Pflügers Archiv

, Volume 449, Issue 2, pp 123–131

The bile salt export pump: molecular properties, function and regulation

  • Marco Arrese
  • Meenakshisundaram Ananthanarayanan
Invited Review

Abstract

Secretion of bile salts from the hepatocyte into bile is the major driving force for the generation of bile flow. Identification of the bile salt export pump (BSEP, ABCB11) as the main adenosine-triphosphate-dependent bile salt transporter in mammalian liver has led to a greater understanding of the biliary bile salt secretory process and its regulation. The biology and pathobiology of BSEP have been the subject of many recent studies. Thus, it has been recognized that while mutations in the gene encoding BSEP are responsible for a subgroup of progressive familial cholestasis (progressive familial intrahepatic cholestasis subtype 2), a pediatric cholestatic disorder that may progress to cirrhosis, defective expression or function of BSEP may underlie some forms of drug-induced cholestasis. The present review summarizes recent data on the molecular properties and regulation of BSEP, as well as the clinical implications of absent or defective function of this hepatic efflux pump.

Keywords

Bile Bile acid transport Bile secretion Cholestasis 

References2

  1. 1.
    Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf DJ, Suchy FJ (2001) Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem 276:28857–28865CrossRefPubMedGoogle Scholar
  2. 2.
    Arrese M, Ananthanarayanan M (2001) Mice and men: are they bile-ologically different? Hepatology 33:1551–1553CrossRefPubMedGoogle Scholar
  3. 3.
    Arrese M, Karpen SJ (2001) New horizons in the regulation of bile acid and lipid homeostasis: critical role of the nuclear receptor FXR as an intracellular bile acid sensor. Gut 49:465–466CrossRefPubMedGoogle Scholar
  4. 4.
    Arrese M, Trauner M (2003) Molecular aspects of bile formation and cholestasis. Trends Mol Med 9:558–564CrossRefPubMedGoogle Scholar
  5. 5.
    Arrese M, Pizarro M, Solis N, Accatino L (1997) Adaptive regulation of hepatic bile salt transport: role of bile salt hydrophobicity and microtubule-dependent vesicular pathway. J Hepatol 26:694–702CrossRefPubMedGoogle Scholar
  6. 6.
    Arrese M, Ananthananarayanan M, Suchy FJ (1998) Hepatobiliary transport: molecular mechanisms of development and cholestasis. Pediatr Res 44:141–147PubMedGoogle Scholar
  7. 7.
    Arrese M, Trauner M, Ananthanarayanan M, Pizarro M, Solis N, Accatino L, Soroka C, Boyer JL, Karpen SJ, Miquel JF, Suchy FJ (2003) Down-regulation of the Na+/taurocholate cotransporting polypeptide during pregnancy in the rat. J Hepatol 38:148–155CrossRefPubMedGoogle Scholar
  8. 8.
    Borst P, Elferink RO (2002) Mammalian ABC transporters in health and disease. Annu Rev Biochem 71:537–592CrossRefPubMedGoogle Scholar
  9. 9.
    Boyer JL (2002) A biliary milestone: functional expression of the human bile salt export pump. Gastroenterology 123:1733–1735PubMedGoogle Scholar
  10. 10.
    Brown RS Jr, Lomri N, De Voss J, Rahmaoui CM, Xie MH, Hua T, Lidofsky SD, Scharschmidt BF (1995) Enhanced secretion of glycocholic acid in a specially adapted cell line is associated with overexpression of apparently novel ATP-binding cassette proteins. Proc Natl Acad Sci U S A 92:5421–5425PubMedGoogle Scholar
  11. 11.
    Byrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ, Thompson RJ (2002) The human bile salt export pump: characterization of substrate specificity and identification of inhibitors. Gastroenterology 123:1649–1658CrossRefPubMedGoogle Scholar
