002; 64: 13.1.
48. Moule SK, McGivan JD. Regulation of the plasma membrane potential in hepatocytes: mechanism and physiological significance. Biochim Biophys Acta 1990; 1031: 383.
49. Haddad P, Noel J, Vadnais J et al. Modulation of liver cell membrane NHE-1, Na+-K+ ATPase, and GLUT-2 protein content after cold preservation and rewarming. Can J Physiol Pharmacol 1999; 77: 852.
50. Fitz JG, Lidofsky SD, Xie M et al. Plasma membrane H+-HCO3 -transport in rat hepatocytes: a principal role for Na+-coupled HCO3 -transport. Am J Physiol 1991; 24: G803.
51. Lidofsky SD, Fitz JG, Scharschmidt BF. Mechanisms and functional role of intracellular pH regulation in hepatocytes. In: Boyer JL, Ockner RK (eds). Progress in Liver Diseases. Philadelphia, PA: WB Saunders, 1993: 69.
52. Sellinger M, Weinman SA, Henderson RM et al. Anion channels in rat liver canalicular plasma membranes reconstituted into planar lipid bilayers. Am J Physiol 1992; 262: G1027.
53. Martinez-Anso E, Castillo JE, Diez J et al. Immunohistochemical detection of chloride/bicarbonate anion exchangers in human liver. Hepatology 1994; 19: 1400.
54. Garcia C, Montuenga LM, Medina JF, Prieto J. In situ detection of AE2 anion-exchanger mRNA in the human liver. Cell Tissue Res 1998; 291: 481.
55. Wondergem R, Wang K. Redistribution of hepatocyte chloride during L-alanine uptake. J Membr Biol 1993; 135: 237.
56. Haddad P, Beck JS, Boyer JL, Graf J. Role of chloride ions in liver cell volume regulation. Am J Physiol 1991; 261: G340.
57. Meng X-J, Weinman SA. Cyclic AMP and swelling activated chloride conductance in rat hepatocytes. Am J Physiol 1996; 271: C112.
58. Lidofsky SD, Roman RM. Alanine uptake activates hepatocellular chloride channels. Am J Physiol 1997; 273: G849.
59. Ballatori N, Simmons TW, Boyer JL. A volume-activated taurine channel in skate hepatocytes: membrane polarity and role of intracellular ATP. Am J Physiol 1994; 30: G285.
60. Haussinger D, Schliess F. Osmotic induction of signaling cascades: role in regulation of cell function. Biochem Biophys Res Commun 1999; 255: 551.
61. Barfod ET, Moore AL, Melnick RF, Lidofsky SD. Src regulates distinct pathways for cell volume control through Vav and phospholipase Cgamma. J Biol Chem 2005; 280: 25548.
62. Feranchak AP, Fitz JG, Roman RM. Volume-sensitive purinergic signaling in human hepatocytes. J Hepatol 2000; 33: 174.
63. Hagenbuch B, Dawson P. The sodium bile salt cotransport family SLC10. Pflugers Arch 2004; 447: 566.
64. Hagenbuch B, Meier PJ. The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta 2003; 1609: 1.
65. Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch 2004; 447: 653.
66. Kullak-Ublick GA, Ismair MG, Stieger B et al. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology 2001; 120: 525.
67. Hagenbuch B, Adler ID, Schmid TE. Molecular cloning and functional characterization of the mouse organic-anion-transporting polypeptide 1 (Oatp1) and mapping of the gene to chromosome X. Biochem J 2000; 345: 115.
68. Sekine T, Cha SH, Endou H. The multispecific organic anion transporter (OAT) family. Pflugers Arch 2000; 440: 337.
69. Koepsell H, Endou H. The SLC22 drug transporter family. Pflugers Arch 2004; 447: 666.
70. St-Pierre MV, Kullak-Ublick GA, Hagenbuch B, Meier PJ. Transport of bile acids in hepatic and non-hepatic tissues. J Exp Biol 2001; 204: 1673.
71. Stieger B, Hagenbuch B, Landmann L et al. In situ localization of the hepatocytic Na+/taurocholate cotransporting polypeptide in rat liver. Gastroenterology 1994; 107: 1781.
72. Hagenbuch B, Meier PJ. Sinusoidal (basolateral) bile salt uptake systems of hepatocytes. Semin Liver Dis 1996; 16: 129.
73. Weinman SA, Carruth MW, Dawson PA. Bile acid uptake via the human apical sodium-bile acid cotransporter is electrogenic. J Biol Chem 1998; 273: 34691.
74. Grüne S, Meng X-J, Weinman SA. Cyclic AMP stimulates fluorescent bile acid uptake into hepatocytes by membrane hyperpolarization. Am J Physiol 1996; 270: G339.
75. Weinman SA, Maglova LM. Free concentrations of intracellular fluorescent anions determined by cytoplasmic dialysis of isolated hepatocytes. Am J Physiol 1994; 267: G922.
76. Wright EM, Loo DDF, Turk E, Hirayama BA. Sodium cotransporters. Curr Opin Cell Biol 1996; 8: 468.
77. Kullak-Ublick G, Hagenbuch B, Stieger B et al. Functional characterization of the basolateral rat liver organic anion transporting polypeptide. Hepatology 1994; 20: 411.
78. Satlin LM, Amin V, Wolkoff AW. Organic anion transporting polypeptide mediates organic anion/HCO3 -exchange. J Biol Chem 1997; 272: 26340.
79. Pauli-Magnus C, Meier PJ. Pharmacogenetics of hepatocellular transporters. Pharmacogenetics 2003; 13: 189.
80. Li L, Lee TK, Meier PJ, Ballatori N. Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatp1, the hepatic sinusoidal organic solute transporter. J Biol Chem 1998; 273: 16184.
81. Ballatori N, Rebbeor JF. Roles of MRP2 and oatp1 in hepatocellular export of reduced glutathione. Semin Liver Dis 1998; 18: 377.
