Download PDF
Semin Liver Dis 2010; 30(2): 125-133
DOI: 10.1055/s-0030-1253222
© Thieme Medical Publishers

The Bile Salt Export Pump: Clinical and Experimental Aspects of Genetic and Acquired Cholestatic Liver Disease

Ping Lam1 , Carol J. Soroka1 , James L. Boyer1
  • 1Liver Center, Yale University School of Medicine, New Haven, Connecticut
Further Information

Publication History

Publication Date:
26 April 2010 (online)

    Permissions and Reprints

ABSTRACT

The primary transporter responsible for bile salt secretion is the bile salt export pump (BSEP, ABCB11), a member of the ATP-binding cassette (ABC) superfamily, which is located at the bile canalicular apical domain of hepatocytes. In humans, BSEP deficiency results in several different genetic forms of cholestasis, which include progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), as well as other acquired forms of cholestasis such as drug-induced cholestasis (DIC) and intrahepatic cholestasis of pregnancy (ICP). Because bile salts play a pivotal role in a wide range of physiologic and pathophysiologic processes, regulation of BSEP expression has been a subject of intense research. The authors briefly describe the molecular characteristics of BSEP and then summarize what is known about its role in the pathogenesis of genetic and acquired cholestatic disorders, emphasizing experimental observations from animal models and cell culture in vitro systems.

KEYWORDS

Cholestasis - progressive familial intrahepatic cholestasis - bile salt export pump (BSEP) mutations - polymorphisms - ATP-binding cassette (ABC) transporters - trafficking - recycling - ubiquitination

