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

• CONCLUSIONS: Obstructive cholestasis in rats results in progressive up-regulation of Mrp4 protein in liver but down-regulation in kidney [4].

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

• These results provide the first direct evidence that Mrp3 and Mrp4 participate in the hepatic basolateral excretion of sulfate conjugates, although additional mechanism(s) are likely involved [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 [7].
• Recently, mice with gene disruptions in Mrp2, Mrp3 and Mrp4 have been developed [9].
• Therefore, Mrp4 and Mrp5 may contribute to the efflux transport of E(2)17betaG and DNP-SG from the CSF [10].

Analytical, diagnostic and therapeutic context of Abcc4

• Real-time RT-PCR demonstrated no major changes of Mrp4 mRNA levels in liver and kidney after BDL [4].
• RESULTS: Western blot analysis revealed a progressive, more than seven-fold increase (P < 0.05) of Mrp4 expression in cholestatic livers, 14 days after BDL [4].
• Immunohistochemistry localized Mrp4 to the basolateral hepatocyte membrane and corroborated its hepatic up-regulation after BDL [4].
• Double immunofluorescence imaging demonstrated the simultaneous down-regulation of Ntcp and up-regulation of Mrp4 in hepatocytes adjacent to the central vein after CCl4 [11].

References