  12. 12.
    Cai SY, Wang L, Ballatori N, Boyer JL (2001) Bile salt export pump is highly conserved during vertebrate evolution and its expression is inhibited by PFIC type II mutations. Am J Physiol 281:G316–G322Google Scholar
  13. 13.
    Cao J, Huang L, Liu Y, Hoffman T, Stieger B, Meier PJ, Vore M (2001) Differential regulation of hepatic bile salt and organic anion transporters in pregnant and postpartum rats and the role of prolactin. Hepatology 33:140–147CrossRefPubMedGoogle Scholar
  14. 14.
    Chen F, Ananthanarayanan M, Emre S, Neimark E, Bull LN, Knisely AS, Strautnieks SS, Thompson RJ, Magid MS, Gordon R, Balasubramanian N, Suchy FJ, Shneider BL (2004) Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity. Gastroenterology 126:756–764CrossRefPubMedGoogle Scholar
  15. 15.
    Childs S, Yeh RL, Georges E, Ling V (1995) Identification of a sister gene to P-glycoprotein. Cancer Res 55:2029–2034PubMedGoogle Scholar
  16. 16.
    Childs S, Yeh RL, Hui D, Ling V (1998) Taxol resistance mediated by transfection of the liver-specific sister gene of P-glycoprotein. Cancer Res 58:4160–4167PubMedGoogle Scholar
  17. 17.
    Crocenzi FA, Mottino AD, Cao J, Veggi LM, Pozzi EJ, Vore M, Coleman R, Roma MG (2003) Estradiol-17beta-d-glucuronide induces endocytic internalization of Bsep in rats. Am J Physiol 285:G449–G459Google Scholar
  18. 18.
    Crocenzi FA, Mottino AD, Sanchez Pozzi EJ, Pellegrino JM, Rodriguez Garay EA, Milkiewicz P, Vore M, Coleman R, Roma MG (2003) Impaired localisation and transport function of canalicular Bsep in taurolithocholate induced cholestasis in the rat. Gut 52:1170–1177CrossRefPubMedGoogle Scholar
  19. 19.
    Elferink RO (2003) Cholestasis. Gut 52[Suppl 2:ii]:42–48Google Scholar
  20. 20.
    Elferink RO, Groen AK (2002) Genetic defects in hepatobiliary transport. Biochim Biophys Acta 1586:129–145PubMedGoogle Scholar
  21. 21.
    Eloranta ML, Hakli T, Hiltunen M, Helisalmi S, Punnonen K, Heinonen S (2003) Association of single nucleotide polymorphisms of the bile salt export pump gene with intrahepatic cholestasis of pregnancy. Scand J Gastroenterol 38:648–652CrossRefPubMedGoogle Scholar
  22. 22.
    Erlinger S (1994) Bile flow. In: Arias IM, Boyer JL, Fausto N, Jakoby WB, Schachter D, Shafritz DA (eds) The liver: biology and pathobiology, 3rd edn. Raven, New York, pp 769–788Google Scholar
  23. 23.
    Fickert P, Zollner G, Fuchsbichler A, Stumptner C, Pojer C, Zenz R, Lammert F, Stieger B, Meier PJ, Zatloukal K, Denk H, Trauner M (2001) Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver. Gastroenterology 121:170–183PubMedGoogle Scholar
  24. 24.
    Figge A, Lammert F, Paigen B, Henkel A, Matern S, Korstanje R, Shneider BL, Chen F, Stoltenberg E, Spatz K, Hoda F, Cohen DE, Green RM (2003) Hepatic overexpression of murine Abcb11 increases hepatobiliary lipid secretion and reduces hepatic steatosis. J Biol Chem 279:2790–2799CrossRefPubMedGoogle Scholar
  25. 25.
    Funk C, Pantze M, Jehle L, Ponelle C, Scheuermann G, Lazendic M, Gasser R (2001) Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate. Toxicology 167:83–98CrossRefPubMedGoogle Scholar
  26. 26.
    Gerloff T, Stieger B, Hagenbuch B, Madon J, Landmann L, Roth J, Hofmann AF, Meier PJ (1998) The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem 273:10046–10050CrossRefPubMedGoogle Scholar
  27. 27.