82. Konig J, Cui Y, Nies AT, Keppler D. Oatp. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol 2000; 278: G156.
83. Abe T, Kakyo M, Tokui T et al. Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J Biol Chem 1999; 274: 17159.
84. Cui Y, Konig J, Leier I et al. Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J Biol Chem 2001; 276: 9626.
85. Konig J, Cui Y, Nies AT, Keppler D. Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem 2000; 275: 23161.
86. Tirona RG, Kim RB. Pharmacogenomics of organic anion-transporting polypeptides (OATP). Adv Drug Deliv Rev 2002; 54: 1343.
87. Kullak-Ublick G, Hagenbuch B, Stieger B et al. Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver. Gastroenterology 1995; 109: 1274.
88. Bossuyt X, Müller M, Meier PJ. Multispecific amphipathic substrate transport by an organic anion transporter of human liver. J Hepatol 1996; 25: 733.
89. Gao B, Hagenbuch B, Kullak-Ublick GA et al. Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J Pharmacol Exp Ther 2000; 294: 73.
90. Kullak-Ublick GA, Beuers U, Fahney C et al. Identification and functional characterization of the promoter region of the human organic anion transporting polypeptide gene. Hepatology 1997; 26: 991.
91. Sweet DH, Wolff NA, Pritchard JB. Expression cloning and characterization of ROAT1. The basolateral organic anion transporter in rat kidney. J Biol Chem 1997; 272: 30088.
92. Sekine T, Cha SH, Tsuda M et al. Identification of multispecific organic anion transporter 2 expressed predominantly in the liver. FEBS Lett 1998; 429: 179.
93. Kusuhara H, Sekine T, Utsunomiya-Tate N et al. Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain. J Biol Chem 1999; 274: 13675.
94. Cha SH, Sekine T, Kusuhara H et al. Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J Biol Chem 2000; 275: 4507.
95. Burckhardt G, Wolff NA. Structure of renal organic anion and cation transporters. Am J Physiol 2000; 278: F853.
96. Sweet DH, Pritchard JB. The molecular biology of renal organic anion and organic cation transporters. Cell Biochem Biophys 1999; 31: 89.
97. Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 2000; 92: 1295.
98. Jansen PL, Strautnieks SS, Jacquemin E et al. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology 1999; 117: 1370.
99. Schmitt M, Kubitz R, Lizun S et al. Regulation of the dynamic localization of the rat Bsep gene-encoded bile salt export pump by anisoosmolarity. Hepatology 2001; 33: 509.
100. Wang R, Salem M, Yousef IM et al. Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis. Proc Natl Acad Sci USA 2001; 98: 2011.
101. Meier PJ, Stieger B. Bile salt transporters. Annu Rev Physiol 2002; 64: 635.
102. Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu Rev Biochem 2002; 71: 537.
103. Strautnieks SS, Bull LN, Knisely AS et al. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet 1998; 20: 233.
104. Mayer R, Kartenbeck J, Büchler M et al. Expression and localization of the MRP-encoded conjugate export pump in human and rat liver [Abstract]. Hepatology 1995; 22: 295A.
105. Paulusma CC, Bosma PJ, Bakker CTM et al. Cloning of a liver-specific MRP-homologue which is deficient in the TR rat [Abstract]. Hepatology 1995; 22: 295A.
106. Kamisako T, Leier I, Cui Y et al. Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2. Hepatology 1999; 30: 485.
107. Cui Y, Konig J, Buchholz JK et al. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol Pharmacol 1999; 55: 929.
108. Konig J, Nies AT, Cui Y et al. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta 1999; 1461: 377.
109. Dietrich CG, Ottenhoff R, de Waart DR, Oude Elferink RP. Role of MRP2 and GSH in intrahepatic cycling of toxins. Toxicology 2001; 167: 73.
110. Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med 1998; 339: 1217.
111. Paulusma CC, Oude Elferink RPJ. The canalicular multispecific organic anion transporter and conjugated hyperbilirubinemia in rat and man. J Mol Med 1997; 75: 420.
112. Ambudkar SV, Dey S, Hrycyna CA et al. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 1999; 39: 361.
113. Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 1993; 62: 385.
114. Arias IM. Multidrug resistance genes, p-glycoprotein and the liver. Hepatology 1990; 12: 159.
115. Gatmaitan ZC, Arias IM. Structure and function of P-glycoprotein in normal liver and small intestine. Adv Pharmacol 1993; 24: 77.
116. Borst P, Zelcer N, van Helvoort A. ABC transporters in lipid transport. Biochim Biophys Acta 2000; 1486: 128.
117. Ruetz S, Gros P. Phosphatidylcholine translocase: a physiological role for the mdr2 gene. Cell 1994; 77: 1071.
118. Nies AT, Gatmaitan Z, Arias IM. ATP-dependent phosphatidylcholine translocation in rat liver canalicular plasma membrane vesicles. J Lipid Res 1996; 37: 1125.
119. Smit JJM, Schinkel AH, Oude Elferink RPJ et al. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 1993; 75: 451.
120. De Vree JM, Jacquemin E, Sturm E et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci USA 1998; 95: 282.
121. Schneider G, Paus TC, Kullak-Ublick GA et al. Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy. Hepatology 2007; 45: 150.
122. Elferink RO, Groen AK. Genetic defects in hepatobiliary transport. Biochim Biophys Acta 2002; 1586: 129.
123. Berge KE, Tian H, Graf GA et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 2000; 290: 1771.
124. Klett EL, Patel S. Genetic defenses against noncholesterol sterols. Curr Opin Lipidol 2003; 14: 341.
125. Harris MJ, Le Couteur DG, Arias IM. Progressive familial intra-hepatic cholestasis: genetic disorders of biliary transporters. J Gastroenterol Hepatol 2005; 20: 807.
126. Eppens EF, van Mil SW, De Vree JM et al. FIC1, the protein affected in two forms of hereditary cholestasis, is localized in the cholangiocyte and the canalicular membrane of the hepatocyte. J Hepatol 2001; 35: 436.
127. van Mil SW, van Oort MM, van den Berg IE, et al. Fic1 is expressed at apical membranes of different epithelial cells in the digestive tract and is induced in the small intestine during postnatal development of mice. Pediatr Res 2004; 56: 981.
