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Hepatobiliary Transport of Bile Acids

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Bile Acids in Gastroenterology

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Abstract

Bile acids are the major driving force of bile excretion from hepatocytes; they are synthesized from cholesterol via at least 17 enzymatic reactions. They play a critical role in cholesterol disposal and the absorption of fat and fat-soluble vitamins. The concentration of intracellular bile acid is tightly regulated by modulating expression of bile acid transporters via nuclear receptors. This article provides a comprehensive overview of the characteristics and regulatory networks of hepatobiliary bile acid transporters.

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References

  1. Strautnieks SS, Kagalwalla AF, Tanner MS, Knisely AS, Bull L, Freimer N, et al. Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24. Am J Hum Genet. 1997;61(3):630–3. doi:10.1086/515501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gerloff T, Stieger B, Hagenbuch B, Madon J, Landmann L, Roth J, et al. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem. 1998;273(16):10046–50.

    Article  CAS  PubMed  Google Scholar 

  3. Strautnieks SS, Bull LN, Knisely AS, Kocoshis SA, Dahl N, Arnell H, et al. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet. 1998;20(3):233–8. doi:10.1038/3034.

    Article  CAS  PubMed  Google Scholar 

  4. Green RM, Hoda F, Ward KL. Molecular cloning and characterization of the murine bile salt export pump. Gene. 2000;241(1):117–23.

    Article  CAS  PubMed  Google Scholar 

  5. Mochizuki K, Kagawa T, Numari A, Harris MJ, Itoh J, Watanabe N, et al. Two N-linked glycans are required to maintain the transport activity of the bile salt export pump (ABCB11) in MDCK II cells. Am J Physiol Gastrointest Liver Physiol. 2007;292(3):G818–28. doi:10.1152/ajpgi.00415.2006.

    Article  CAS  PubMed  Google Scholar 

  6. Kipp H, Arias IM. Newly synthesized canalicular ABC transporters are directly targeted from the Golgi to the hepatocyte apical domain in rat liver. J Biol Chem. 2000;275(21):15917–25. doi:10.1074/jbc.M909875199.

    Article  CAS  PubMed  Google Scholar 

  7. Kipp H, Pichetshote N, Arias IM. Transporters on demand: intrahepatic pools of canalicular ATP binding cassette transporters in rat liver. J Biol Chem. 2001;276(10):7218–24. doi:10.1074/jbc.M007794200.

    Article  CAS  PubMed  Google Scholar 

  8. Wakabayashi Y, Lippincott-Schwartz J, Arias IM. Intracellular trafficking of bile salt export pump (ABCB11) in polarized hepatic cells: constitutive cycling between the canalicular membrane and rab11-positive endosomes. Mol Biol Cell. 2004;15(7):3485–96. doi:10.1091/mbc.E03-10-0737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ortiz DF, Moseley J, Calderon G, Swift AL, Li S, Arias IM. Identification of HAX-1 as a protein that binds bile salt export protein and regulates its abundance in the apical membrane of Madin-Darby canine kidney cells. J Biol Chem. 2004;279(31):32761–70. doi:10.1074/jbc.M404337200.

    Article  CAS  PubMed  Google Scholar 

  10. Chan W, Calderon G, Swift AL, Moseley J, Li S, Hosoya H, et al. Myosin II regulatory light chain is required for trafficking of bile salt export protein to the apical membrane in Madin-Darby canine kidney cells. J Biol Chem. 2005;280(25):23741–7. doi:10.1074/jbc.M502767200.

    Article  CAS  PubMed  Google Scholar 

  11. Hayashi H, Inamura K, Aida K, Naoi S, Horikawa R, Nagasaka H, et al. AP2 adaptor complex mediates bile salt export pump internalization and modulates its hepatocanalicular expression and transport function. Hepatology. 2012;55(6):1889–900. doi:10.1002/hep.25591.