    Green RM, Hoda F, Ward KL (2000) Molecular cloning and characterization of the murine bile salt export pump. Gene 241:117–123CrossRefPubMedGoogle Scholar
  28. 28.
    Hagenbuch B, Dawson P (2004) The sodium bile salt cotransport family SLC10. Pflugers Arch 4:566–570Google Scholar
  29. 29.
    Hagenbuch B, Meier PJ (2004) Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch 447:653–665CrossRefPubMedGoogle Scholar
  30. 30.
    Haussinger D, Schmitt M, Weiergraber O, Kubitz R (2000) Short-term regulation of canalicular transport. Semin Liver Dis 20:307–321CrossRefPubMedGoogle Scholar
  31. 31.
    Higgins CF (2001) ABC transporters: physiology, structure and mechanism—an overview. Res Microbiol 152:205–210CrossRefPubMedGoogle Scholar
  32. 32.
    Higuchi H, Gores GJ (2003) Bile acid regulation of hepatic physiology: IV. Bile acids and death receptors. Am J Physiol 284:G734–G738Google Scholar
  33. 33.
    Hoda F, Green RM (2003) Hepatic canalicular membrane transport of bile salt in C57L/J and AKR/J mice: implications for cholesterol gallstone formation. J Membr Biol 196:9–14CrossRefPubMedGoogle Scholar
  34. 34.
    Hofmann AF (2002) Cholestatic liver disease: pathophysiology and therapeutic options. Liver 22 [Suppl 2]:14–19Google Scholar
  35. 35.
    Jacquemin E, Hadchouel M (1999) Genetic basis of progressive familial intrahepatic cholestasis. J Hepatol 31:377–381CrossRefPubMedGoogle Scholar
  36. 36.
    Jansen PL, Sturm E (2003) Genetic cholestasis, causes and consequences for hepatobiliary transport. Liver Int 23:315–322CrossRefPubMedGoogle Scholar
  37. 37.
    Jansen PL, Muller M, Sturm E (2000) Genes and cholestasis. Hepatology 34:1067–1074CrossRefGoogle Scholar
  38. 38.
    Karpen SJ (2002) Nuclear receptor regulation of hepatic function. J Hepatol 36:832–850CrossRefPubMedGoogle Scholar
  39. 39.
    Kipp H, Arias IM (2000) Newly synthesized canalicular ABC transporters are directly targeted from the Golgi to the hepatocyte apical domain in rat liver. J Biol Chem 275:15917–15925CrossRefPubMedGoogle Scholar
  40. 40.
    Kipp H, Arias IM (2002) Trafficking of canalicular ABC transporters in hepatocytes. Annu Rev Physiol 64:595–608CrossRefPubMedGoogle Scholar
  41. 41.
    Kipp H, Pichetshote N, Arias IM (2001) Transporters on demand: intrahepatic pools of canalicular ATP binding cassette transporters in rat liver. J Biol Chem 276:7218–7224CrossRefPubMedGoogle Scholar
  42. 42.
    Kubitz R, Sutfels G, Kuhlkamp T, Kolling R, Haussinger D (2004) Trafficking of the bile salt export pump from the Golgi to the canalicular membrane is regulated by the p38 MAP kinase. Gastroenterology 126:541–553CrossRefPubMedGoogle Scholar
  43. 43.
    Kullak-Ublick GA, Stieger B, Hagenbuch B, Meier PJ (2000) Hepatic transport of bile salts. Semin Liver Dis 20:273–292CrossRefPubMedGoogle Scholar
  44. 44.
    Kullak-Ublick GA, Stieger B, Meier PJ (2004) Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 126:322–342CrossRefPubMedGoogle Scholar
  45. 45.
    Lee J, Boyer JL (2000) Molecular alterations in hepatocyte transport mechanisms in acquired cholestatic liver disorders. Semin Liver Dis 20:373–384CrossRefPubMedGoogle Scholar
  46. 46.
    Liu Y, Binz J, Numerick MJ, Dennis S, Luo G, Desai B, MacKenzie KI, Mansfield TA, Kliewer SA, Goodwin B, Jones SA (2003) Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J Clin Invest 112:1678–1687CrossRefPubMedGoogle Scholar
  47. 47.
    Meier PJ (2002) Canalicular bile formation: beyond single transporter functions. J Hepatol 37:272–273CrossRefPubMedGoogle Scholar
