Abstract
The bile salt export pump, ABCB11, selectively expressed in the hepatocytes, mediates the transport of monovalent bile salts into the bile. Mutations and polymorphisms in ABCB11 may lead to various forms of cholestatic liver diseases ranging from milder symptoms to lethal conditions. Similarly, inborn errors in ABCC6, another hepatic ABC transporter, may result in diverse conditions, which are characterized by soft tissue mineralization. In this chapter we review the recent knowledge on the structure, transport function, tissue distribution, transcriptional and posttranscriptional regulation, as well as the physiological and pathophysiological role of these medically important hepatic transporters. Substantial data on the pathomechanisms of the diseases associated with the dysfunction of these hepatic transporters have been accumulated in the recent years. This knowledge allows novel, mutation-specific therapeutic interventions opening a new perspective for the treatment of these diseases.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Aessopos A, Savvides P, Stamatelos G, Rombos I, Tassiopoulos T, Karagiorga M, Kaklamanis P, Fessas P (1992) Pseudoxanthoma elasticum-like skin lesions and angioid streaks in beta-thalassemia. Am J Hematol 41(3):159–164
Aherrahrou Z, Doehring LC, Kaczmarek PM, Liptau H, Ehlers EM, Pomarino A, Wrobel S, Gotz A, Mayer B, Erdmann J et al (2007) Ultrafine mapping of Dyscalc1 to an 80-kb chromosomal segment on chromosome 7 in mice susceptible for dystrophic calcification. Physiol Genomics 28(2):203–212
Aranyi T, Ratajewski M, Bardoczy V, Pulaski L, Bors A, Tordai A, Varadi A (2005) Identification of a DNA methylation-dependent activator sequence in the pseudoxanthoma elasticum gene, ABCC6. J Biol Chem 280(19):18643–18650
Bacq Y, Sentilhes L, Reyes HB, Glantz A, Kondrackiene J, Binder T, Nicastri PL, Locatelli A, Floreani A, Hernandez I et al (2012) Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology 143(6):1492–1501
Baghdasaryan A, Chiba P, Trauner M (2014) Clinical application of transcriptional activators of bile salt transporters. Mol Aspects Med 37:57–76
Belinsky MG, Chen ZS, Shchaveleva I, Zeng H, Kruh GD (2002) Characterization of the drug resistance and transport properties of multidrug resistance protein 6 (MRP6, ABCC6). Cancer Res 62(21):6172–6177
Brampton C, Aherrahrou Z, Chen LH, Martin L, Bergen AA, Gorgels TG, Erdmann J, Schunkert H, Szabo Z, Varadi A et al (2014) The level of hepatic ABCC6 expression determines the severity of calcification after cardiac injury. Am J Pathol 184(1):159–170
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(5):1649–1658
Byrne JA, Strautnieks SS, Ihrke G, Pagani F, Knisely AS, Linton KJ, Mieli-Vergani G, Thompson RJ (2009) Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing. Hepatology 49(2):553–567
Cai SY, Lionarons DA, Hagey L, Soroka CJ, Mennone A, Boyer JL (2012) Adult sea lamprey tolerates biliary atresia by altering bile salt composition and renal excretion. Hepatology 57(6):2418–2426
Cancado EL, Leitao RM, Carrilho FJ, Laudanna AA (1998) Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of gamma-glutamyl transpeptidase. Am J Gastroenterol 93(9):1510–1517
Chan W, Calderon G, Swift AL, Moseley J, Li S, Hosoya H, Arias IM, Ortiz DF (2005) 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 280(25):23741–23747
Chappell LC, Gurung V, Seed PT, Chambers J, Williamson C, Thornton JG (2012) Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial. BMJ 344:e3799