    Article  CAS  PubMed  Google Scholar 

  12. Lam P, Xu S, Soroka CJ, Boyer JL. A C-terminal tyrosine-based motif in the bile salt export pump directs clathrin-dependent endocytosis. Hepatology. 2012;55(6):1901–11. doi:10.1002/hep.25523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kubitz R, Sutfels G, Kuhlkamp T, Kolling R, Haussinger D. Trafficking of the bile salt export pump from the Golgi to the canalicular membrane is regulated by the p38 MAP kinase. Gastroenterology. 2004;126(2):541–53.

    Article  CAS  PubMed  Google Scholar 

  14. Hayashi H, Sugiyama Y. Short-chain ubiquitination is associated with the degradation rate of a cell-surface-resident bile salt export pump (BSEP/ABCB11). Mol Pharmacol. 2009;75(1):143–50. doi:10.1124/mol.108.049288.

    Article  CAS  PubMed  Google Scholar 

  15. Byrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ, Thompson RJ. The human bile salt export pump: characterization of substrate specificity and identification of inhibitors. Gastroenterology. 2002;123(5):1649–58.

    Article  CAS  PubMed  Google Scholar 

  16. Noe J, Stieger B, Meier PJ. Functional expression of the canalicular bile salt export pump of human liver. Gastroenterology. 2002;123(5):1659–66.

    Article  CAS  PubMed  Google Scholar 

  17. Hayashi H, Takada T, Suzuki H, Onuki R, Hofmann AF, Sugiyama Y. Transport by vesicles of glycine- and taurine-conjugated bile salts and taurolithocholate 3-sulfate: a comparison of human BSEP with rat Bsep. Biochim Biophys Acta. 2005;1738(1–3):54–62. doi:10.1016/j.bbalip.2005.10.006.

    Article  CAS  PubMed  Google Scholar 

  18. Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, et al. Identification of a nuclear receptor for bile acids. Science. 1999;284(5418):1362–5.

    Article  CAS  PubMed  Google Scholar 

  19. Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf DJ, Suchy FJ. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem. 2001;276(31):28857–65. doi:10.1074/jbc.M011610200.

    Article  CAS  PubMed  Google Scholar 

  20. Plass JR, Mol O, Heegsma J, Geuken M, Faber KN, Jansen PL, et al. Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump. Hepatology. 2002;35(3):589–96. doi:10.1053/jhep.2002.31724.

    Article  CAS  PubMed  Google Scholar 

  21. Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002;45(17):3569–72.

    Article  CAS  PubMed  Google Scholar 

  22. Rizzo G, Passeri D, De Franco F, Ciaccioli G, Donadio L, Rizzo G, et al. Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist. Mol Pharmacol. 2010;78(4):617–30. doi:10.1124/mol.110.064501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yu J, Lo JL, Huang L, Zhao A, Metzger E, Adams A, et al. Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity. J Biol Chem. 2002;277(35):31441–7. doi:10.1074/jbc.M200474200.

    Article  CAS  PubMed  Google Scholar 

  24. Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013;17(2):225–35. doi:10.1016/j.cmet.2013.01.003.

    Article  CAS  PubMed  Google Scholar 

  25. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000;102(6):731–44.

    Article  CAS  PubMed  Google Scholar 

  26. Gomez-Ospina N, Potter CJ, Xiao R, Manickam K, Kim MS, Kim KH, et al. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat Commun. 2016;7:10713. doi:10.1038/ncomms10713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Song X, Kaimal R, Yan B, Deng R. Liver receptor homolog 1 transcriptionally regulates human bile salt export pump expression. J Lipid Res. 2008;49(5):973–84. doi:10.1194/jlr.M700417-JLR200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mataki C, Magnier BC, Houten SM, Annicotte JS, Argmann C, Thomas C, et al. Compromised intestinal lipid absorption in mice with a liver-specific deficiency of liver receptor homolog 1. Mol Cell Biol. 2007;27(23):8330–9. doi:10.1128/MCB.00852-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Weerachayaphorn J, Cai SY, Soroka CJ, Boyer JL. Nuclear factor erythroid 2-related factor 2 is a positive regulator of human bile salt export pump expression. Hepatology. 2009;50(5):1588–96. doi:10.1002/hep.23151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tanaka Y, Aleksunes LM, Cui YJ, Klaassen CD. ANIT-induced intrahepatic cholestasis alters hepatobiliary transporter expression via Nrf2-dependent and independent signaling. Toxicol Sci. 2009;108(2):247–57. doi:10.1093/toxsci/kfp020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Song X, Vasilenko A, Chen Y, Valanejad L, Verma R, Yan B, et al. Transcriptional dynamics of bile salt export pump during pregnancy: mechanisms and implications in intrahepatic cholestasis of pregnancy. Hepatology. 2014;60(6):1993–2007. doi:10.1002/hep.27171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Morotti RA, Suchy FJ, Magid MS. Progressive familial intrahepatic cholestasis (PFIC) type 1, 2, and 3: a review of the liver pathology findings. Semin Liver Dis. 2011;31(1):3–10. doi:10.1055/s-0031-1272831.