  48. 48.
    Meier PJ, Stieger B (2002) Bile salt transporters. Annu Rev Physiol 64:635–661CrossRefPubMedGoogle Scholar
  49. 49.
    Micheline D, Emmanuel J, Serge E (2002) Effect of ursodeoxycholic acid on the expression of the hepatocellular bile acid transporters (Ntcp and Bsep) in rats with estrogen-induced cholestasis. J Pediatr Gastroenterol Nutr 35:185–191CrossRefPubMedGoogle Scholar
  50. 50.
    Moreno M, Molina H, Amigo L, Zanlungo S, Arrese M, Rigotti A, Miquel JF (2003) Hepatic overexpression of caveolins increases bile salt secretion in mice. Hepatology 38:1477–1488PubMedGoogle Scholar
  51. 51.
    Muller M, Ishikawa T, Berger U, Klunemann C, Lucka L, Schreyer A, Kannich C, Reutter W, Kurz G, Keppler D (1991) ATP-dependent transport of taurocholate across the hepatocyte canalicular membrane mediated by a 110-kDa glycoprotein binding ATP and bile salt. J Biol Chem 266:18920–18926PubMedGoogle Scholar
  52. 52.
    Nishida T, Gatmaitan Z, Che MX, Arias IM (1991) Rat liver canalicular membrane vesicles containing an ATP-dependent bile acid transport system. Proc Natl Acad Sci U S A 88:6590–6594PubMedGoogle Scholar
  53. 53.
    Noe J, Hagenbuch B, Meier PJ, St-Pierre MV (2001) Characterization of the mouse bile salt export pump overexpressed in the baculovirus system. Hepatology 33:1223–1231CrossRefPubMedGoogle Scholar
  54. 54.
    Noe J, Stieger B, Meier PJ (2002) Functional expression of the canalicular bile salt export pump of human liver. Gastroenterology 123:1659–1666PubMedGoogle Scholar
  55. 55.
    Oswald M, Kullak-Ublick GA, Paumgartner G, Beuers U (2001) Expression of hepatic transporters OATP-C and MRP2 in primary sclerosing cholangitis. Liver 21:247–253CrossRefPubMedGoogle Scholar
  56. 56.
    Paolini M, Pozzetti L, Montagnani M, Potenza G, Sabatini L, Antelli A, Cantelli-Forti G, Roda A Ursodeoxycholic acid (UDCA) prevents DCA effects on male mouse liver via up-regulation of CYP [correction of CXP] and preservation of BSEP activities. Hepatology 36:305–314Google Scholar
  57. 57.
    Patel P, Weerasekera N, Hitchins M, Boyd CA, Johnston DG, Williamson C (2003) Semi quantitative expression analysis of MDR3, FIC1, BSEP, OATP-A, OATP-C,OATP-D, OATP-E and NTCP gene transcripts in 1st and 3rd trimester human placenta. Placenta 24:39–44CrossRefPubMedGoogle Scholar
  58. 58.
    Paumgartner G, Beuers U (2002) Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 36:525–531CrossRefPubMedGoogle Scholar
  59. 59.
    Pauli-Magnus C, Meier PJ (2003) Pharmacogenetics of hepatocellular transporters. Pharmacogenetics 13:189–198CrossRefPubMedGoogle Scholar
  60. 60.
    Pauli-Magnus C, Lang T, Meier Y, Zodan-Marin T, Jung D, Breymann C, Zimmermann R, Kenngott S, Beuers U, Reichel C, Kerb R, Penger A, Meier PJ, Kullak-Ublick GA (2004) Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics 14:91–102CrossRefPubMedGoogle Scholar
  61. 61.
    Pauli-Magnus C, Kerb R, Fattinger K, Lang T, Anwald B, Kullak-Ublick GA, Beuers U, Meier PJ (2004) BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology 39:779–791CrossRefPubMedGoogle Scholar
  62. 62.
    Perwaiz S, Forrest D, Mignault D, Tuchweber B, Phillip MJ, Wang R, Ling V, Yousef IM (2003) Appearance of atypical 3 alpha,6 beta,7 beta,12 alpha-tetrahydroxy-5 beta-cholan-24-oic acid in spgp knockout mice. J Lipid Res 44:494–502CrossRefPubMedGoogle Scholar
  63. 63.