Chen RR, Li YJ, Zhou XM, Wang L, Xing J, Han S, Cui LN, Zheng LH, Wu KC, Shi YQ et al (2014) The association between bile salt export pump single-nucleotide polymorphisms and primary biliary cirrhosis susceptibility and ursodeoxycholic acid response. Dis Markers 2014:350690
Childs S, Yeh RL, Georges E, Ling V (1995) Identification of a sister gene to P-glycoprotein. Cancer Res 55(10):2029–2034
Davit-Spraul A, Fabre M, Branchereau S, Baussan C, Gonzales E, Stieger B, Bernard O, Jacquemin E (2010) 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 51(5):1645–1655
Dawson S, Stahl S, Paul N, Barber J, Kenna JG (2011) In vitro inhibition of the bile salt export pump correlates with risk of cholestatic drug-induced liver injury in humans. Drug Metab Dispos 40(1):130–138
de Boussac H, Ratajewski M, Sachrajda I, Koblos G, Tordai A, Pulaski L, Buday L, Varadi A, Aranyi T (2010) The ERK1/2-hepatocyte nuclear factor 4alpha axis regulates human ABCC6 gene expression in hepatocytes. J Biol Chem 285(30):22800–22808
Dixon PH, van Mil SW, Chambers J, Strautnieks S, Thompson RJ, Lammert F, Kubitz R, Keitel V, Glantz A, Mattsson LA et al (2009) Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut 58(4):537–544
Dombrowski F, Stieger B, Beuers U (2006) Tauroursodeoxycholic acid inserts the bile salt export pump into canalicular membranes of cholestatic rat liver. Lab Invest 86(2):166–174
Dover GJ, Brusilow S, Samid D (1992) Increased fetal hemoglobin in patients receiving sodium 4-phenylbutyrate. N Engl J Med 327(8):569–570
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(6):648–652
Festi D, Montagnani M, Azzaroli F, Lodato F, Mazzella G, Roda A, Di Biase AR, Roda E, Simoni P, Colecchia A (2007) Clinical efficacy and effectiveness of ursodeoxycholic acid in cholestatic liver diseases. Curr Clin Pharmacol 2(2):155–177
Fickert P, Zollner G, Fuchsbichler A, Stumptner C, Pojer C, Zenz R, Lammert F, Stieger B, Meier PJ, Zatloukal K et al (2001) Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver. Gastroenterology 121(1):170–183
Folvik G, Hilde O, Helge GO (2012) Benign recurrent intrahepatic cholestasis: review and long-term follow-up of five cases. Scand J Gastroenterol 47(4):482–488
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(16):10046–10050
Gonzales E, Grosse B, Cassio D, Davit-Spraul A, Fabre M, Jacquemin E (2012) Successful mutation-specific chaperone therapy with 4-phenylbutyrate in a child with progressive familial intrahepatic cholestasis type 2. J Hepatol 57(3):695–698
Guyot C, Hofstetter L, Stieger B (2014) Differential effects of membrane cholesterol content on the transport activity of multidrug resistance-associated protein 2 (ABCC2) and of the bile salt export pump (ABCB11). Mol Pharmacol 85(6):909–920
Gyimesi G, Borsodi D, Saranko H, Tordai H, Sarkadi B, Hegedus T (2012) ABCMdb: a database for the comparative analysis of protein mutations in ABC transporters, and a potential framework for a general application. Hum Mutat 33(11):1547–1556
Hayashi H, Sugiyama Y (2007) 4-phenylbutyrate enhances the cell surface expression and the transport capacity of wild-type and mutated bile salt export pumps. Hepatology 45(6):1506–1516
Hayashi H, Takada T, Suzuki H, Onuki R, Hofmann AF, Sugiyama Y (2005a) 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 1738(1–3):54–62
Hayashi H, Takada T, Suzuki H, Akita H, Sugiyama Y (2005b) Two common PFIC2 mutations are associated with the impaired membrane trafficking of BSEP/ABCB11. Hepatology 41(4):916–924
Hirano M, Maeda K, Hayashi H, Kusuhara H, Sugiyama Y (2005) Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin. J Pharmacol Exp Ther 314(2):876–882