    Article  CAS  PubMed  Google Scholar 

  33. van Mil SW, van der Woerd WL, van der Brugge G, Sturm E, Jansen PL, Bull LN, et al. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology. 2004;127(2):379–84.

    Article  PubMed  CAS  Google Scholar 

  34. Strautnieks SS, Byrne JA, Pawlikowska L, Cebecauerova D, Rayner A, Dutton L, et al. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology. 2008;134(4):1203–14. doi:10.1053/j.gastro.2008.01.038.

    Article  CAS  PubMed  Google Scholar 

  35. Byrne JA, Strautnieks SS, Ihrke G, Pagani F, Knisely AS, Linton KJ, et al. Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing. Hepatology. 2009;49(2):553–67. doi:10.1002/hep.22683.

    Article  CAS  PubMed  Google Scholar 

  36. Davit-Spraul A, Fabre M, Branchereau S, Baussan C, Gonzales E, Stieger B, et al. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology. 2010;51(5):1645–55. doi:10.1002/hep.23539.

    Article  CAS  PubMed  Google Scholar 

  37. Jansen PL, Strautnieks SS, Jacquemin E, Hadchouel M, Sokal EM, Hooiveld GJ, et al. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology. 1999;117(6):1370–9.

    Article  CAS  PubMed  Google Scholar 

  38. Wang L, Soroka CJ, Boyer JL. The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II. J Clin Invest. 2002;110(7):965–72. doi:10.1172/JCI15968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Plass JR, Mol O, Heegsma J, Geuken M, de Bruin J, Elling G, et al. A progressive familial intrahepatic cholestasis type 2 mutation causes an unstable, temperature-sensitive bile salt export pump. J Hepatol. 2004;40(1):24–30.

    Article  CAS  PubMed  Google Scholar 

  40. Hayashi H, Takada T, Suzuki H, Akita H, Sugiyama Y. Two common PFIC2 mutations are associated with the impaired membrane trafficking of BSEP/ABCB11. Hepatology. 2005;41(4):916–24. doi:10.1002/hep.20627.

    Article  CAS  PubMed  Google Scholar 

  41. Lam P, Pearson CL, Soroka CJ, Xu S, Mennone A, Boyer JL. Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases. Am J Phys Cell Physiol. 2007;293(5):C1709–16. doi:10.1152/ajpcell.00327.2007.

    Article  CAS  Google Scholar 

  42. Kagawa T, Watanabe N, Mochizuki K, Numari A, Ikeno Y, Itoh J, et al. Phenotypic differences in PFIC2 and BRIC2 correlate with protein stability of mutant Bsep and impaired taurocholate secretion in MDCK II cells. Am J Physiol Gastrointest Liver Physiol. 2008;294(1):G58–67. doi:10.1152/ajpgi.00367.2007.

    Article  CAS  PubMed  Google Scholar 

  43. van Ooteghem NA, Klomp LW, van Berge-Henegouwen GP, Houwen RH. Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum. J Hepatol. 2002;36(3):439–43.

    Article  PubMed  Google Scholar 

  44. Cai SY, Gautam S, Nguyen T, Soroka CJ, Rahner C, Boyer JL. ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained. Gastroenterology. 2009;136(3):1060–9. doi:10.1053/j.gastro.2008.10.025.