REFERENCES

  • 1 Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily.  Genome Res. 2001;  11(7) 1156-1166
    CrossrefPubMedGoogle Scholar
  • 2 Meier P J, Meier-Abt A S, Boyer J L. Properties of the canalicular bile acid transport system in rat liver.  Biochem J. 1987;  242(2) 465-469
    PubMedGoogle Scholar
  • 3 Weinman S A, Graf J, Boyer J L. Voltage-driven, taurocholate-dependent secretion in isolated hepatocyte couplets.  Am J Physiol. 1989;  256(5 Pt 1) G826-G832
    PubMedGoogle Scholar
  • 4 Adachi Y, Kobayashi H, Kurumi Y, Shouji M, Kitano M, Yamamoto T. ATP-dependent taurocholate transport by rat liver canalicular membrane vesicles.  Hepatology. 1991;  14(4 Pt 1) 655-659
    CrossrefPubMedGoogle Scholar
  • 5 Müller M, Ishikawa T, Berger U et al.. ATP-dependent transport of taurocholate across the hepatocyte canalicular membrane mediated by a 110-kDa glycoprotein binding ATP and bile salt.  J Biol Chem. 1991;  266(28) 18920-18926
    PubMedGoogle Scholar
  • 6 Nishida T, Gatmaitan Z, Che M, Arias I M. Rat liver canalicular membrane vesicles contain an ATP-dependent bile acid transport system.  Proc Natl Acad Sci U S A. 1991;  88(15) 6590-6594
    CrossrefPubMedGoogle Scholar
  • 7 Stieger B, O'Neill B, Meier P J. ATP-dependent bile-salt transport in canalicular rat liver plasma-membrane vesicles.  Biochem J. 1992;  284(Pt 1) 67-74
    PubMedGoogle Scholar
  • 8 Childs S, Yeh R L, Georges E, Ling V. Identification of a sister gene to P-glycoprotein.  Cancer Res. 1995;  55(10) 2029-2034
    PubMedGoogle Scholar
  • 9 Gerloff T, Stieger B, Hagenbuch B et al.. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver.  J Biol Chem. 1998;  273(16) 10046-10050
    CrossrefPubMedGoogle Scholar
  • 10 Strautnieks S S, Kagalwalla A F, Tanner M S et al.. Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24.  Am J Hum Genet. 1997;  61(3) 630-633
    CrossrefPubMedGoogle Scholar
  • 11 Strautnieks S S, Bull L N, Knisely A S et al.. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis.  Nat Genet. 1998;  20(3) 233-238
    CrossrefPubMedGoogle Scholar
  • 12 Bull L N, van Eijk M J, Pawlikowska L et al.. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis.  Nat Genet. 1998;  18(3) 219-224
    CrossrefPubMedGoogle Scholar
  • 13 van Mil S W, Klomp L W, Bull L N, Houwen R H. FIC1 disease: a spectrum of intrahepatic cholestatic disorders.  Semin Liver Dis. 2001;  21(4) 535-544
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 de Vree J M, Jacquemin E, Sturm E et al.. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.  Proc Natl Acad Sci U S A. 1998;  95(1) 282-287
    CrossrefPubMedGoogle Scholar
  • 15 Mochizuki K, Kagawa T, Numari A 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-G828
    CrossrefPubMedGoogle Scholar
  • 16 Chan W, Calderon G, Swift A L 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) 23741-23747
    CrossrefPubMedGoogle Scholar
  • 17 Ortiz D F, Moseley J, Calderon G, Swift A L, Li S, Arias I M. 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) 32761-32770
    CrossrefPubMedGoogle Scholar
  • 18 Childs S, Yeh R L, Hui D, Ling V. Taxol resistance mediated by transfection of the liver-specific sister gene of P-glycoprotein.  Cancer Res. 1998;  58(18) 4160-4167
    PubMedGoogle Scholar
  • 19 Lecureur V, Sun D, Hargrove P et al.. Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein.  Mol Pharmacol. 2000;  57(1) 24-35
    PubMedGoogle Scholar
  • 20 Noé J, Stieger B, Meier P J. Functional expression of the canalicular bile salt export pump of human liver.  Gastroenterology. 2002;  123(5) 1659-1666
    CrossrefPubMedGoogle Scholar
  • 21 Byrne J A, Strautnieks S S, Mieli-Vergani G, Higgins C F, Linton K J, Thompson R J. The human bile salt export pump: characterization of substrate specificity and identification of inhibitors.  Gastroenterology. 2002;  123(5) 1649-1658
    CrossrefPubMedGoogle Scholar
  • 22 Green R M, Hoda F, Ward K L. Molecular cloning and characterization of the murine bile salt export pump.  Gene. 2000;  241(1) 117-123
    CrossrefPubMedGoogle Scholar
  • 23 Noe J, Hagenbuch B, Meier P J, St-Pierre M V. Characterization of the mouse bile salt export pump overexpressed in the baculovirus system.  Hepatology. 2001;  33(5) 1223-1231
    CrossrefPubMedGoogle Scholar
  • 24 Anuchapreeda S, Leechanachai P, Smith M M, Ambudkar S V, Limtrakul P N. Modulation of P-glycoprotein expression and function by curcumin in multidrug-resistant human KB cells.  Biochem Pharmacol. 2002;  64(4) 573-582