Hirschfield GM, Chapman RW, Karlsen TH, Lammert F, Lazaridis KN, Mason AL (2013) The genetics of complex cholestatic disorders. Gastroenterology 144(7):1357–1374
Ho RH, Leake BF, Kilkenny DM, Meyer Zu Schwabedissen HE, Glaeser H, Kroetz DL, Kim RB (2009) Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability. Pharmacogenet Genomics 20(1):45–57
Homolya L, Fu D, Sengupta P, Jarnik M, Gillet JP, Vitale-Cross L, Gutkind JS, Lippincott-Schwartz J, Arias IM (2014) LKB1/AMPK and PKA control ABCB11 trafficking and polarization in hepatocytes. PLoS ONE 9(3):e91921
Iannelli F, Collino A, Sinha S, Radaelli E, Nicoli P, D’Antiga L, Sonzogni A, Faivre J, Buendia MA, Sturm E et al (2014) Massive gene amplification drives paediatric hepatocellular carcinoma caused by bile salt export pump deficiency. Nat Commun 5:3850
Ilias A, Urban Z, Seidl TL, Le Saux O, Sinko E, Boyd CD, Sarkadi B, Varadi A (2002) Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). J Biol Chem 277(19):16860–16867
Jacquemin E (1999) Progressive familial intrahepatic cholestasis. J Gastroenterol Hepatol 14(6):594–599
Jansen RS, Kucukosmanoglu A, de Haas M, Sapthu S, Otero JA, Hegman IE, Bergen AA, Gorgels TG, Borst P, van de Wetering K (2013) ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release. Proc Natl Acad Sci USA 110(50):20206–20211
Jansen RS, Duijst S, Mahakena S, Sommer D, Szeri F, Varadi A, Plomp A, Bergen AA, Oude Elferink RP, Borst P et al (2014) ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report. Arterioscler Thromb Vasc Biol 34(9):1985–1989
Jara P, Hierro L, Martinez-Fernandez P, Alvarez-Doforno R, Yanez F, Diaz MC, Camarena C, De la Vega A, Frauca E, Munoz-Bartolo G et al (2009) Recurrence of bile salt export pump deficiency after liver transplantation. N Engl J Med 361(14):1359–1367
Kagawa T, Watanabe N, Mochizuki K, Numari A, Ikeno Y, Itoh J, Tanaka H, Arias IM, Mine T (2008) 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 294(1):G58–G67
Kagawa T, Orii R, Hirose S, Arase Y, Shiraishi K, Mizutani A, Tsukamoto H, Mine T (2014) Ursodeoxycholic acid stabilizes the bile salt export pump in the apical membrane in MDCK II cells. J Gastroenterol 49(5):890–899
Keitel V, Vogt C, Haussinger D, Kubitz R (2006) Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy. Gastroenterology 131(2):624–629
Keitel V, Burdelski M, Vojnisek Z, Schmitt L, Haussinger D, Kubitz R (2009) De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis. Hepatology 50(2):510–517
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(21):15917–15925
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(10):7218–7224
Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC, Bull LN, Pawlikowska L, Bilezikci B, Ozcay F et al (2006) Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology 44(2):478–486
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(2):541–553
Kubitz R, Droge C, Kluge S, Stross C, Walter N, Keitel V, Haussinger D, Stindt J (2015) Autoimmune BSEP Disease: Disease Recurrence After Liver Transplantation for Progressive Familial Intrahepatic Cholestasis. Clin Rev Allergy Immunol 48(2–3):273–84
Lam CW, Cheung KM, Tsui MS, Yan MS, Lee CY, Tong SF (2006) A patient with novel ABCB11 gene mutations with phenotypic transition between BRIC2 and PFIC2. J Hepatol 44(1):240–242
Lam P, Pearson CL, Soroka CJ, Xu S, Mennone A, Boyer JL (2007) 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 Physiol Cell Physiol 293(5):C1709–C1716