    Article  CAS  PubMed  Google Scholar 

  45. Paulusma CC, de Waart DR, Kunne C, Mok KS, Elferink RP. Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content. J Biol Chem. 2009;284(15):9947–54. doi:10.1074/jbc.M808667200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Girard M, Lacaille F, Verkarre V, Mategot R, Feldmann G, Grodet A, et al. MYO5B and bile salt export pump contribute to cholestatic liver disorder in microvillous inclusion disease. Hepatology. 2014;60(1):301–10. doi:10.1002/hep.26974.

    Article  CAS  PubMed  Google Scholar 

  47. Dixon PH, van Mil SW, Chambers J, Strautnieks S, Thompson RJ, Lammert F, et al. Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut. 2009;58(4):537–44. doi:10.1136/gut.2008.159541.

    Article  CAS  PubMed  Google Scholar 

  48. Dixon PH, Wadsworth CA, Chambers J, Donnelly J, Cooley S, Buckley R, et al. A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy. Am J Gastroenterol. 2014;109(1):76–84. doi:10.1038/ajg.2013.406.

    Article  CAS  PubMed  Google Scholar 

  49. Meier Y, Pauli-Magnus C, Zanger UM, Klein K, Schaeffeler E, Nussler AK, et al. Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology. 2006;44(1):62–74. doi:10.1002/hep.21214.

    Article  CAS  PubMed  Google Scholar 

  50. Ho RH, Leake BF, Kilkenny DM, Meyer Zu Schwabedissen HE, Glaeser H, Kroetz DL, et al. Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability. Pharmacogenet Genomics. 2010;20(1):45–57. doi:10.1097/FPC.0b013e3283349eb0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lang C, Meier Y, Stieger B, Beuers U, Lang T, Kerb R, et al. Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury. Pharmacogenet Genomics. 2007;17(1):47–60. doi:10.1097/01.fpc.0000230418.28091.76.

    Article  CAS  PubMed  Google Scholar 

  52. Kagawa T, Hirose S, Arase Y, Oka A, Anzai K, Tsuruya K, et al. No contribution of the ABCB11 p.444A polymorphism in Japanese patients with drug-induced cholestasis. Drug Metab Dispos. 2015; doi:10.1124/dmd.114.061325.

    PubMed  Google Scholar 

  53. Aleo MD, Luo Y, Swiss R, Bonin PD, Potter DM, Will Y. Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump. Hepatology. 2014;60(3):1015–22. doi:10.1002/hep.27206.

    Article  CAS  PubMed  Google Scholar 

  54. Beuers U, Nathanson MH, Isales CM, Boyer JL. Tauroursodeoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca++ mechanisms defective in cholestasis. J Clin Invest. 1993;92(6):2984–93. doi:10.1172/JCI116921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kurz AK, Graf D, Schmitt M, Vom Dahl S, Haussinger D. Tauroursodesoxycholate-induced choleresis involves p38(MAPK) activation and translocation of the bile salt export pump in rats. Gastroenterology. 2001;121(2):407–19.

    Article  CAS  PubMed  Google Scholar 

  56. Kagawa T, Orii R, Hirose S, Arase Y, Shiraishi K, Mizutani A, et al. Ursodeoxycholic acid stabilizes the bile salt export pump in the apical membrane in MDCK II cells. J Gastroenterol. 2013; doi:10.1007/s00535-013-0833-y.

    PubMed  Google Scholar 

  57. Varma S, Revencu N, Stephenne X, Scheers I, Smets F, Beleza-Meireles A, et al. Retargeting of bile salt export pump and favorable outcome in children with progressive familial intrahepatic cholestasis type 2. Hepatology. 2015;62(1):198–206. doi:10.1002/hep.27834.

    Article  CAS  PubMed  Google Scholar 

  58. Hayashi H, Sugiyama Y. 4-phenylbutyrate enhances the cell surface expression and the transport capacity of wild-type and mutated bile salt export pumps. Hepatology. 2007;45(6):1506–16. doi:10.1002/hep.21630.

