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Gene Review

Abcc4  -  ATP-binding cassette, sub-family C...

Mus musculus

Synonyms: D630049P08Rik, MOAT-B, MOATB, MRP4
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Disease relevance of Abcc4

  • We show that FXR modulates cholestasis by controlling bile acids within the hepatocyte and is involved in bile acid synthesis, bile excretion via BSEP, and serum export via Mrp4 [1].

High impact information on Abcc4

  • Mechanisms proposed for this protection include the lowering of bile acid concentrations and altered expression of the hepatic transporters Mdr1, Mdr2, BSEP, and Mrp4 [1].
  • The highly similar mouse Abcc4 gene also contained these exons, which were remarkable because their size and sequence identity were much higher than the overall similarity between these genes [2].
  • Mrp3 and Ostalpha-Ostbeta were upregulated in Mrp4-/- mice but were unable to compensate for the loss of Mrp4 [3].
  • Mrp4 is a member of the multidrug resistance-associated gene family that is expressed on the basolateral membrane of hepatocytes and undergoes adaptive upregulation in response to cholestatic injury or bile acid feeding [3].
  • Mrp4-/- mice have an impaired cytoprotective response in obstructive cholestasis [3].

Biological context of Abcc4


Anatomical context of Abcc4

  • To address this issue, common bile duct ligation (CBDL) was performed in wild-type and Mrp4-/- mice and animals followed for 7 days [3].
  • Evidence is also presented that expression of MRP3 and/or PLF1, but not MRP4, is negatively regulated by feedback from the uterus [5].
  • Our results suggest that Mrp4, together with other unknown transporters, accounts for the luminal efflux of HCT and furosemide from proximal tubular epithelial cells [6].

Associations of Abcc4 with chemical compounds

  • In the livers of Abcc3(-/-) and Abcc4(-/-) mice, the basolateral excretory clearance of acetaminophen sulfate was reduced approximately 20 and approximately 20%, 4-methylumbelliferyl sulfate was reduced approximately 50 and approximately 65%, and harmol sulfate was decreased approximately 30 and approximately 45%, respectively [7].
  • In contrast, basolateral excretory clearance of these glucuronide conjugates was unaffected by the absence of Mrp4 [7].
  • Whereas cGMP transport into human vesicles was efficiently inhibited by the ABCC4-specific substrate prostaglandin E(1), cGMP transport into mouse vesicles was inhibited equally by Abcg2 and Abcc4 inhibitors/substrates [8].
  • High-performance liquid chromatography analysis on liver extracts revealed that taurine tetrahydroxy bile acid/beta-muricholic acid ratios were increased twofold in Mrp4-/- mice [3].
  • Serum bile acid levels were significantly lower in Mrp4-/- mice than in wild-type CBDL mice, whereas serum bilirubin levels were the same, suggesting that Mrp4 was required to effectively extrude bile acids from the cholestatic liver [3].

Other interactions of Abcc4


Analytical, diagnostic and therapeutic context of Abcc4


  1. Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Stedman, C., Liddle, C., Coulter, S., Sonoda, J., Alvarez, J.G., Evans, R.M., Downes, M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  2. Nonsense mediated decay downregulates conserved alternatively spliced ABCC4 transcripts bearing nonsense codons. Lamba, J.K., Adachi, M., Sun, D., Tammur, J., Schuetz, E.G., Allikmets, R., Schuetz, J.D. Hum. Mol. Genet. (2003) [Pubmed]
  3. Mrp4-/- mice have an impaired cytoprotective response in obstructive cholestasis. Mennone, A., Soroka, C.J., Cai, S.Y., Harry, K., Adachi, M., Hagey, L., Schuetz, J.D., Boyer, J.L. Hepatology (2006) [Pubmed]
  4. Multidrug resistance-associated protein 4 is up-regulated in liver but down-regulated in kidney in obstructive cholestasis in the rat. Denk, G.U., Soroka, C.J., Takeyama, Y., Chen, W.S., Schuetz, J.D., Boyer, J.L. J. Hepatol. (2004) [Pubmed]
  5. Signaling between the placenta and the uterus involving the mitogen-regulated protein/proliferins. Fang, Y., Lepont, P., Fassett, J.T., Ford, S.P., Mubaidin, A., Hamilton, R.T., Nilsen-Hamilton, M. Endocrinology (1999) [Pubmed]
  6. Multidrug resistance-associated protein 4 is involved in the urinary excretion of hydrochlorothiazide and furosemide. Hasegawa, M., Kusuhara, H., Adachi, M., Schuetz, J.D., Takeuchi, K., Sugiyama, Y. J. Am. Soc. Nephrol. (2007) [Pubmed]
  7. Evaluation of the role of multidrug resistance-associated protein (mrp) 3 and mrp4 in hepatic basolateral excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in abcc3-/- and abcc4-/- mice. Zamek-Gliszczynski, M.J., Nezasa, K., Tian, X., Bridges, A.S., Lee, K., Belinsky, M.G., Kruh, G.D., Brouwer, K.L. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  8. cGMP transport by vesicles from human and mouse erythrocytes. de Wolf, C.J., Yamaguchi, H., van der Heijden, I., Wielinga, P.R., Hundscheid, S.L., Ono, N., Scheffer, G.L., de Haas, M., Schuetz, J.D., Wijnholds, J., Borst, P. FEBS J. (2007) [Pubmed]
  9. Physiological and pharmacological functions of Mrp2, Mrp3 and Mrp4 as determined from recent studies on gene-disrupted mice. Kruh, G.D., Belinsky, M.G., Gallo, J.M., Lee, K. Cancer Metastasis Rev. (2007) [Pubmed]
  10. Do multidrug resistance-associated protein-1 and -2 play any role in the elimination of estradiol-17 beta-glucuronide and 2,4-dinitrophenyl-S-glutathione across the blood-cerebrospinal fluid barrier? Lee, Y.J., Kusuhara, H., Sugiyama, Y. Journal of pharmaceutical sciences. (2004) [Pubmed]
  11. Coordinated expression of multidrug resistance-associated proteins (Mrps) in mouse liver during toxicant-induced injury. Aleksunes, L.M., Scheffer, G.L., Jakowski, A.B., Pruimboom-Brees, I.M., Manautou, J.E. Toxicol. Sci. (2006) [Pubmed]
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