    CrossrefPubMedGoogle Scholar
  • 25 Makishima M, Okamoto A Y, Repa J J et al.. Identification of a nuclear receptor for bile acids.  , [see comments] Science. 1999;  284(5418) 1362-1365
    CrossrefPubMedGoogle Scholar
  • 26 Parks D J, Blanchard S G, Bledsoe R K et al.. Bile acids: natural ligands for an orphan nuclear receptor.  , [see comments] Science. 1999;  284(5418) 1365-1368
    CrossrefPubMedGoogle Scholar
  • 27 Wang H, Chen J, Hollister K, Sowers L C, Forman B M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.  Mol Cell. 1999;  3(5) 543-553
    PubMedGoogle Scholar
  • 28 Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf D J, Suchy F J. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor.  J Biol Chem. 2001;  276(31) 28857-28865
    CrossrefPubMedGoogle Scholar
  • 29 Plass J R, Mol O, Heegsma J 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) 589-596
    CrossrefPubMedGoogle Scholar
  • 30 Gerloff T, Geier A, Roots I, Meier P J, Gartung C. Functional analysis of the rat bile salt export pump gene promoter.  Eur J Biochem. 2002;  269(14) 3495-3503
    CrossrefPubMedGoogle Scholar
  • 31 Sinal C J, Tohkin M, Miyata M, Ward J M, Lambert G, Gonzalez F J. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis.  Cell. 2000;  102(6) 731-744
    CrossrefPubMedGoogle Scholar
  • 32 Van Mil S W, Milona A, Dixon P H et al.. Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy.  Gastroenterology. 2007;  133(2) 507-516
    CrossrefPubMedGoogle Scholar
  • 33 Zimmer V, Müllenbach R, Simon E, Bartz C, Matern S, Lammert F. Combined functional variants of hepatobiliary transporters and FXR aggravate intrahepatic cholestasis of pregnancy.  Liver Int. 2009;  29(8) 1286-1288
    CrossrefPubMedGoogle Scholar
  • 34 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) 973-984
    CrossrefPubMedGoogle Scholar
  • 35 Mataki C, Magnier B C, Houten S M et al.. Compromised intestinal lipid absorption in mice with a liver-specific deficiency of liver receptor homolog 1.  Mol Cell Biol. 2007;  27(23) 8330-8339
    CrossrefPubMedGoogle Scholar
  • 36 Honjo Y, Sasaki S, Kobayashi Y, Misawa H, Nakamura H. 1,25-dihydroxyvitamin D3 and its receptor inhibit the chenodeoxycholic acid-dependent transactivation by farnesoid X receptor.  J Endocrinol. 2006;  188(3) 635-643
    CrossrefPubMedGoogle Scholar
  • 37 Weerachayaphorn J, Cai S Y, Soroka C J, Boyer J L. Nuclear factor erythroid 2-related factor 2 is a positive regulator of human bile salt export pump expression.  Hepatology. 2009;  50 1588-1596
    CrossrefPubMedGoogle Scholar
  • 38 Enomoto A, Itoh K, Nagayoshi E et al.. High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes.  Toxicol Sci. 2001;  59(1) 169-177
    CrossrefPubMedGoogle Scholar
  • 39 Jowsey I R, Jiang Q, Itoh K, Yamamoto M, Hayes J D. Expression of the aflatoxin B1-8,9-epoxide-metabolizing murine glutathione S-transferase A3 subunit is regulated by the Nrf2 transcription factor through an antioxidant response element.  Mol Pharmacol. 2003;  64(5) 1018-1028
    CrossrefPubMedGoogle Scholar
  • 40 Okawa H, Motohashi H, Kobayashi A, Aburatani H, Kensler T W, Yamamoto M. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity.  Biochem Biophys Res Commun. 2006;  339(1) 79-88
    CrossrefPubMedGoogle Scholar
  • 41 Tanaka Y, Aleksunes L M, Cui Y J, Klaassen C D. ANIT-induced intrahepatic cholestasis alters hepatobiliary transporter expression via Nrf2-dependent and independent signaling.  Toxicol Sci. 2009;  108(2) 247-257
    CrossrefPubMedGoogle Scholar
  • 42 Jansen P L, Strautnieks S S, Jacquemin E et al.. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis.  Gastroenterology. 1999;  117(6) 1370-1379
    CrossrefPubMedGoogle Scholar
  • 43 Scheimann A O, Strautnieks S S, Knisely A S, Byrne J A, Thompson R J, Finegold M J. Mutations in bile salt export pump (ABCB11) in two children with progressive familial intrahepatic cholestasis and cholangiocarcinoma.  J Pediatr. 2007;  150(5) 556-559
    PubMedGoogle Scholar
  • 44 van Mil S W, van der Woerd W L, van der Brugge G et al.. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11.  Gastroenterology. 2004;  127(2) 379-384
    CrossrefPubMedGoogle Scholar
  • 45 Lam C W, Cheung K M, Tsui M S, Yan M S, Lee C Y, Tong S F. A patient with novel ABCB11 gene mutations with phenotypic transition between BRIC2 and PFIC2.  J Hepatol. 2006;  44(1) 240-242