    Article  CAS  PubMed  Google Scholar 

  59. Naoi S, Hayashi H, Inoue T, Tanikawa K, Igarashi K, Nagasaka H, et al. Improved liver function and relieved pruritus after 4-phenylbutyrate therapy in a patient with progressive familial intrahepatic cholestasis type 2. J Pediatr. 2014;164(5):1219–27. e3 doi:10.1016/j.jpeds.2013.12.032.

    Article  PubMed  Google Scholar 

  60. Gonzales E, Grosse B, Schuller B, Davit-Spraul A, Conti F, Guettier C, et al. Targeted pharmacotherapy in progressive familial intrahepatic cholestasis type 2: evidence for improvement of cholestasis with 4-phenylbutyrate. Hepatology. 2015;62(2):558–66. doi:10.1002/hep.27767.

    Article  CAS  PubMed  Google Scholar 

  61. Hayashi H, Naoi S, Hirose Y, Matsuzaka Y, Tanikawa K, Igarashi K, et al. Successful treatment with 4-phenylbutyrate in a patient with benign recurrent intrahepatic cholestasis type 2 refractory to biliary drainage and bilirubin absorption. Hepatol Res. 2016;46(2):192–200. doi:10.1111/hepr.12561.

    Article  CAS  PubMed  Google Scholar 

  62. Keitel V, Burdelski M, Vojnisek Z, Schmitt L, Haussinger D, Kubitz R. De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis. Hepatology. 2009;50(2):510–7. doi:10.1002/hep.23083.

    Article  CAS  PubMed  Google Scholar 

  63. Jara P, Hierro L, Martinez-Fernandez P, Alvarez-Doforno R, Yanez F, Diaz MC, et al. Recurrence of bile salt export pump deficiency after liver transplantation. N Engl J Med. 2009;361(14):1359–67. doi:10.1056/NEJMoa0901075.

    Article  CAS  PubMed  Google Scholar 

  64. Maggiore G, Gonzales E, Sciveres M, Redon MJ, Grosse B, Stieger B, et al. Relapsing features of bile salt export pump deficiency after liver transplantation in two patients with progressive familial intrahepatic cholestasis type 2. J Hepatol. 2010;53(5):981–6. doi:10.1016/j.jhep.2010.05.025.

    Article  CAS  PubMed  Google Scholar 

  65. Lin HC, Alvarez L, Laroche G, Melin-Aldana H, Pfeifer K, Schwarz K, et al. Rituximab as therapy for the recurrence of bile salt export pump deficiency after liver transplantation. Liver Transpl. 2013;19(12):1403–10. doi:10.1002/lt.23754.

    Article  PubMed  Google Scholar 

  66. Stindt J, Kluge S, Droge C, Keitel V, Stross C, Baumann U, et al. Bile salt export pump-reactive antibodies form a polyclonal, multi-inhibitory response in antibody-induced bile salt export pump deficiency. Hepatology. 2016;63(2):524–37. doi:10.1002/hep.28311.

    Article  CAS  PubMed  Google Scholar 

  67. Boyer JL, Ng OC, Ananthanarayanan M, Hofmann AF, Schteingart CD, Hagenbuch B, et al. Expression and characterization of a functional rat liver Na+ bile acid cotransport system in COS-7 cells. Am J Phys. 1994;266(3 Pt 1):G382–7.

    CAS  Google Scholar 

  68. Hagenbuch B, Meier PJ. Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter. J Clin Invest. 1994;93(3):1326–31. doi:10.1172/JCI117091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hagenbuch B, Meier PJ. Sinusoidal (basolateral) bile salt uptake systems of hepatocytes. Semin Liver Dis. 1996;16(2):129–36. doi:10.1055/s-2007-1007226.

    Article  CAS  PubMed  Google Scholar 

  70. Hata S, Wang P, Eftychiou N, Ananthanarayanan M, Batta A, Salen G, et al. Substrate specificities of rat oatp1 and ntcp: implications for hepatic organic anion uptake. Am J Physiol Gastrointest Liver Physiol. 2003;285(5):G829–39. doi:10.1152/ajpgi.00352.2002.

