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Abcb4  -  ATP-binding cassette, sub-family B...

Mus musculus

Synonyms: ATP-binding cassette sub-family B member 4, Mdr2, Multidrug resistance protein 2, Multidrug resistance protein 3, P-glycoprotein 2, ...
 
 
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Disease relevance of Abcb4

  • CONCLUSIONS: 24-norUrsodeoxycholic acid ameliorates sclerosing cholangitis in Mdr2(-/-) mice [1].
  • CONCLUSIONS: Sclerosing cholangitis in Mdr2(-/-) mice is a multistep process with regurgitation of bile from leaky ducts into the portal tracts, leading to induction of periductal inflammation, followed by activation of periductal fibrogenesis, finally causing obliterative cholangitis owing to atrophy and death of bile duct epithelial cells [2].
  • Mice homozygous for a disruption of their mdr2 gene, however, develop liver disease and this appears to be due to their complete inability to secrete phospholipids into bile [3].
  • Therefore, we constructed first-generation recombinant adenoviruses encoding different shRNAs against murine ATP-binding cassette multidrug resistance protein 2 (Abcc2), which is involved in liver transport of bilirubin to bile, and analyzed Abcc2 silencing kinetics [4].
  • Mdr2 (Abcb4)-/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes [5].
 

High impact information on Abcb4

  • This phenotype is similar to human conjugated hyperbilirubinemia in Dubin-Johnson syndrome, which is caused by mutations in the multidrug resistance protein 2 (MRP2, gene symbol ABCC2), although this syndrome is not associated with overt liver injury [6].
  • Phosphatidylcholine translocase: a physiological role for the mdr2 gene [7].
  • P-glycoproteins (P-gps) encoded by the mouse mdr2 and mdr3 genes were expressed in secretory vesicles (SVs) from the yeast mutant sec6-4, and their capacity to function as a lipid translocase/flippase was tested [7].
  • The latter is encoded by the human MDR3 (also called MDR2) and the mouse mdr2 genes, and its tissue distribution (bile canalicular membrane of hepatocytes, B cells, heart, and muscle) suggests a specialized metabolic function [8].
  • Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease [8].
 

Chemical compound and disease context of Abcb4

 

Biological context of Abcb4

 

Anatomical context of Abcb4

  • The inhibition of PC translocation by glibenclamide, an inhibitor of various ATP binding cassette transporters, and its reduction in erythrocytes from both Abcb1a/1b and Abcb4 knockout mice, suggest the involvement of ATP binding cassette transporters in natural PC cell surface translocation [16].
  • Mdr3 was detected in intestinal brush border membrane vesicles and also in CMV, although at levels much lower than Mdr2 [17].
  • Exposure of cultured wild-type mouse hepatocytes to PPARalpha agonists specifically induced Mdr2 mRNA levels and did not affect expression of Mdr1a / 1b [14].
  • The expression of murine mdr genes, as analyzed by Northern blotting, revealed a baseline expression of murine mdr2 in parental cells that was unchanged in the drug-resistant cell lines [18].
  • (3)H-triglycerides accumulated in enterocytes in Mdr2((-/-)) mice [19].
 

Associations of Abcb4 with chemical compounds

  • BACKGROUND & AIMS: mdr2 P-glycoprotein (Pgp) deficiency in mice leads to the absence of biliary phospholipids and cholesterol in the presence of normal bile salt secretion [15].
  • METHODS: Hepatic lipid content, enzyme activities, plasma lipoprotein levels, and fecal sterol excretion were measured in wild-type (+/+) and mdr2 Pgp-deficient (-/-) mice [15].
  • In contrast to actinomycin D-resistant SEWA cells, in which higher amplification levels of Pgy1 than of Pgy2 are regularly present, the COL-resistant lines showed a preference for Pgy2 gene amplification [20].
  • Neither UDCA nor CA affected Mdr2 expression [21].
  • After intragastric [(3)H]triolein administration in Triton WR1339-pretreated animals, the appearance of (3)H-triglycerides in plasma was reduced by 70% in Mdr2((-/-)) compared with Mdr2((+/+)) mice, excluding accelerated lipolysis as the cause of defective triglyceride response in Mdr2((-/-)) mice [19].
 