128. Ujhazy P, Ortiz D, Misra S et al. Familial intrahepatic cholestasis 1: studies of localization and function. Hepatology 2001; 34: 768.
129. Chen F, Ananthanarayanan M, Emre S et al. Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity. Gastroenterology 2004; 126: 756.
130. Paulusma CC, Oude Elferink RP. The type 4 subfamily of P-type ATPases, putative aminophospholipid translocases with a role in human disease. Biochim Biophys Acta 2005; 1741: 11.
131. Ballatori N. Biology of a novel organic solute and steroid transporter, OSTalpha-OSTbeta. Exp Biol Med (Maywood) 2005; 230: 689.
132. Konig J, Rost D, Cui Y, Keppler D. Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane. Hepatology 1999; 29: 1156.
133. Zollner G, Fickert P, Silbert D et al. Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol 2003; 38: 717.
134. Chen ZS, Lee K, Kruh GD. Transport of cyclic nucleotides and estradiol 17-beta-D-glucuronide by multidrug resistance protein 4. Resistance to 6-mercaptopurine and 6-thioguanine. J Biol Chem 2001; 276: 33747.
135. Weisiger RA. When is a carrier not a membrane carrier? The cytoplasmic trasport of amphipathic molecules. Hepatology 1996; 24: 1288.
136. Stolz A, Hammond L, Lou H. Rat and human bile acid binders are members of the monomeric reductase gene family. Adv Exp Med Biol 1995; 372: 269.
137. Storch J, Thumser AE. The fatty acid transport function of fatty acid-binding proteins. Biochim Biophys Acta 2000; 1486: 28.
138. Sugiyama Y, Stolz A, Sugimoto M, Kaplowitz N. Evidence for a common high affinity binding site on glutathione S-transferase B for lithocholic acid and bilirubin. J Lipid Res 1989; 25: 1177.
139. Luxon BA. Inhibition of binding to fatty acid binding protein reduces the intracellular transport of fatty acids. Am J Physiol 1996; 271: G113.
140. Hoppe CA, Connolly TP, Hubbard AL. Transcellular transport of polymeric IgA in the rat hepatocyte: biochemical and morphological characterization of the transport pathway. J Cell Biol 1985; 101: 2113.
141. Crawford JM. Role of vesicle-mediated transport pathways in hepatocellular bile secretion. Semin Liver Dis 1996; 16: 169.
142. Cater MA, La FS, Shield K et al. ATP7B mediates vesicular sequestration of copper: insight into biliary copper excretion. Gastroenterology 2006; 130: 493.
143. Groen AK, Oude Elferink RP. Lipid transport into bile and role in bile formation. Curr Drug Targets Immune Endocr Metabol Disord 2005; 5: 131.
144. Crawford J. Canalicular lipid secretion. In: Afdhal NH (ed). Gallbladder and Biliary Tract Diseases. New York: Marcel Dekker, 2000: 65.
145. Fuchs M, Carey MC, Cohen DE. Evidence for an ATP-independent long-chain phosphatidylcholine translocator in hepatocyte membranes. Am J Physiol 1997; 273: G1312.
146. Cohen DE, Leonard MR, Carey MC. In vitro evidence that phospholipid secretion into bile may be coordinated intracellularly by the combined actions of bile salts and the specific phosphatidylcholine transfer protein of liver. Biochemistry 1994; 33: 9975.
147. Oude Elferink RPJ, Tytgat GNJ, Groen AK. The role of mdr2 Pglycoprotein in hepatobiliary lipid transport. FASEB J 1997; 11: 19.
148. Crawford AR, Smith AJ, Hatch VC, et al. Hepatic secretion of phospholipid vesicles in the mouse critically depends on mdr2 or MDR3 P-glycoprotein expression. J Clin Invest 1997; 100: 2562.
149. Ruetz S, Gros P. Enhancement of Mdr2-mediated phosphatidylcholine translocation by the bile salt taurocholate. Implications for hepatic bile formation. J Biol Chem 1995; 270: 25388.
150. Groen AK, Oude Elferink RP, Verkade HJ, Kuipers F. The ins and outs of reverse cholesterol transport. Ann Med 2004; 36: 135.
151. Acton S, Rigotti A, Landschulz KT et al. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 1996; 271: 518.
152. Kozarsky KF, Donahee MH, Rigotti A, et al. Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels. Nature 1997; 387: 414.
153. Zanlungo S, Amigo L, Mendoza H, et al. Sterol carrier protein 2 gene transfer changes lipid metabolism and enterohepatic sterol circulation in mice. Gastroenterology 2000; 119: 1708.
154. Lee MH, Lu K, Patel SB. Genetic basis of sitosterolemia. Curr Opin Lipidol 2001; 12: 141.
155. Graf GA, Li WP, Gerard RD, et al. Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface. J Clin Invest 2002; 110: 659.
156. van Erpecum KJ. Biliary lipids, water and cholesterol gallstones. Biol Cell 2005; 97: 815.
157. Yu L, Hammer RE, Li-Hawkins J, et al. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci USA 2002; 99: 16237.
158. Yu L, Li-Hawkins J, Hammer RE, et al. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest 2002; 110: 671.
159. Groen AK, Bloks VW, Bandsma RH, et al. Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL. J Clin Invest 2001; 108: 843.
160. Culotta VC, Lin SJ, Schmidt P, et al. Intracellular pathways of copper trafficking in yeast and humans. Adv Exp Med Biol 1999; 448: 247.
161. De Freitas J, Wintz H, Kim JH, et al. Yeast, a model organism for iron and copper metabolism studies. Biometals 2003; 16: 185.
162. Wijmenga C, Klomp LW. Molecular regulation of copper excretion in the liver. Proc Nutr Soc 2004; 63: 31.
163. Suzuki M, Gitlin JD. Intracellular localization of the Menkes and Wilson's disease proteins and their role in intracellular copper transport. Pediatr Int 1999; 41: 436.
164. Schaefer M, Hopkins RG, Failla ML, Gitlin JD. Hepatocyte-specific localization and copper-dependent trafficking of the Wilson's disease protein in the liver. Am J Physiol 1999; 276: G639.