    Article  CAS  PubMed  Google Scholar 

  71. Mita S, Suzuki H, Akita H, Stieger B, Meier PJ, Hofmann AF, et al. Vectorial transport of bile salts across MDCK cells expressing both rat Na+−taurocholate cotransporting polypeptide and rat bile salt export pump. Am J Physiol Gastrointest Liver Physiol. 2005;288(1):G159–67. doi:10.1152/ajpgi.00360.2003.

    Article  CAS  PubMed  Google Scholar 

  72. Mita S, Suzuki H, Akita H, Hayashi H, Onuki R, Hofmann AF, et al. Vectorial transport of unconjugated and conjugated bile salts by monolayers of LLC-PK1 cells doubly transfected with human NTCP and BSEP or with rat Ntcp and Bsep. Am J Physiol Gastrointest Liver Physiol. 2006;290(3):G550–6. doi:10.1152/ajpgi.00364.2005.

    Article  CAS  PubMed  Google Scholar 

  73. Hagenbuch B, Meier PJ. The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta. 2003;1609(1):1–18.

    Article  CAS  PubMed  Google Scholar 

  74. Vaz FM, Paulusma CC, Huidekoper H, de Ru M, Lim C, Koster J, et al. Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype. Hepatology. 2015;61(1):260–7. doi:10.1002/hep.27240.

    Article  CAS  PubMed  Google Scholar 

  75. Slijepcevic D, Kaufman C, Wichers CG, Gilglioni EH, Lempp FA, Duijst S, et al. Impaired uptake of conjugated bile acids and hepatitis b virus pres1-binding in na(+) – taurocholate cotransporting polypeptide knockout mice. Hepatology. 2015;62(1):207–19. doi:10.1002/hep.27694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zollner G, Fickert P, Zenz R, Fuchsbichler A, Stumptner C, Kenner L, et al. Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology. 2001;33(3):633–46. doi:10.1053/jhep.2001.22646.

    Article  CAS  PubMed  Google Scholar 

  77. Zollner G, Fickert P, Silbert D, Fuchsbichler A, Marschall HU, Zatloukal K, et al. Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol. 2003;38(6):717–27.

    Article  CAS  PubMed  Google Scholar 

  78. Gartung C, Ananthanarayanan M, Rahman MA, Schuele S, Nundy S, Soroka CJ, et al. Down-regulation of expression and function of the rat liver Na+/bile acid cotransporter in extrahepatic cholestasis. Gastroenterology. 1996;110(1):199–209.

    Article  CAS  PubMed  Google Scholar 

  79. Trauner M, Arrese M, Lee H, Boyer JL, Karpen SJ. Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors. J Clin Invest. 1998;101(10):2092–100. doi:10.1172/JCI1680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, Moore DD. The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression. Mol Cell Biol. 2000;20(1):187–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Halilbasic E, Claudel T, Trauner M. Bile acid transporters and regulatory nuclear receptors in the liver and beyond. J Hepatol. 2013;58(1):155–68. doi:10.1016/j.jhep.2012.08.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Denson LA, Sturm E, Echevarria W, Zimmerman TL, Makishima M, Mangelsdorf DJ, et al. The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology. 2001;121(1):140–7.

    Article  CAS  PubMed  Google Scholar 

  83. 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 coactivator-1alpha, and suppressed by bile acids via a small heterodimer partner-dependent mechanism. Mol Endocrinol. 2006;20(1):65–79. doi:10.1210/me.2005-0159.

    Article  CAS  PubMed  Google Scholar 

  84. Wang L, Han Y, Kim CS, Lee YK, Moore DD. Resistance of SHP-null mice to bile acid-induced liver damage. J Biol Chem. 2003;278(45):44475–81. doi:10.1074/jbc.M305258200.

    Article  CAS  PubMed  Google Scholar 

  85. Webster CR, Anwer MS. Role of the PI3K/PKB signaling pathway in cAMP-mediated translocation of rat liver Ntcp. Am J Phys. 1999;277(6 Pt 1):G1165–72.