Physical interactions of Abcb4

  • Labeling experiments using membrane-enriched fractions and a photoactivatable analogue of ATP showed that the Mdr2 protein was properly inserted in the membrane of transfected cells and could bind this ligand with an apparent affinity similar to that of Mdr1 [13].
  • METHODS: Plasma membranes were isolated from male wild-type (+/+) and mdr2 (-/-) mice for measurement of Na+-dependent taurocholate transport and assessment of Ntcp protein levels by Western blotting [22].
 

Regulatory relationships of Abcb4

  • Hybridization studies with gene specific probes in independently derived multidrug resistant cell lines and transfection experiments with full length cDNA clones indicate that mdr1 and mdr3 but not mdr2 overexpression can induce multidrug resistance [23].
  • Additionally, LXR activation stimulated the excretion of plasma-derived [ 3 H]cholesterol into the fecal neutral sterol fraction in Mdr2 -/- mice [24].
  • METHODS: Transgenic MDR3-expressing hepatocytes as well as normal mdr2(+/+) hepatocytes were transplanted in mdr2(-/-) mice, and liver repopulation was assessed by immunohistochemistry and measurement of biliary lipid secretion [25].
  • However, the effect of decreased phosphatidylcholine secretion and modulation of PEMT on the development of diet-induced steatohepatitis in Mdr2 (+/-) mice has not been explored [26].
 

Other interactions of Abcb4

  • CONCLUSIONS: Induction of Mdr2 expression and function is part of the PPARalpha-mediated fasting response in mice [27].
  • The inability of the mouse mdr2 gene to confer multidrug resistance is linked to reduced drug binding to the protein [13].
  • An RNase protection assay revealed that elevated levels of mdr1 and mdr2 mRNA were detected in R1 and R2 cells, with an additional increase in mdr3 mRNA in the R2 subline [28].
  • Lack of biliary lipid excretion in the little skate, Raja erinacea, indicates the absence of functional Mdr2, Abcg5, and Abcg8 transporters [29].
  • Fractional cholesterol absorption was reduced on LXR activation in both strains but was more pronounced in Mdr2 -/- mice, coinciding with reduced Npc111 expression [24].
 

Analytical, diagnostic and therapeutic context of Abcb4

  • Immunoblotting of normal mouse tissues revealed that the Mdr2 isoform was expressed at very high levels in liver canalicular membrane vesicles (CMV) but not in membrane vesicles prepared from the basolateral (sinusoidal) domain (SMV) [17].
  • Photolabeling experiments with [125I]iodoarylazidoprazosin followed by immunoprecipitation with isoform-specific antibodies indicated that, in CMV, Mdr3 but not Mdr2 could bind the drug analogue [17].
  • In this work, we analyzed by RT-PCR the expression of mdr1, mdr2 and mdr3 in several organs of BALB/c and C57BL/6 mice during ontogeny [30].
  • Southern blotting of genomic DNAs from a series of six MDR cell lines revealed that five of these lines had 5'-end amplification of mdr2, whereas only three contained 3'-end amplification [31].
  • In wild-type mdr2 (+/+) mice, ultrarapid cryofixation of livers in situ revealed abundant unilamellar lipid vesicles within bile canalicular lumina [32].