165. Harada M, Sakisaka S, Terada K, et al. Role of ATP7B in biliary copper excretion in a human hepatoma cell line and normal rat hepatocytes. Gastroenterology 2000; 118: 921.
166. Roelofsen H, Wolters H, Van Luyn MJ, et al. Copper-induced apical trafficking of ATP7B in polarized hepatoma cells provides a mechanism for biliary copper excretion. Gastroenterology 2000; 119: 782.
167. van De SB, Rothuizen J, Pearson PL, et al. Identification of a new copper metabolism gene by positional cloning in a purebred dog population. Hum Mol Genet 2002; 11: 165.
168. Coronado VA, Damaraju D, Kohijoki R, Cox DW. New haplotypes in the Bedlington terrier indicate complexity in copper toxicosis. Mamm Genome 2003; 14: 483.
169. Tao TY, Gitlin JD. Hepatic copper metabolism: insights from genetic disease. Hepatology 2003; 37: 1241.
170. Muller T, van De SB, Zhernakova A, et al. The canine copper toxicosis gene MURR1 does not cause non-Wilsonian hepatic copper toxicosis. J Hepatol 2003; 38: 164.
171. Cho WK. Bile ductal secretion and its regulation. In: Afdhal NH (ed). Gallbladder and Biliary Tract Diseases. New York: Marcel Dekker, 2000: 99.
172. Roberts SK, Ludwig J, LaRusso NF. The pathobiology of biliary epithelia. Gastroenterology 1997; 112: 269.
173. Yoon YB, Hagey LR, Hofmann AF, et al. Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents. Gastroenterology 1986; 90: 837.
174. Alpini G, Ulrich CD, Phillips JO, et al. Upregulation of secretin receptor gene expression in rat cholangiocytes after bile duct ligation. Am J Physiol 1994; 266: G922.
175. Pilewski JM, Frizzell RA. Role of CFTR in airway disease. Physiol Rev 1999; 79: S215.
176. Baiocchi L, LeSage G, Glaser S, Alpini G. Regulation of cholangiocyte bile secretion. J Hepatol 1999; 31: 179.
177. Scoazec JY, Bringuier AF, Medina JF, et al. The plasma membrane polarity of human biliary epithelial cells: in situ immunohistochemical analysis and functional implications. J Hepatol 1997; 26: 543.
178. Basavappa S, Middleton J, Mangel AW, et al. Cl-and K+ transport in human biliary cell lines. Gastroenterology 1993; 104: 1796.
179. Cohn JA, Strong TV, Picciotto MR, et al. Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells. Gastroenterology 1993; 105: 1857.
180. McGill JM, Basavappa S, Gettys T, Fitz G. Secretin activated Cl-channels in bile duct epithelial cells through a cAMP-dependent mechanism. Am J Physiol 1994; 266: G731.
181. McGill JM, Basavappa S, Gettys TW, Fitz JG. Secretin activates Cl-channels in bile duct epithelial cells through a cAMP-dependent mechanism. Am J Physiol 1994; 29: G731.
182. Marinelli RA, Tietz PS, Pham LD, et al. Secretin induces the apical insertion of aquaporin-1 water channels in rat cholangiocytes. Am J Physiol 1999; 276: G280.
183. Strazzabosco M, Mennone A, Boyer J. Intracellular pH regulation in isolated rat bile duct epithelial cells. J Clin Invest 1991; 87: 1503.
184. Alvaro D, Cho WK, Mennone A, Boyer JL. Effect of secretion on intracellular pH regulation in isolated rat bile duct epithelial cells. J Clin Invest 1993; 92: 1314.
185. Marti U, Elsing C, Renner EL, et al. Differential expression of Na+, H(+)-antiporter mRNA in biliary epithelial cells and in hepatocytes. J Hepatol 1996; 24: 498.
186. Kanno N, LeSage G, Glaser S, et al. Functional heterogeneity of the intrahepatic biliary epithelium. Hepatology 2000; 31: 555.
187. Colombo C, Battezzati PM, Strazzabosco M, Podda M. Liver and biliary problems in cystic fibrosis. Semin Liver Dis 1998; 18: 227.
188. Fuller CM, Benos DJ. Electrophysiological characteristics of the Ca2+-activated Cl-channel family of anion transport proteins. Clin Exp Pharmacol Physiol 2000; 27: 906.
189. Tietz PS, LaRusso NF. Cholangiocyte biology. Curr Opin Gastroenterol 2006; 22: 279.
190. Feranchak AP. Hepatobiliary complications of cystic fibrosis. Curr Gastroenterol Rep 2004; 6: 231.
191. Xia X, Francis H, Glaser S, et al. Bile acid interactions with cholangiocytes. World J Gastroenterol 2006; 12: 3553.
192. Lazaridis KN, Tietz P, Wu T, et al. Alternative splicing of the rat sodium/bile acid transporter changes its cellular localization and transport properties. Proc Natl Acad Sci USA 2000; 97: 11092.
193. Soroka CJ, Lee JM, Azzaroli F, Boyer JL. Cellular localization and up-regulation of multidrug resistance-associated protein 3 in hepatocytes and cholangiocytes during obstructive cholestasis in rat liver. Hepatology 2001; 33: 783.
194. Anderson JM. Hepatocyte tight junctions in health and disease. Prog Liver Dis 1993; 11: 45.
195. Kullak-Ublick GA. Regulation of organic anion and drug transporters of the sinusoidal membrane. J Hepatol 1999; 31: 563.
196. Kipp H, Arias IM. Intracellular trafficking and regulation of canalicular ATP-binding cassette transporters. Semin Liver Dis 2000; 20: 339.
197. Haussinger D, Schmitt M, Weiergraber O, Kubitz R. Short-term regulation of canalicular transport. Semin Liver Dis 2000; 20: 307.
198. Ballatori N, Wondergem R, Boyer JL. Effects of L-alanine on membrane potential, potassium (86Rb) permeability and cell volume in hepatocytes from Raja erinacea. Biochim Biophys Acta 1988; 946: 261.