    CAS  Google Scholar 

  86. Webster CR, Srinivasulu U, Ananthanarayanan M, Suchy FJ, Anwer MS. Protein kinase B/Akt mediates cAMP – and cell swelling-stimulated Na+/taurocholate cotransport and Ntcp translocation. J Biol Chem. 2002;277(32):28578–83. doi:10.1074/jbc.M201937200.

    Article  CAS  PubMed  Google Scholar 

  87. Webster CR, Blanch C, Anwer MS. Role of PP2B in cAMP-induced dephosphorylation and translocation of NTCP. Am J Physiol Gastrointest Liver Physiol. 2002;283(1):G44–50. doi:10.1152/ajpgi.00530.2001.

    Article  CAS  PubMed  Google Scholar 

  88. Muhlfeld S, Domanova O, Berlage T, Stross C, Helmer A, Keitel V, et al. Short-term feedback regulation of bile salt uptake by bile salts in rodent liver. Hepatology. 2012;56(6):2387–97. doi:10.1002/hep.25955.

    Article  PubMed  CAS  Google Scholar 

  89. Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife. 2012;1:e00049. doi:10.7554/eLife.00049.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Ni Y, Lempp FA, Mehrle S, Nkongolo S, Kaufman C, Falth M, et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology. 2014;146(4):1070–83. doi:10.1053/j.gastro.2013.12.024.

    Article  CAS  PubMed  Google Scholar 

  91. Oehler N, Volz T, Bhadra OD, Kah J, Allweiss L, Giersch K, et al. Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism. Hepatology. 2014;60(5):1483–93. doi:10.1002/hep.27159.

    Article  CAS  PubMed  Google Scholar 

  92. Ho RH, Leake BF, Roberts RL, Lee W, Kim RB. Ethnicity-dependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition. J Biol Chem. 2004;279(8):7213–22. doi:10.1074/jbc.M305782200.

    Article  CAS  PubMed  Google Scholar 

  93. Peng L, Zhao Q, Li Q, Li M, Li C, Xu T, et al. The p.Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B. Hepatology. 2015;61(4):1251–60. doi:10.1002/hep.27608.

    Article  CAS  PubMed  Google Scholar 

  94. Hu HH, Liu J, Lin YL, Luo WS, Chu YJ, Chang CL, et al. The rs2296651 (S267F) variant on NTCP (SLC10A1) is inversely associated with chronic hepatitis B and progression to cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B. Gut. 2015; doi:10.1136/gutjnl-2015-310686.

    PubMed Central  Google Scholar 

  95. Dawson PA, Hubbert M, Haywood J, Craddock AL, Zerangue N, Christian WV, et al. The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. J Biol Chem. 2005;280(8):6960–8. doi:10.1074/jbc.M412752200.

    Article  CAS  PubMed  Google Scholar 

  96. Li N, Cui Z, Fang F, Lee JY, Ballatori N. Heterodimerization, trafficking and membrane topology of the two proteins, Ost alpha and Ost beta, that constitute the organic solute and steroid transporter. Biochem J. 2007;407(3):363–72. doi:10.1042/BJ20070716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Boyer JL, Trauner M, Mennone A, Soroka CJ, Cai SY, Moustafa T, et al. Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents. Am J Physiol Gastrointest Liver Physiol. 2006;290(6):G1124–30. doi:10.1152/ajpgi.00539.2005.

    Article  CAS  PubMed  Google Scholar 

  98. Cui YJ, Aleksunes LM, Tanaka Y, Goedken MJ, Klaassen CD. Compensatory induction of liver efflux transporters in response to ANIT-induced liver injury is impaired in FXR-null mice. Toxicol Sci. 2009;110(1):47–60. doi:10.1093/toxsci/kfp094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zollner G, Wagner M, Moustafa T, Fickert P, Silbert D, Gumhold J, et al. Coordinated induction of bile acid detoxification and alternative elimination in mice: role of FXR-regulated organic solute transporter-alpha/beta in the adaptive response to bile acids. Am J Physiol Gastrointest Liver Physiol. 2006;290(5):G923–32. doi:10.1152/ajpgi.00490.2005.