    Pizarro M, Solis N, Accatino L, Arrese M (2003) Bile secretory function in the obese zucker rat: cholestatic features and down-regulation of the multidrug resistance-associated protein 2. J Hepatol 38:10Google Scholar
  64. 64.
    Plass JR, Mol O, Heegsma J, Geuken M, Faber KN, Jansen PL, Muller M (2002) Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump. Hepatology 35:589–596CrossRefPubMedGoogle Scholar
  65. 65.
    Plass JR, Mol O, Heegsma J, Geuken M, de Bruin J, Elling G, Muller M, Faber KN, Jansen PL (2004) A progressive familial intrahepatic cholestasis type 2 mutation causes an unstable, temperature-sensitive bile salt export pump. J Hepatol 40:24–30CrossRefPubMedGoogle Scholar
  66. 66.
    Redinger RN (2003) Nuclear receptors in cholesterol catabolism: molecular biology of the enterohepatic circulation of bile salts and its role in cholesterol homeostasis. J Lab Clin Med 142:7–20CrossRefPubMedGoogle Scholar
  67. 67.
    Rippin SJ, Hagenbuch B, Meier PJ, Stieger B (2001) Cholestatic expression pattern of sinusoidal and canalicular organic anion transport systems in primary cultured rat hepatocytes. Hepatology 33:776–782CrossRefPubMedGoogle Scholar
  68. 68.
    Roman ID, Fernandez-Moreno MD, Fueyo JA, Roma MG, Coleman R (2003) Cyclosporin A induced internalization of the bile salt export pump in isolated rat hepatocyte couplets. Toxicol Sci 71:276–281CrossRefPubMedGoogle Scholar
  69. 69.
    Savander M, Ropponen A, Avela K, Weerasekera N, Cormand B, Hirvioja ML, Riikonen S, Ylikorkala O, Lehesjoki AE, Williamson C, Aittomaki K (2003) Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy. Gut 52:1025–1029CrossRefPubMedGoogle Scholar
  70. 70.
    Schmitt M, Kubitz R, Lizun S, Wettstein M, Haussinger D (2001) Regulation of the dynamic localization of the rat Bsep gene-encoded bile salt export pump by anisoosmolarity. Hepatology 33:509–518CrossRefPubMedGoogle Scholar
  71. 71.
    Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ (2000) Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102:731–744CrossRefPubMedGoogle Scholar
  72. 72.
    Stieger B, O’Neill B, Meier PJ (1992) ATP-dependent bile-salt transport in canalicular rat liver plasma-membrane vesicles. Biochem J 284:67–74PubMedGoogle Scholar
  73. 73.
    Stieger B, Fattinger K, Madon J, Kullak-Ublick GA, Meier PJ (2000) Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology 118:422–430PubMedGoogle Scholar
  74. 74.
    Strautnieks SS, Kagalwalla AF, Tanner MS, Knisely AS, Bull L, Freimer N, Kocoshis SA, Gardiner RM, Thompson RJ (1997) Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24. Am J Hum Genet 61:630–633PubMedGoogle Scholar
  75. 75.
    Strautnieks SS, Bull LN, Knisely AS, Kocoshis SA, Dahl N, Arnell H, Sokal E, Dahan K, Childs S, Ling V, Tanner MS, Kagalwalla AF, Nemeth A, Pawlowska J, Baker A, Mieli-Vergani G, Freimer NB, Gardiner RM, Thompson RJ (1998) A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet 20:233–238CrossRefPubMedGoogle Scholar
  76. 76.
    Taguchi Y, Morishima M, Komano T, Ueda K (1997) Amino acid substitutions in the first transmembrane domain (TM1) of P-glycoprotein that alter substrate specificity. FEBS Lett 413:142–146CrossRefPubMedGoogle Scholar
  77. 77.
    Thompson R, Strautnieks S (2001) BSEP: function and role in progressive familial intrahepatic cholestasis. Semin Liver Dis 21:545–550CrossRefPubMedGoogle Scholar
  78. 78.
    Tomer G, Ananthanarayanan M, Weymann A, Balasubramanian N, Suchy FJ (2003) Differential developmental regulation of rat liver canalicular membrane transporters Bsep and Mrp2. Pediatr Res 53:288–294CrossRefPubMedGoogle Scholar