199. Fitz JG, Scharschmidt BF. Regulation of transmembrane electrical potential gradient in rat hepatocytes in situ. Am J Physiol 1987; 252: G56.
200. Mukhopadhyay S, Webster CR, Anwer MS. Role of protein phosphatases in cyclic AMP-mediated stimulation of hepatic Na+/taurocholate cotransport. J Biol Chem 1998; 273: 30039.
201. Mukhopadhyay S, Ananthanarayanan M, Stieger B, et al. Sodium taurocholate cotransporting polypeptide is a serine, threonine phosphoprotein and is dephosphorylated by cyclic adenosine mono-phosphate. Hepatology 1998; 28: 1629.
202. Mukhopadhayay S, Ananthanarayanan M, Stieger B, et al. cAMP increases liver Na+-taurocholate cotransport by translocating transporter to plasma membranes. Am J Physiol 1997; 273: G842.
203. Noe J, Hagenbuch B, Meier PJ, St-Pierre MV. Characterization of the mouse bile salt export pump overexpressed in the baculovirus system. Hepatology 2001; 33: 1223.
204. Roelofsen H, Ottenhoff R, Elferink RPO, Jansen PLM. Hepatocanalicular organic-anion transport is regulated by protein kinase C. Biochem J 1991; 278: 637.
205. Glavy JS, Wu SM, Wang PJ, et al. Down-regulation by extracellular ATP of rat hepatocyte organic anion transport is mediated by serine phosphorylation of oatp1. J Biol Chem 2000; 275: 1479.
206. Guo GL, Klaassen CD. Protein kinase C suppresses rat organic anion transporting polypeptide 1-and 2-mediated uptake. J Pharmacol Exp Ther 2001; 299: 551.
207. Misra S, Ujhazy P, Varticovski L, Arias IM. Phosphoinositide 3kinase lipid products regulate ATP-dependent transport by sister of P-glycoprotein and multidrug resistance associated protein 2 in bile canalicular membrane vesicles. Proc Natl Acad Sci USA 1999; 96: 5814.
208. Marinelli RA, Tietz PS, LaRusso NF. Regulated vesicle trafficking of membrane transporters in hepatic epithelia. J Hepatol 2005; 42: 592.
209. Anwer MS. Cellular regulation of hepatic bile acid transport in health and cholestasis. Hepatology 2004; 39: 581.
210. Gatmaitan ZC, Nies AT, Arias IM. Regulation and translocation of ATP-dependent apical membrane proteins in rat liver. Am J Physiol 1997; 272: G1041.
211. Che M, Gatmaitan Z, Arias I. Ectonucleotidases, purine nucleoside transporter, and function of the bile canalicular plasma membrane of the hepatocyte. FASEB J 1997; 11: 101.
212. Kubitz R, D'urso D, Keppler D, Haussinger D. Osmodependent dynamic localization of the multidrug resistance protein 2 in the rat hepatocyte canalicular membrane. Gastroenterology 1997; 113: 1438.
213. Dombrowski F, Kubitz R, Chittattu A, et al. Electron-microscopic demonstration of multidrug resistance protein 2 (Mrp2) retrieval from the canalicular membrane in response to hyperosmolarity and lipopolysaccharide. Biochem J 2000; 348: 183.
214. Webster CR, Blanch C, Anwer MS. Role of PP2B in cAMP-induced dephosphorylation and translocation of NTCP. Am J Physiol 2002; 283: G44.
215. Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu Rev Biochem 1998; 67: 481.
216. Crawford JM, Berken C, Gollan JL. Role of the hepatocyte micro-tubular system in the excretion of bile salts and biliary lipid: implications for intracellular vesicular transport. J Lipid Res 1988; 99: 478.
217. Sakisaka S, Harada M, Gondo K, et al. Tubulovesicular transport of horseradish peroxidase in isolated rat hepatocyte couplets: effects of low temperature, cytochalasin B and bile acids. Hepatology 1994; 20: 1015.
218. Misra S, Ujhazy P, Gatmaitan Z, et al. The role of phosphoinositide 3-kinase in taurocholate-induced trafficking of ATP-dependent canalicular transporters in rat liver. J Biol Chem 1998; 273: 26638.
219. Chand N, Sanyal AJ. Sepsis-induced cholestasis. Hepatology 2007; 45: 230.
220. Lee J, Boyer JL. Molecular alterations in hepatocyte transport mechanisms in acquired cholestatic liver disorders. Semin Liver Dis 2000; 20: 373.
221. Karpen SJ. Nuclear receptor regulation of hepatic function. J Hepatol 2002; 36: 832.
222. Lee JW, Lee YC, Na SY, et al. Transcriptional coregulators of the nuclear receptor superfamily: coactivators and corepressors. Cell Mol Life Sci 2001; 58: 289.
223. Beyersmann D. Regulation of mammalian gene expression. EXS 2000; 89: 11.
224. Makishima M, Okamoto AY, Repa JJ, et al. Identification of a nuclear receptor for bile acids. Science 1999; 284: 1362.
225. Parks DJ, Blanchard SG, Bledsoe RK, et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 1999; 284: 1365.
226. Wang H, Chen J, Hollister K, et al. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 1999; 3: 543.
227. Lu TT, Makishima M, Repa JJ, et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 2000; 6: 507.
228. Noy N. Retinoid-binding proteins: mediators of retinoid action. Biochem J 2000; 348: 481.
229. Tu H, Okamoto AY, Shan B. FXR, a bile acid receptor and biological sensor. Trends Cardiovasc Med 2000; 10: 30.
230. Karpen SJ. Exercising the nuclear option to treat cholestasis: CAR and PXR ligands. Hepatology 2005; 42: 266.
231. Lee FY, Lee H, Hubbert ML, et al. FXR, a multipurpose nuclear receptor. Trends Biochem Sci 2006; 31: 572.
232. Claudel T, Staels B, Kuipers F. The farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism. Arterioscler Thromb Vasc Biol 2005; 25: 2020.