    Article  CAS  PubMed  Google Scholar 

  100. Landrier JF, Eloranta JJ, Vavricka SR, Kullak-Ublick GA. The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-alpha and – beta genes. Am J Physiol Gastrointest Liver Physiol. 2006;290(3):G476–85. doi:10.1152/ajpgi.00430.2005.

    Article  CAS  PubMed  Google Scholar 

  101. Lee H, Zhang Y, Lee FY, Nelson SF, Gonzalez FJ, Edwards PA. FXR regulates organic solute transporters alpha and beta in the adrenal gland, kidney, and intestine. J Lipid Res. 2006;47(1):201–14. doi:10.1194/jlr.M500417-JLR200.

    Article  CAS  PubMed  Google Scholar 

  102. Wagner M, Fickert P, Zollner G, Fuchsbichler A, Silbert D, Tsybrovskyy O, et al. Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Gastroenterology. 2003;125(3):825–38.

    Article  CAS  PubMed  Google Scholar 

  103. Zelcer N, van de Wetering K, de Waart R, Scheffer GL, Marschall HU, Wielinga PR, et al. Mice lacking Mrp3 (Abcc3) have normal bile salt transport, but altered hepatic transport of endogenous glucuronides. J Hepatol. 2006;44(4):768–75. doi:10.1016/j.jhep.2005.07.022.

    Article  CAS  PubMed  Google Scholar 

  104. Mennone A, Soroka CJ, Cai SY, Harry K, Adachi M, Hagey L, et al. Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis. Hepatology. 2006;43(5):1013–21. doi:10.1002/hep.21158.

    Article  CAS  PubMed  Google Scholar 

  105. Keitel V, Burdelski M, Warskulat U, Kuhlkamp T, Keppler D, Haussinger D, et al. Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis. Hepatology. 2005;41(5):1160–72. doi:10.1002/hep.20682.

    Article  CAS  PubMed  Google Scholar 

  106. Lazaridis KN, Pham L, Tietz P, Marinelli RA, deGroen PC, Levine S, et al. Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium-dependent bile acid transporter. J Clin Invest. 1997;100(11):2714–21. doi:10.1172/JCI119816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kool M, van der Linden M, de Haas M, Scheffer GL, de Vree JM, Smith AJ, et al. MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci U S A. 1999;96(12):6914–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lazaridis KN, Tietz P, Wu T, Kip S, Dawson PA, LaRusso NF. Alternative splicing of the rat sodium/bile acid transporter changes its cellular localization and transport properties. Proc Natl Acad Sci U S A. 2000;97(20):11092–7. doi:10.1073/pnas.200325297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 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(4):783–91. doi:10.1053/jhep.2001.23501.

    Article  CAS  PubMed  Google Scholar 

  110. Ballatori N, Christian WV, Lee JY, Dawson PA, Soroka CJ, Boyer JL, et al. OSTalpha-OSTbeta: a major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia. Hepatology. 2005;42(6):1270–9. doi:10.1002/hep.20961.

    Article  CAS  PubMed  Google Scholar 

  111. Hofmann AF. Bile acids: trying to understand their chemistry and biology with the hope of helping patients. Hepatology. 2009;49(5):1403–18. doi:10.1002/hep.22789.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by the Japan Agency for Medical Research and Development (16mk0101045s0202). I thank Ms. Satsuki Ieda and Reiko Orii for their technical assistance.

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  1. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Shimokasuya 143, Isehara, 259-1193, Japan

    Tatehiro Kagawa

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  1. Department of General Medicine, Hiroshima University Hospital, Hiroshima, Japan

    Susumu Tazuma

  2. Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan

    Hajime Takikawa

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Kagawa, T. (2017). Hepatobiliary Transport of Bile Acids. In: Tazuma, S., Takikawa, H. (eds) Bile Acids in Gastroenterology. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56062-3_2

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