References

  1. 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Fickert, P., Wagner, M., Marschall, H.U., Fuchsbichler, A., Zollner, G., Tsybrovskyy, O., Zatloukal, K., Liu, J., Waalkes, M.P., Cover, C., Denk, H., Hofmann, A.F., Jaeschke, H., Trauner, M. Gastroenterology (2006) [Pubmed]
  2. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Fickert, P., Fuchsbichler, A., Wagner, M., Zollner, G., Kaser, A., Tilg, H., Krause, R., Lammert, F., Langner, C., Zatloukal, K., Marschall, H.U., Denk, H., Trauner, M. Gastroenterology (2004) [Pubmed]
  3. Classical and novel forms of multidrug resistance and the physiological functions of P-glycoproteins in mammals. Borst, P., Schinkel, A.H., Smit, J.J., Wagenaar, E., Van Deemter, L., Smith, A.J., Eijdems, E.W., Baas, F., Zaman, G.J. Pharmacol. Ther. (1993) [Pubmed]
  4. Effect of Adenovirus-Mediated RNA Interference on Endogenous MicroRNAs in a Mouse Model of Multidrug Resistance Protein 2 Gene Silencing. Narvaiza, I., Aparicio, O., Vera, M., Razquin, N., Bortolanza, S., Prieto, J., Fortes, P. J. Virol. (2006) [Pubmed]
  5. Mdr2 (Abcb4)-/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. Popov, Y., Patsenker, E., Fickert, P., Trauner, M., Schuppan, D. J. Hepatol. (2005) [Pubmed]
  6. Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes. Kikuchi, S., Hata, M., Fukumoto, K., Yamane, Y., Matsui, T., Tamura, A., Yonemura, S., Yamagishi, H., Keppler, D., Tsukita, S., Tsukita, S. Nat. Genet. (2002) [Pubmed]
  7. Phosphatidylcholine translocase: a physiological role for the mdr2 gene. Ruetz, S., Gros, P. Cell (1994) [Pubmed]
  8. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Smit, J.J., Schinkel, A.H., Oude Elferink, R.P., Groen, A.K., Wagenaar, E., van Deemter, L., Mol, C.A., Ottenhoff, R., van der Lugt, N.M., van Roon, M.A. Cell (1993) [Pubmed]
  9. The role of bile salt composition in liver pathology of mdr2 (-/-) mice: differences between males and females. van Nieuwerk, C.M., Groen, A.K., Ottenhoff, R., van Wijland, M., van den Bergh Weerman, M.A., Tytgat, G.N., Offerhaus, J.J., Oude Elferink, R.P. J. Hepatol. (1997) [Pubmed]
  10. Effect of mdr2 mutation with combined tandem disruption of canalicular glycoprotein transporters by cyclosporine A on bile formation in mice. Elamiri, A., Perwaiz, S., Tuchweber, B., Yousef, I.M. Pharmacol. Res. (2003) [Pubmed]
  11. Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2+/- mice. Hoekstra, H., Porte, R.J., Tian, Y., Jochum, W., Stieger, B., Moritz, W., Slooff, M.J., Graf, R., Clavien, P.A. Hepatology (2006) [Pubmed]
  12. Physical mapping, amplification, and overexpression of the mouse mdr gene family in multidrug-resistant cells. Raymond, M., Rose, E., Housman, D.E., Gros, P. Mol. Cell. Biol. (1990) [Pubmed]
  13. The inability of the mouse mdr2 gene to confer multidrug resistance is linked to reduced drug binding to the protein. Buschman, E., Gros, P. Cancer Res. (1994) [Pubmed]
  14. Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice. Kok, T., Bloks, V.W., Wolters, H., Havinga, R., Jansen, P.L., Staels, B., Kuipers, F. Biochem. J. (2003) [Pubmed]
  15. Reduced plasma cholesterol and increased fecal sterol loss in multidrug resistance gene 2 P-glycoprotein-deficient mice. Voshol, P.J., Havinga, R., Wolters, H., Ottenhoff, R., Princen, H.M., Oude Elferink, R.P., Groen, A.K., Kuipers, F. Gastroenterology (1998) [Pubmed]
  16. Natural phosphatidylcholine is actively translocated across the plasma membrane to the surface of mammalian cells. Kälin, N., Fernandes, J., Hrafnsdóttir, S., van Meer, G. J. Biol. Chem. (2004) [Pubmed]