  79. 79.
    Trauner M, Boyer JL (2003) Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev 83:633–671PubMedGoogle Scholar
  80. 80.
    Wagner M, Fickert P, Zollner G, Fuchsbichler A, Silbert D, Tsybrovskyy O, Zatloukal K, Guo GL, Schuetz JD, Gonzalez FJ, Schall HU, Denk H, Trauner M (2003) Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Gastroenterology 125:825–838CrossRefPubMedGoogle Scholar
  81. 81.
    Wang DQ, Lammert F, Paigen B, Carey MC (1999) Phenotypic characterization of lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice. Pathophysiology of biliary lipid secretion J Lipid Res 40:2066–2079Google Scholar
  82. 82.
    Wang L, Soroka CJ, Boyer JL (2002) The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II. J Clin Invest 110:965–972CrossRefPubMedGoogle Scholar
  83. 83.
    Wang R, Salem M, Yousef IM, Tuchweber B, Lam P, Childs SJ, Helgason CD, Ackerley C, Phillips MJ, Ling V (2001) Targeted inactivation of Sister of P-glycoprotein gene (spgp) in mice results in non-progressive but persistent intrahepatic cholestasis. Proc Natl Acad Sci U S A 98:2011–2016CrossRefPubMedGoogle Scholar
  84. 84.
    Wang R, Lam P, Liu L, Forrest D, Yousef IM, Mignault D, Phillips MJ, Ling V (2003) Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P-glycoprotein. Hepatology 38:1489–1499PubMedGoogle Scholar
  85. 85.
    Wolters H, Elzinga BM, Baller JF, Boverhof R, Schwarz M, Stieger B, Verkade HJ, Kuipers F (2002) Effects of bile salt flux variations on the expression of hepatic bile salt transporters in vivo in mice. J Hepatol 37:556–563CrossRefPubMedGoogle Scholar
  86. 86.
    Xu G, Pan LX, Erickson SK, Forman BM, Shneider BL, Ananthanarayanan M, Li X, Shefer S, Balasubramanian N, Ma L, Asaoka H, Lear SR, Nguyen LB, Dussault I, Suchy FJ, Tint GS, Salen G (2002) Removal of the bile acid pool upregulates cholesterol 7alpha-hydroxylase by deactivating FXR in rabbits. J Lipid Res 43:45–50PubMedGoogle Scholar
  87. 87.
    Yu J, Lo JL, Huang L, Zhao A, Metzger E, Adams A, Meinke PT, Wright SD, Cui J (2002) Lithocholic acid increases expression of bile salt export pump through farnesoid X receptor antagonist activity. J Biol Chem 277:31441–31447CrossRefPubMedGoogle Scholar
  88. 88.
    Zollner G, Fickert P, Zenz R, Fuchsbichler A, Stumptner C, Kenner L, Ferenci P, Stauber RE, Krejs GJ, Denk H, Zatloukal K, Trauner M (2001) Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 33:633–646CrossRefPubMedGoogle Scholar
  89. 89.
    Zollner G, Fickert P, Silbert D, Fuchsbichler A, Marschall HU, Zatloukal K, Denk H, Trauner M (2003) Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol 38:717–727CrossRefPubMedGoogle Scholar
  90. 90.
    Zollner G, Fickert P, Fuchsbichler A, Silbert D, Wagner M, Arbeiter S, Gonzalez FJ, Marschall HU, Zatloukal K, Denk H, Trauner M (2003) Role of nuclear bile acid receptor, FXR, in adaptive ABC transporter regulation by cholic and ursodeoxycholic acid in mouse liver and kidney. J Hepatol 39:480–448CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag  2004

Authors and Affiliations

  • Marco Arrese
    • 1
  • Meenakshisundaram Ananthanarayanan
    • 2
  1. 1.Departamento de Gastroenterología, Facultad de MedicinaPontificia Universidad Católica de ChileSantiagoChile
  2. 2.Laboratory of Developmental and Molecular Hepatology, Department of PediatricsMount Sinai School of MedicineNew YorkUSA

Personalised recommendations