Lang T, Haberl M, Jung D, Drescher A, Schlagenhaufer R, Keil A, Mornhinweg E, Stieger B, Kullak-Ublick GA, Kerb R (2006) Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11). Drug Metab Dispos 34(9):1582–1599
Lang C, Meier Y, Stieger B, Beuers U, Lang T, Kerb R, Kullak-Ublick GA, Meier PJ, Pauli-Magnus C (2007) Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury. Pharmacogenet Genomics 17(1):47–60
Langmann T, Mauerer R, Zahn A, Moehle C, Probst M, Stremmel W, Schmitz G (2003) Real-time reverse transcription-PCR expression profiling of the complete human ATP-binding cassette transporter superfamily in various tissues. Clin Chem 49(2):230–238
Le Saux O, Fulop K, Yamaguchi Y, Ilias A, Szabo Z, Brampton CN, Pomozi V, Huszar K, Aranyi T, Varadi A (2011) Expression and in vivo rescue of human ABCC6 disease-causing mutants in mouse liver. PLoS ONE 6(9):e24738
Lecureur V, Sun D, Hargrove P, Schuetz EG, Kim RB, Lan LB, Schuetz JD (2000) Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein. Mol Pharmacol 57(1):24–35
Liu LY, Wang XH, Lu Y, Zhu QR, Wang JS (2013) Association of variants of ABCB11 with transient neonatal cholestasis. Pediatr Int 55(2):138–144
Maestri NE, Hauser ER, Bartholomew D, Brusilow SW (1991) Prospective treatment of urea cycle disorders. J Pediatr 119(6):923–928
Maggiore G, Gonzales E, Sciveres M, Redon MJ, Grosse B, Stieger B, Davit-Spraul A, Fabre M, Jacquemin E (2010) Relapsing features of bile salt export pump deficiency after liver transplantation in two patients with progressive familial intrahepatic cholestasis type 2. J Hepatol 53(5):981–986
Mano Y, Usui T, Kamimura H (2007) Effects of bosentan, an endothelin receptor antagonist, on bile salt export pump and multidrug resistance-associated protein 2. Biopharm Drug Dispos 28(1):13–18
Marschall HU, Wagner M, Zollner G, Fickert P, Diczfalusy U, Gumhold J, Silbert D, Fuchsbichler A, Benthin L, Grundstrom R et al (2005) Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology 129(2):476–485
Martin L, Douet V, VanWart CM, Heller MB, Le Saux O (2011) A mouse model of beta-thalassemia shows a liver-specific down-regulation of Abcc6 expression. Am J Pathol 178(2):774–783
Matsushima S, Maeda K, Hayashi H, Debori Y, Schinkel AH, Schuetz JD, Kusuhara H, Sugiyama Y (2008) Involvement of multiple efflux transporters in hepatic disposition of fexofenadine. Mol Pharmacol 73(5):1474–1483
Meier Y, Zodan T, Lang C, Zimmermann R, Kullak-Ublick GA, Meier PJ, Stieger B, Pauli-Magnus C (2008) Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T> C polymorphism in the bile salt export pump. World J Gastroenterol 14(1):38–45
Misawa T, Hayashi H, Sugiyama Y, Hashimoto Y (2012) Discovery and structural development of small molecules that enhance transport activity of bile salt export pump mutant associated with progressive familial intrahepatic cholestasis type 2. Bioorg Med Chem 20(9):2940–2949
Misra S, Ujhazy P, Gatmaitan Z, Varticovski L, Arias IM (1998) The role of phosphoinositide 3-kinase in taurocholate-induced trafficking of ATP-dependent canalicular transporters in rat liver. J Biol Chem 273(41):26638–26644
Misra S, Varticovski L, Arias IM (2003) Mechanisms by which cAMP increases bile acid secretion in rat liver and canalicular membrane vesicles. Am J Physiol Gastrointest Liver Physiol 285(2):G316–G324
Morgan RE, van Staden CJ, Chen Y, Kalyanaraman N, Kalanzi J, Dunn RT 2nd, Afshari CA, Hamadeh HK (2013) A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci 136(1):216–241