  17. mdr2 encodes P-glycoprotein expressed in the bile canalicular membrane as determined by isoform-specific antibodies. Buschman, E., Arceci, R.J., Croop, J.M., Che, M., Arias, I.M., Housman, D.E., Gros, P. J. Biol. Chem. (1992) [Pubmed]
  18. Overexpression of the multidrug resistance-associated protein (MRP) gene in vincristine but not doxorubicin-selected multidrug-resistant murine erythroleukemia cells. Slapak, C.A., Fracasso, P.M., Martell, R.L., Toppmeyer, D.L., Lecerf, J.M., Levy, S.B. Cancer Res. (1994) [Pubmed]
  19. Postprandial chylomicron formation and fat absorption in multidrug resistance gene 2 P-glycoprotein-deficient mice. Voshol, P.J., Minich, D.M., Havinga, R., Elferink, R.P., Verkade, H.J., Groen, A.K., Kuipers, F. Gastroenterology (2000) [Pubmed]
  20. Colcemid resistance in murine SEWA cells: non-Pgy gene amplification at low levels of resistance and preferential Pgy2 gene amplification at high levels of resistance. Wettergren, Y., Kullberg, A., Levan, G. Hereditas (1995) [Pubmed]
  21. Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver. Fickert, P., Zollner, G., Fuchsbichler, A., Stumptner, C., Pojer, C., Zenz, R., Lammert, F., Stieger, B., Meier, P.J., Zatloukal, K., Denk, H., Trauner, M. Gastroenterology (2001) [Pubmed]
  22. Decreased Na+-dependent taurocholate uptake and low expression of the sinusoidal Na+-taurocholate cotransporting protein (Ntcp) in livers of mdr2 P-glycoprotein-deficient mice. Koopen, N.R., Wolters, H., Voshol, P., Stieger, B., Vonk, R.J., Meier, P.J., Kuipers, F., Hagenbuch, B. J. Hepatol. (1999) [Pubmed]
  23. Structural and functional characterization of the mouse multidrug resistance gene family. Dhir, R., Buschman, E., Gros, P. Bulletin du cancer. (1990) [Pubmed]
  24. Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in mice. Kruit, J.K., Plösch, T., Havinga, R., Boverhof, R., Groot, P.H., Groen, A.K., Kuipers, F. Gastroenterology (2005) [Pubmed]
  25. Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis. De Vree, J.M., Ottenhoff, R., Bosma, P.J., Smith, A.J., Aten, J., Oude Elferink, R.P. Gastroenterology (2000) [Pubmed]
  26. Mice heterozygous for the Mdr2 gene demonstrate decreased PEMT activity and diminished steatohepatitis on the MCD diet. Igolnikov, A.C., Green, R.M. J. Hepatol. (2006) [Pubmed]
  27. Induction of hepatic ABC transporter expression is part of the PPARalpha-mediated fasting response in the mouse. Kok, T., Wolters, H., Bloks, V.W., Havinga, R., Jansen, P.L., Staels, B., Kuipers, F. Gastroenterology (2003) [Pubmed]
  28. Relationship between expression of P-glycoprotein and efficacy of trifluoperazine in multidrug-resistant cells. Ganapathi, R., Kuo, T., Teeter, L., Grabowski, D., Ford, J. Mol. Pharmacol. (1991) [Pubmed]
  29. Lack of biliary lipid excretion in the little skate, Raja erinacea, indicates the absence of functional Mdr2, Abcg5, and Abcg8 transporters. Elferink, R.P., Ottenhoff, R., Fricker, G., Seward, D.J., Ballatori, N., Boyer, J. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  30. Multidrug resistance gene expression during the murine ontogeny. Schiengold, M., Schwantes, L., Schwartsmann, G., Chies, J.A., Nardi, N.B. Mech. Ageing Dev. (2001) [Pubmed]
  31. Amplification of the murine mdr2 gene and a reconsideration of the structure of the murine mdr gene locus. Kirschner, L.S. DNA Cell Biol. (1995) [Pubmed]
  32. Hepatic secretion of phospholipid vesicles in the mouse critically depends on mdr2 or MDR3 P-glycoprotein expression. Visualization by electron microscopy. Crawford, A.R., Smith, A.J., Hatch, V.C., Oude Elferink, R.P., Borst, P., Crawford, J.M. J. Clin. Invest. (1997) [Pubmed]
 
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