    CrossrefPubMedGoogle Scholar
  • 46 Keitel V, Vogt C, Häussinger D, Kubitz R. Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy.  Gastroenterology. 2006;  131(2) 624-629
    CrossrefPubMedGoogle Scholar
  • 47 Strautnieks S S, Byrne J A, Pawlikowska L et al.. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.  Gastroenterology. 2008;  134(4) 1203-1214
    CrossrefPubMedGoogle Scholar
  • 48 Byrne J A, Strautnieks S S, Ihrke G 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) 553-567
    CrossrefPubMedGoogle Scholar
  • 49 Ho R H, Leake B F, Kilkenny D M 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
    CrossrefPubMedGoogle Scholar
  • 50 Lang T, Haberl M, Jung D et al.. Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11).  Drug Metab Dispos. 2006;  34(9) 1582-1599
    CrossrefPubMedGoogle Scholar
  • 51 Lang C, Meier Y, Stieger B 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
    CrossrefPubMedGoogle Scholar
  • 52 Meier Y, Zodan T, Lang C et al.. 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. 2008;  14(1) 38-45
    CrossrefPubMedGoogle Scholar
  • 53 Dixon P H, van Mil S W, Chambers J et al.. Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy.  Gut. 2009;  58(4) 537-544
    CrossrefPubMedGoogle Scholar
  • 54 Wang L, Soroka C J, Boyer J L. The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II.  J Clin Invest. 2002;  110(7) 965-972
    PubMedGoogle Scholar
  • 55 Plass J R, Mol O, Heegsma J 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
    PubMedGoogle Scholar
  • 56 Lam P, Pearson C L, Soroka C J, Xu S, Mennone A, Boyer J L. 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. 2007;  293(5) C1709-C1716
    CrossrefPubMedGoogle Scholar
  • 57 Kagawa T, Watanabe N, Mochizuki K 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-G67
    CrossrefPubMedGoogle Scholar
  • 58 Wang L, Dong H, Soroka C J, Wei N, Boyer J L, Hochstrasser M. Degradation of the bile salt export pump at endoplasmic reticulum in progressive familial intrahepatic cholestasis type II.  Hepatology. 2008;  48(5) 1558-1569
    CrossrefPubMedGoogle Scholar
  • 59 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) 143-150
    CrossrefPubMedGoogle Scholar
  • 60 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) 1506-1516
    CrossrefPubMedGoogle Scholar
  • 61 Wang R, Salem M, Yousef I M et al.. Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis.  Proc Natl Acad Sci U S A. 2001;  98(4) 2011-2016
    CrossrefPubMedGoogle Scholar
  • 62 Perwaiz S, Forrest D, Mignault D et al.. 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. 2003;  44(3) 494-502
    CrossrefPubMedGoogle Scholar
  • 63 Wang R, Lam P, Liu L et al.. Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P-glycoprotein.  Hepatology. 2003;  38(6) 1489-1499
    PubMedGoogle Scholar
  • 64 Lam P, Wang R, Ling V. Bile acid transport in sister of P-glycoprotein (ABCB11) knockout mice.  Biochemistry. 2005;  44(37) 12598-12605
    CrossrefPubMedGoogle Scholar
  • 65 Wang R, Chen H L, Liu L, Sheps J A, Phillips M J, Ling V. Compensatory role of P-glycoproteins in knockout mice lacking the bile salt export pump.  Hepatology. 2009;  50(3) 948-956
    CrossrefPubMedGoogle Scholar
  • 66 Kipp H, Arias I M. Intracellular trafficking and regulation of canalicular ATP-binding cassette transporters.  Semin Liver Dis. 2000;  20(3) 339-351
    Article in Thieme ConnectPubMedGoogle Scholar
  • 67 Kipp H, Arias I M. 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) 15917-15925
    CrossrefPubMedGoogle Scholar
  • 68 Kipp H, Pichetshote N, Arias I M. Transporters on demand: Intrahepatic pools of canalicular ATP-binding cassette transporters in rat liver.  J Biol Chem. 2001;  276 7218-7224
    CrossrefPubMedGoogle Scholar
  • 69 Wakabayashi Y, Lippincott-Schwartz J, Arias I M. 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) 3485-3496
    CrossrefPubMedGoogle Scholar
  • 70 Wakabayashi Y, Dutt P, Lippincott-Schwartz J, Arias I M. Rab11a and myosin Vb are required for bile canalicular formation in WIF-B9 cells.  Proc Natl Acad Sci U S A. 2005;  102(42) 15087-15092
    CrossrefPubMedGoogle Scholar
  • 71 Crocenzi F A, Mottino A D, Cao J et al.. Estradiol-17beta-D-glucuronide induces endocytic internalization of Bsep in rats.  Am J Physiol Gastrointest Liver Physiol. 2003;  285(2) G449-G459
    PubMedGoogle Scholar