233. Timsit YE, Negishi M. CAR and PXR: the xenobiotic-sensing receptors. Steroids 2007; 72: 231.
234. Tien ES, Negishi M. Nuclear receptors CAR and PXR in the regulation of hepatic metabolism. Xenobiotica 2006; 36: 1152.
235. Sugatani J, Kojima H, Ueda A, et al. The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 2001; 33: 1232.
236. Zelcer N, Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 2006; 116: 607.
237. Lala DS. The liver X receptors. Curr Opin Investig Drugs 2005; 6: 934.
238. Chianale J, Vollrath V, Wielandt AM, et al. Fibrates induce mdr2 gene expression and biliary phospholipid secretion in the mouse. Biochem J 1996; 314: 781.
239. Ganguly TC, O'Brien ML, Karpen SJ, et al. Regulation of the rat liver sodium-dependent bile acid cotransporter gene by prolactin. Mediation of transcriptional activation by Stat5. J Clin Invest 1997; 99: 2906.
240. Denson LA, Auld KL, Schiek DS, et al. Interleukin-1beta suppresses retinoid transactivation of two hepatic transporter genes involved in bile formation. J Biol Chem 2000; 275: 8835.
241. Jung D, Hagenbuch B, Fried M, et al. Role of liver-enriched transcription factors and nuclear receptors in regulating the human, mouse, and rat NTCP gene. Am J Physiol 2004; 286: G752.
242. Zollner G, Wagner M, Fickert P, et al. Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver. Am J Physiol 2005; 289: G798.
243. Denson LA, Sturm E, Echevarria W, et al. The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology 2001; 121: 140.
244. Zollner G, Wagner M, Fickert P, et al. Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver. Am J Physiol 2005; 289: G798.
245. Moore JT, Goodwin B, Willson TM, Kliewer SA. Nuclear receptor regulation of genes involved in bile acid metabolism. Crit Rev Eukaryot Gene Expr 2002; 12: 119.
246. Handschin C, Meyer UA. Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR. Arch Biochem Biophys 2005; 433: 387.
247. Geier A, Dietrich CG, Voigt S, et al. Cytokine-dependent regulation of hepatic organic anion transporter gene transactivators in mouse liver. Am J Physiol 2005; 289: G831.
248. Trauner M, Meier PJ, Boyer JL. Molecular regulation of hepatocellular transport systems in cholestasis. J Hepatol 1999; 31: 165.
249. Trauner M, Arrese M, Soroka CJ, et al. The rat canlicular conjugate export pump (Mrp2) is down-regulated in intrahepatic and obstructive cholestasis. Gastroenterology 1997; 113: 255.
250. Thibault N, Claude JR, Ballet F. Actin filament alteration as a potential marker for cholestasis: a study in isolated rat hepatocyte couplets. Toxicology 1992; 73: 269.
251. Song JY, van Marle J, Van Noorden CJ, Frederiks WF. Redistribution of Ca2+, Mg2+-ATPase activity in relation to alterations of the cytoskeleton and tight junctions in hepatocytes of cholestatic rat liver. Eur J Cell Biol 1996; 71: 277.
252. Marks DL, LaRusso NF, McNiven MA. Isolation of the microtubulevesicle motor kinesin from rat liver: selective inhibition by cholestatic bile acids. Gastroenterology 1995; 108: 824.
253. Fallon MB, Mennone A, Anderson JM. Altered expression and localization of the tight junction protein ZO-1 after common bile duct ligation. Am J Physiol 1993; 264: C1439.
254. Rahner C, Stieger B, Landmann L. Structure-function correlation of tight junctional impairment after intrahepatic and extrahepatic cholestasis in rat liver. Gastroenterology 1996; 110: 1564.
255. Sakisaka S, Kawaguchi T, Taniguchi E, et al. Alterations in tight junctions differ between primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology 2001; 33: 1460.
256. Kunzelmann K. The cystic fibrosis transmembrane conductance regulator and its function in epithelial transport. Rev Physiol Biochem Pharmacol 1999; 137: 1.
257. McCarty NA. Permeation through the CFTR chloride channel. J Exp Biol 2000; 203: 1947.
258. Tietz PS, Alpini G, Pham LD, LaRusso NF. Somatostatin inhibits secretin-induced ductal hypercholeresis and exocytosis by cholangiocytes. Am J Physiol 1995; 269: G110.
259. Glaser SS, Rodgers RE, Phinizy JL, et al. Gastrin inhibits secretininduced ductal secretion by interaction with specific receptors on rat cholangiocytes. Am J Physiol 1997; 273: G1061.
260. Cho WK, Boyer JL. Characterization of ion transport mechanisms involved in bombesin-stimulated biliary secretion in rat cholangiocytes. J Hepatol 1999; 30: 1045.
261. Nyberg B, Einarsson K, Sonnenfeld T. Evidence that vasoactive intestinal peptide induces ductular secretion of bile in humans. Gastroenterology 1989; 96: 920.
262. Cho WK, Boyer JL. Vasoactive intestinal polypeptide is a potent regulator of bile secretion from rat cholangiocytes. Gastroenterology 1999; 117: 420.
263. Caligiuri A, Glaser S, Rodgers RE, et al. Endothelin-1 inhibits secretin-stimulated ductal secretion by interacting with ETA receptors on large cholangiocytes. Am J Physiol 1998; 275: G835.
264. Roman RM, Fitz JG. Emerging roles of purinergic signaling in gastrointestinal epithelial secretion and hepatobiliary function. Gastroenterology 1999; 116: 964.
265. Roman RM, Wang Y, Lidofsky SD, et al. Hepatocellular ATP-binding cassette protein expression enhances ATP release and autocrine regulation of cell volume. J Biol Chem 1997; 272: 21970.
266. Wang Y, Roman R, Lidofsky SD, Fitz JG. Autocrine signaling through ATP release represents a novel mechanism for cell volume regulation. Proc Natl Acad Sci USA 1996; 93: 12020.
267. Schlenker T, Romac JM, Sharara AI, et al. Regulation of biliary secretion through apical purinergic receptors in cultured rat cholangiocytes. Am J Physiol 1997; 273: G1108.