Naoi S, Hayashi H, Inoue T, Tanikawa K, Igarashi K, Nagasaka H, Kage M, Takikawa H, Sugiyama Y, Inui A et al (2014) Improved liver function and relieved pruritus after 4-phenylbutyrate therapy in a patient with progressive familial intrahepatic cholestasis type 2. J Pediatr 164(5):1219–1227 (e1213)
Nitschke Y, Baujat G, Botschen U, Wittkampf T, du Moulin M, Stella J, Le Merrer M, Guest G, Lambot K, Tazarourte-Pinturier MF et al (2012) Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet 90(1):25–39
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(5):1223–1231
Noe J, Stieger B, Meier PJ (2002) Functional expression of the canalicular bile salt export pump of human liver. Gastroenterology 123(5):1659–1666
Noe J, Kullak-Ublick GA, Jochum W, Stieger B, Kerb R, Haberl M, Mullhaupt B, Meier PJ, Pauli-Magnus C (2005) Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis. J Hepatol 43(3):536–543
Pan S, Li X, Jiang P, Jiang Y, Shuai L, He Y, Li Z (2014) Variations of ABCB4 and ABCB11 genes are associated with primary intrahepatic stones. Mol Med Rep 11(1):434–446
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(3):779–791
Pauli-Magnus C, Stieger B, Meier Y, Kullak-Ublick GA, Meier PJ (2005) Enterohepatic transport of bile salts and genetics of cholestasis. J Hepatol 43(2):342–357
Pauli-Magnus C, Meier PJ, Stieger B (2010) Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy. Semin Liver Dis 30(2):147–159
Paulusma CC, de Waart DR, Kunne C, Mok KS, Elferink RP (2009) Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content. J Biol Chem 284(15):9947–9954
Pawlikowska L, Strautnieks S, Jankowska I, Czubkowski P, Emerick K, Antoniou A, Wanty C, Fischler B, Jacquemin E, Wali S et al (2010) Differences in presentation and progression between severe FIC1 and BSEP deficiencies. J Hepatol 53(1):170–178
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(3):589–596
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(1):24–30
Pomozi V, Le Saux O, Brampton C, Apana A, Ilias A, Szeri F, Martin L, Monostory K, Paku S, Sarkadi B et al (2013a) ABCC6 is a basolateral plasma membrane protein. Circ Res 112(11):e148–e151
Pomozi V, Brampton C, Fulop K, Chen LH, Apana A, Li Q, Uitto J, Le Saux O, Varadi A (2013b) Analysis of pseudoxanthoma elasticum-causing missense mutants of ABCC6 in vivo; pharmacological correction of the mislocalized proteins. J Invest Dermatol 134(4):946–953
Pomozi V, Brampton C, Fulop K, Chen LH, Apana A, Li Q, Uitto J, Le Saux O, Varadi A (2014) Analysis of pseudoxanthoma elasticum-causing missense mutants of ABCC6 in vivo; pharmacological correction of the mislocalized proteins. J Invest Dermatol 134(4):946–953
Pusl T, Beuers U (2007) Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis 2:26
Ratajewski M, de Boussac H, Sachrajda I, Bacquet C, Kovacs T, Varadi A, Pulaski L, Aranyi T (2012) ABCC6 expression is regulated by CCAAT/enhancer-binding protein activating a primate-specific sequence located in the first intron of the gene. J Invest Dermatol 132(12):2709–2717
Rubenstein RC, Egan ME, Zeitlin PL (1997) In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing delta F508-CFTR. J Clin Invest 100(10):2457–2465
Rudashevskaya EL, Stockner T, Trauner M, Freissmuth M, Chiba P (2014) Pharmacological correction of misfolding of ABC proteins. Drug Discov Today Technol 12:e87–e94
Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Hohne W, Schauer G, Lehmann M, Roscioli T, Schnabel D et al (2003) Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet 34(4):379–381