  • 72 Crocenzi F A, Mottino A D, Sánchez Pozzi E J et al.. Impaired localisation and transport function of canalicular Bsep in taurolithocholate induced cholestasis in the rat.  Gut. 2003;  52(8) 1170-1177
    CrossrefPubMedGoogle Scholar
  • 73 Román I D, Fernández-Moreno M D, Fueyo J A, Roma M G, Coleman R. Cyclosporin A induced internalization of the bile salt export pump in isolated rat hepatocyte couplets.  Toxicol Sci. 2003;  71(2) 276-281
    CrossrefPubMedGoogle Scholar
  • 74 Crocenzi F A, Sánchez Pozzi E J, Ruiz M L et al.. Ca(2+)-dependent protein kinase C isoforms are critical to estradiol 17beta-D-glucuronide-induced cholestasis in the rat.  Hepatology. 2008;  48(6) 1885-1895
    CrossrefPubMedGoogle Scholar
  • 75 Dombrowski F, Stieger B, Beuers U. Tauroursodeoxycholic acid inserts the bile salt export pump into canalicular membranes of cholestatic rat liver.  Lab Invest. 2006;  86(2) 166-174
    CrossrefPubMedGoogle Scholar
  • 76 Crocenzi F A, Basiglio C L, Pérez L M, Portesio M S, Pozzi E J, Roma M G. Silibinin prevents cholestasis-associated retrieval of the bile salt export pump, Bsep, in isolated rat hepatocyte couplets: possible involvement of cAMP.  Biochem Pharmacol. 2005;  69(7) 1113-1120
    CrossrefPubMedGoogle Scholar
  • 77 Paulson J C. Glycoproteins: what are the sugar chains for?.  Trends Biochem Sci. 1989;  14(7) 272-276
    CrossrefPubMedGoogle Scholar
  • 78 Varki A. Biological roles of oligosaccharides: all of the theories are correct.  Glycobiology. 1993;  3(2) 97-130
    CrossrefPubMedGoogle Scholar
  • 79 Klausner R D, Sitia R. Protein degradation in the endoplasmic reticulum.  Cell. 1990;  62(4) 611-614
    CrossrefPubMedGoogle Scholar
  • 80 Plemper R K, Wolf D H. Retrograde protein translocation: ERADication of secretory proteins in health and disease.  Trends Biochem Sci. 1999;  24(7) 266-270
    CrossrefPubMedGoogle Scholar
  • 81 Kubitz R, Sütfels G, Kühlkamp T, Kölling R, Häussinger 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) 541-553
    CrossrefPubMedGoogle Scholar
  • 82 Sachs C W, Chambers T C, Fine R L. Differential phosphorylation of sites in the linker region of P-glycoprotein by protein kinase C isozymes alpha, betaI, betaII, gamma, delta, epsilon, eta, and zeta.  Biochem Pharmacol. 1999;  58(10) 1587-1592
    CrossrefPubMedGoogle Scholar
  • 83 Ahmed M, Borsch C M, Taylor S S, Vázquez-Laslop N, Neyfakh A A. A protein that activates expression of a multidrug efflux transporter upon binding the transporter substrates.  J Biol Chem. 1994;  269(45) 28506-28513
    PubMedGoogle Scholar
  • 84 Matsushima-Nishiwaki R, Okuno M, Adachi S et al.. Phosphorylation of retinoid X receptor alpha at serine 260 impairs its metabolism and function in human hepatocellular carcinoma.  Cancer Res. 2001;  61(20) 7675-7682
    PubMedGoogle Scholar
  • 85 Knisely A S, Strautnieks S S, Meier Y et al.. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.  Hepatology. 2006;  44(2) 478-486
    CrossrefPubMedGoogle Scholar
  • 86 Ward C L, Omura S, Kopito R R. Degradation of CFTR by the ubiquitin-proteasome pathway.  Cell. 1995;  83(1) 121-127
    CrossrefPubMedGoogle Scholar
  • 87 Hicke L, Dunn R. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins.  Annu Rev Cell Dev Biol. 2003;  19 141-172
    CrossrefPubMedGoogle Scholar
  • 88 Dupré S, Urban-Grimal D, Haguenauer-Tsapis R. Ubiquitin and endocytic internalization in yeast and animal cells.  Biochim Biophys Acta. 2004;  1695(1-3) 89-111
    CrossrefPubMedGoogle Scholar
  • 89 Ismair M G, Häusler S, Stuermer C A et al.. ABC-transporters are localized in caveolin-1-positive and reggie-1-negative and reggie-2-negative microdomains of the canalicular membrane in rat hepatocytes.  Hepatology. 2009;  49(5) 1673-1682
    CrossrefPubMedGoogle Scholar
  • 90 Moreno M, Molina H, Amigo L et al.. Hepatic overexpression of caveolins increases bile salt secretion in mice.  Hepatology. 2003;  38(6) 1477-1488
    PubMedGoogle Scholar
  • 91 Paulusma C C, de Waart D R, Kunne C, Mok K S, Elferink R P. Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content.  J Biol Chem. 2009;  284(15) 9947-9954
    CrossrefPubMedGoogle Scholar
  • 92 Mosesson Y, Mills G B, Yarden Y. Derailed endocytosis: an emerging feature of cancer.  Nat Rev Cancer. 2008;  8(11) 835-850
    CrossrefPubMedGoogle Scholar

Ping LamPh.D. 

Liver Center, Yale University School of Medicine

333 Cedar Street/1080 LMP, P.O. Box 208019, New Haven, CT 06510-8019

Email: ping.lam@yale.edu