268. Vu DD, Tuchweber B, Raymond P, Yousef IM. Tight junction permeability and liver plasma membrane fluidity in lithocholateinduced cholestasis. Exp Mol Pathol 1992; 57: 47.
269. Kullak-Ublick GA, Meier PJ. Mechanisms of cholestasis. Clin Liver Dis 2000; 4: 357.
270. Carlton VE, Pawlikowska L, Bull LN. Molecular basis of intrahepatic cholestasis. Ann Med 2004; 36: 606.
271. Elferink RO. Cholestasis. Gut 2003; 52(Suppl 2): ii 42.
272. Arrese M, Trauner M. Molecular aspects of bile formation and cholestasis. Trends Mol Med 2003; 9: 558.
273. Jansen PL, Sturm E. Genetic cholestasis, causes and consequences for hepatobiliary transport. Liver Int 2003; 23: 315.
274. Trauner M, Fickert P, Stauber RE. Inflammation-induced cholestasis. J Gastroenterol Hepatol 1999; 14: 946.
275. Hartmann G, Cheung AK, Piquette-Miller M. Inflammatory cytokines, but not bile acids, regulate expression of murine hepatic anion transporters in endotoxemia. J Pharmacol Exp Ther 2002; 303: 273.
276. Zollner G, Fickert P, Zenz R, et al. Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 2001; 33: 633.
277. Feingold KR, Spady DK, Pollock AS, et al. Endotoxin, TNF, and IL-1 decrease cholesterol 7 alpha-hydroxylase mRNA levels and activity. J Lipid Res 1996; 37: 223.
278. Trauner M, Arrese M, Lee H, et al. Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors. J Clin Invest 1998; 101: 2092.
279. Zimmerman TL, Thevananther S, Ghose R, et al. Nuclear export of retinoid X receptor alpha in response to interleukin-1betamediated cell signaling: roles for JNK and SER260. J Biol Chem 2006; 281: 15434.
280. Trauner M, Arrese M, Lee H, et al. Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors. J Clin Invest 1998; 101: 2092.
281. Setchell KD, Rodrigues CM, Clerici C, et al. Bile acid concentrations in human and rat liver tissue and in hepatocyte nuclei. Gastroenterology 1997; 112: 226.
282. Dumont M, Jacquemin E, D'Hont C, et al. Expression of the liver Na+-independent organic anion transporting polypeptide (oatp-1) in rats with bile duct ligation. J Hepatol 1997; 27: 1051.
283. Gartung C, Ananthanarayanan M, Rahman M, et al. Down-regulation of expression and function of the rat liver Na+/bile acid contransporter in extrahepatic cholestasis. Gastroenterology 1996; 110: 199.
284. Lee JM, Trauner M, Soroka CJ, et al. Expression of the bile salt export pump is maintained after chronic cholestasis in the rat. Gastroenterology 2000; 118: 163.
285. Shoda J, Kano M, Oda K, et al. The expression levels of plasma membrane transporters in the cholestatic liver of patients undergoing biliary drainage and their association with the impairment of biliary secretory function. Am J Gastroenterol 2001; 96: 3368.
286. Denk GU, Soroka CJ, Takeyama Y, et al. Multidrug resistance-associated protein 4 is up-regulated in liver but down-regulated in kidney in obstructive cholestasis in the rat. J Hepatol 2004; 40: 585.
287. Xia X, Francis H, Glaser S, et al. Bile acid interactions with cholangiocytes. World J Gastroenterol 2006; 12: 3553.
288. Frankenberg T, Rao A, Chen F, et al. Regulation of the mouse organic solute transporter alpha-beta, Ostalpha-Ostbeta, by bile acids. Am J Physiol 2006; 290: G912.
289. Jung D, Kullak-Ublick GA. Hepatocyte nuclear factor 1 alpha: a key mediator of the effect of bile acids on gene expression. Hepatology 2003; 37: 622.
290. Eloranta JJ, Jung D, Kullak-Ublick GA. The human Na+-taurocholate cotransporting polypeptide gene is activated by glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma coactivator1alpha, and suppressed by bile acids via a small heterodimer partner-dependent mechanism. Mol Endocrinol 2006; 20: 65.
291. McConkey M, Gillin H, Webster CR, Anwer MS. Cross-talk between protein kinases Czeta and B in cyclic AMP-mediated sodium taurocholate co-transporting polypeptide translocation in hepatocytes. J Biol Chem 2004; 279: 20882.
292. Lammert F, Marschall HU, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 2000; 33: 1012.
293. Fagan EA. Intrahepatic cholestasis of pregnancy. Clin Liver Dis 1999; 3: 603.
294. Simon FR, Fortune J, Iwahashi M, et al. Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters. Am J Physiol 1996; 271: G1043.
295. Stieger B, Fattinger K, Madon J, et al. Drug-and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology 2000; 118: 422.
296. Huang L, Smit JW, Meijer DK, Vore M. Mrp2 is essential for estradiol-17beta(beta-D-glucuronide)-induced cholestasis in rats. Hepatology 2000; 32: 66.
297. Yamamoto Y, Moore R, Hess HA, et al. Estrogen receptor alpha mediates 17alpha-ethinylestradiol causing hepatotoxicity. J Biol Chem 2006; 281: 16625.
298. Fiorucci S, Clerici C, Antonelli E, et al. Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther 2005; 313: 604.
299. Reyes H, Sjovall J. Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy. Ann Med 2000; 32: 94.
300. Leevy CB, Koneru B, Klein KM. Recurrent familial prolonged intrahepatic cholestasis of pregnancy associated with chronic liver disease. Gastroenterology 1997; 113: 966.
301. Meng LJ, Reyes H, Axelson M, et al. Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: effect of ursodeoxycholic acid therapy. Hepatology 1997; 26: 1573.
302. Dixon PH, Weerasekera N, Linton KJ, et al. Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Hum Mol Genet 2000; 9: 1209.
303. Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. Semin Liver Dis 2001; 21: 551.