Scheimann AO, Strautnieks SS, Knisely AS, Byrne JA, Thompson RJ, Finegold MJ (2007) Mutations in bile salt export pump (ABCB11) in two children with progressive familial intrahepatic cholestasis and cholangiocarcinoma. J Pediatr 150(5):556–559
Song X, Vasilenko A, Chen Y, Valanejad L, Verma R, Yan B, Deng R (2014) Transcriptional dynamics of bile salt export pump during pregnancy: mechanisms and implications in intrahepatic cholestasis of pregnancy. Hepatology 60(6):1993–2007
Soroka CJ, Boyer JL (2013) Biosynthesis and trafficking of the bile salt export pump, BSEP: therapeutic implications of BSEP mutations. Mol Aspects Med 37:3–14
St. Hilaire C, Ziegler SG, Markello TC, Brusco A, Groden C, Gill F, Carlson-Donohoe H, Lederman RJ, Chen MY, Yang D et al (2011) NT5E mutations and arterial calcifications. N Engl J Med 364(5):432–442
Stieger B, Beuers U (2010) The canalicular bile salt export pump BSEP (ABCB11) as a potential therapeutic target. Curr Drug Targets 12(5):661–670
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(2):422–430
Stindt J, Ellinger P, Weissenberger K, Droge C, Herebian D, Mayatepek E, Homey B, Braun S, Schulte am Esch J, Horacek M et al (2013) A novel mutation within a transmembrane helix of the bile salt export pump (BSEP, ABCB11) with delayed development of cirrhosis. Liver Int 33(10):1527–1535
Strautnieks SS, Byrne JA, Pawlikowska L, Cebecauerova D, Rayner A, Dutton L, Meier Y, Antoniou A, Stieger B, Arnell H et al (2008) Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology 134(4):1203–1214
Torok M, Gutmann H, Fricker G, Drewe J (1999) Sister of P-glycoprotein expression in different tissues. Biochem Pharmacol 57(7):833–835
Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, Zwahlen M, Kampf C, Wester K, Hober S et al (2010) Towards a knowledge-based human protein atlas. Nat Biotechnol 28(12):1248–1250
Vallejo M, Briz O, Serrano MA, Monte MJ, Marin JJ (2006) Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy. J Hepatol 44(6):1150–1157
van Beusekom CD, van den Heuvel JJ, Koenderink JB, Schrickx JA, Russel FG (2013) The feline bile salt export pump: a structural and functional comparison with canine and human Bsep/BSEP. BMC Vet Res 9:259
van Ooteghem NA, Klomp LW, van Berge-Henegouwen GP, Houwen RH (2002) Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum. J Hepatol 36(3):439–443
Vilarinho S, Erson-Omay EZ, Harmanci AS, Morotti R, Carrion-Grant G, Baranoski J, Knisely AS, Ekong U, Emre S, Yasuno K et al (2014) Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations. J Hepatol 61(5):1178–1183
Wakabayashi Y, Lippincott-Schwartz J, Arias IM (2004) 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 15(7):3485–3496
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(7):965–972
Woodhead JL, Yang K, Siler SQ, Watkins PB, Brouwer KL, Barton HA, Howell BA (2014) Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury. Front Pharmacol 5:240
Acknowledgements
The authors are grateful for the support of the Momentum Program of the Hungarian Academy of Sciences (LP 2012–025) to L.H. and for the OTKA Hungarian Research Grants (K104227 and NN114136) to A.V.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Váradi, A., Homolya, L. (2016). Two Liver Transporters, ABCB11 and ABCC6; Novel Therapeutic Approaches in the Related Disorders. In: George, A. (eds) ABC Transporters - 40 Years on. Springer, Cham. https://doi.org/10.1007/978-3-319-23476-2_15
Download citation
DOI: https://doi.org/10.1007/978-3-319-23476-2_15
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-23475-5
Online ISBN: 978-3-319-23476-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)