304. Eloranta ML, Hakli T, Hiltunen M, et al. Association of single nucleotide polymorphisms of the bile salt export pump gene with intrahepatic cholestasis of pregnancy. Scand J Gastroenterol 2003; 38: 648.
305. Pauli-Magnus C, Lang T, Meier Y, et al. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics 2004; 14: 91.
306. Savander M, Ropponen A, Avela K, et al. Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy. Gut 2003; 52: 1025.
307. Kullak-Ublick GA, Baretton GB, Oswald M, et al. Expression of the hepatocyte canalicular multidrug resistance protein (MRP2) in primary biliary cirrhosis. Hepatol Res 2002; 23: 78.
308. Pauli-Magnus C, Kerb R, Fattinger K, et al. BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology 2004; 39: 779.
309. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999; 30: 1356.
310. Loftus EV Jr, Harewood GC, Loftus CG, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005; 54: 91.
311. Fickert P, Fuchsbichler A, Wagner M, et al. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 2004; 127: 261.
312. Xie W, Radominska-Pandya A, Shi Y, et al. An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc Natl Acad Sci USA 2001; 98: 3375.
313. Karlsen TH, Lie BA, Frey FK, et al. Polymorphisms in the steroid and xenobiotic receptor gene influence survival in primary sclerosing cholangitis. Gastroenterology 2006; 131: 781.
314. Clayton RJ, Iber FL, Ruebner BH, McKusick VA. Byler disease. Fatal familial intrahepatic cholestasis in an Amish kindred. Am J Dis Child 1969; 117: 112.
315. Carlton VE, Knisely AS, Freimer NB. Mapping of a locus for progressive familial intrahepatic cholestasis (Byler disease) to 18q21-q22, the benign recurrent intrahepatic cholestasis region. Hum Mol Genet 1995; 4: 1049.
316. Harris MJ, Le Couteur DG, Arias IM. Progressive familial intra-hepatic cholestasis: genetic disorders of biliary transporters. J Gastroenterol Hepatol 2005; 20: 807.
317. Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology 1988; 95: 130.
318. Ismail H, Kalicinski P, Markiewicz M, et al. Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial external biliary diversion. Pediatr Transplant 1999; 3: 219.
319. Kalicinski PJ, Ismail H, Jankowska I, et al. Surgical treatment of progressive familial intrahepatic cholestasis: comparison of partial external biliary diversion and ileal bypass. Eur J Pediatr Surg 2003; 13: 307.
320. Summerskill WHJ, Walshe JM. Benign recurrant intrahepatic obstructive jaundice. Lancet 1959; ii: 686.
321. Houwen RH, Baharloo S, Blankenship K, et al. Genome screening by searching for shared segments: mapping a gene for benign recurrent intrahepatic cholestasis. Nat Genet 1994; 8: 380.
322. Bull LN, van Eijk MJT, Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholesis. Nat Genet 1998; 18: 219.
323. Klomp LW, Vargas JC, van Mil SW, et al. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology 2004; 40: 27.
324. van Mil SW, van der Woerd WL, van der Brugge G, et al. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology 2004; 127: 379.
325. Stapelbroek JM, van Erpecum KJ, Klomp LW, et al. Nasobiliary drainage induces long-lasting remission in benign recurrent intra-hepatic cholestasis. Hepatology 2006; 43: 51.
326. Chen HL, Chang PS, Hsu HC, et al. FIC1 and BSEP defects in Taiwanese patients with chronic intrahepatic cholestasis with low gamma-glutamyltranspeptidase levels. J Pediatr 2002; 140: 119.
327. Noe J, Kullak-Ublick GA, Jochum W, et al. Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis. J Hepatol 2005; 43: 536.
328. Deleuze JF, Jacquemin E, Dubuisson C, et al. Defect of multidrugresistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis. Hepatology 1996; 23: 904.
329. Rosmorduc O, Hermelin B, Poupon R. Mdr3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Gastroenterology 2001; 120: 1459.
330. Jacquemin E, De Vree JM, Cresteil D, et al. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 2001; 120: 1448.
331. Kartenbeck J, Leuschner U, Mayer R, Keppler D. Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome. Hepatology 1996; 23: 1061.
332. Paulusma CC, Kool M, Bosma PJ, et al. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. Hepatology 1997; 25: 1539.
333. Marschall HU, Wagner M, Zollner G, et al. Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology 2005; 129: 476.
334. Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 2002; 36: 525.
335. Paumgartner G, Beuers U. Mechanisms of action and therapeutic efficacy of ursodeoxycholic acid in cholestatic liver disease. Clin Liver Dis 2004; 8: 67.
336. Schuetz EG, Strom S, Yasuda K, et al. Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J Biol Chem 2001; 276: 39411.
337. Bodin K, Bretillon L, Aden Y, et al. Antiepileptic drugs increase plasma levels of 4beta-hydroxycholesterol in humans: evidence for involvement of cytochrome p450 3A4. J Biol Chem 2001; 276: 38685.
338. Ellis E, Axelson M, Abrahamsson A, et al. Feedback regulation of bile acid synthesis in primary human hepatocytes: evidence that CDCA is the strongest inhibitor. Hepatology 2003; 38: 930.
339. Zollner G, Fickert P, Fuchsbichler A, et al. Role of nuclear bile acid receptor, FXR, in adaptive ABC transporter regulation by cholic and ursodeoxycholic acid in mouse liver, kidney and intestine. J Hepatol 2003; 39: 480.
340. Modica S, Moschetta A. Nuclear bile acid receptor FXR as pharmacological target: are we there yet? FEBS Lett 2006; 580: 5492.
341. Liu Y, Binz J, Numerick MJ, et al. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra-and extrahepatic cholestasis. J Clin Invest 2003; 112: 1678.
342. Stedman C, Liddle C, Coulter S, et al. Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Proc Natl Acad Sci USA 2006; 103: 11323.
343. Gregorio GV, Ball CS, Mowat AP, Mieli-Vergani G. Effect of rifampicin in the treatment of pruritus in hepatic cholestasis. Arch Dis Child 1993; 69: 141.
344. Staudinger JL, Goodwin B, Jones SA, et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci USA 2001; 98: 3369.