Disease relevance of Abcb11

• Mice overexpressing hepatic Abcb11 rapidly develop cholesterol gallstones [1].
• However, as reported previously, because the spgp(-)(/)(-) knockout mice do not express severe cholestasis and have substantial bile acid secretion, we investigated the "alternative transport system" that allows these mice to be physiologically relatively normal [2].
• C57L/J (gallstone-susceptible) and AKR/J (gallstone-resistant) mice have been utilized for quantitative trait loci (QTL) analysis to identify the Lith 1 locus for cholelithiasis [3].
• In this study, we show that the knockout of spgp gene in mice results in intrahepatic cholestasis, but with significantly less severity than PFIC2 in humans [4].
• With the exception of Bsep, UDCA stimulated expression of hepatic, renal and intestinal ABC transporters independent of FXR without inducing liver toxicity [5].

High impact information on Abcb11

• Maintenance of Bsep expression strictly depends on FXR and is a critical determinant of the cholestatic phenotype [6].
• In addition, the spgp(-/-) mice display a significant increase in the secretion of cholesterol and phospholipids into the bile [4].
• Spgp is predominantly expressed in the canalicular membranes of liver [4].
• These results suggest that hydroxylation and an alternative canalicular transport mechanism for bile acids compensate for the absence of Spgp function and protect the mutant mice from severe cholestatic damage [4].
• The spgp(-/-) mice thus provide a unique model for gaining new insights into therapeutic intervention for intrahepatic cholestasis and understanding mechanisms associated with lipid homeostasis [4].

Chemical compound and disease context of Abcb11

• Interestingly, hepatic cholestasis was observed in 100% of the bezafibrate-fed (-/-) mice, and this was accompanied by significantly elevated hepatic expression of mRNA encoding bile salt export pump and lower expression of mRNA encoding cytochrome P450 7A1, consistent with enhanced activation of the bile acid receptor, farnesoid X receptor [7].

Biological context of Abcb11

• We employed quantitative trait locus/loci (QTL) analyses of an intercross between inbred strains CAST/Ei (susceptible) and DBA/2J (resistant) to determine the subset of gallstone susceptibility (Lith) genes these strains possess [8].
• Its gene map in Lith 1 region (Chromosome 2) and its expression is increased in susceptible inbred strains of mice (C57L) of inbred mice [9].
• In this study, we fed spgp(-/-) knockout mice with a cholic acid (CA)-supplemented diet to determine whether a more pronounced PFIC2-like phenotype could be induced [10].
• Western immunoblotting results for the most affected isoenzymes (CYP3A1/2 and CYP2E1) and Bsep confirmed that UDCA can both prevent and reduce the CYP-dependent MFO inactivation and Bsep down-regulation caused by DCA [11].
• METHODS: The extent of lipid peroxidation in livers, kidneys, hearts and brains harvested from cholemic homozygous (spgp -/-) mice using the thiobarbituric acid reactive substances (TBARS) assay [12].

Anatomical context of Abcb11

• In support of this hypothesis, we showed that plasma membrane vesicles isolated from a drug resistant cell line expressing high levels of P-glycoprotein were capable of transporting bile acids, albeit with a 5-fold lower affinity compared to Spgp [2].
• In females, cyp7A1 deficiency also caused changes in hepatic fatty acid metabolism, decreased hepatic canalicular bile acid transporter, Bsep, and gallbladder bile composition altered to a lithogenic profile [13].
• The most parsimonious explanation for the multiple enzymatic alterations is that the primary Lith phenotype induces secondary events to increase availability of cholesterol to supply the sterol to the hepatocyte canalicular membrane for hypersecretion into bile [14].
• SPGP cells had decreased uptake of taurocholate and vinblastine compared with LLC-PK1 cells [15].
• Although TACA inhibited ATP-dependent TCA transport across plasma membrane vesicles from Sf9 cells expressing rat or mouse bile salt export pump (Bsep), no ATP-dependent TACA transport was found [16].

Associations of Abcb11 with chemical compounds

• These data indicate that hepatic overexpression of Abcb11 increases the rate of cholesterol gallstone formation [1].
• We conclude that gallstone-susceptible C57L/J mice demonstrate increased gene and canalicular membrane expression of Abcb11, however, taurocholate transport is functionally diminished [3].
• Bile acid treatment increased the in vivo expression of Bsep but not Mrp or Oatp [17].
• A significant reduction in the hepatic expression of mdr1a, mdr1b, mdr2 and spgp genes were seen in endotoxin (lipopolysaccharide (LPS)) and turpentine-treated mice [18].
• Cyclosporin A, glibenclamide and rifamycin SV, all competitive inhibitors of Bsep transport, also reduced the bile salt-stimulated ATPase activity [19].

Regulatory relationships of Abcb11

• TTR-Abcb11 and FVB/NJ strain control mice were fed a lithogenic or chow diet and cholesterol crystal and gallstone formation were measured [1].

Other interactions of Abcb11

• In response to the lithogenic diet, Bsep (Abcb11) protein expression was up-regulated only marginally and bile salt secretion did not increase [20].
• No changes were seen in the protein mass of BS transporters Ntcp and Bsep [21].
• The levels were clearly higher in wild-type mice than in FXR-null mice, despite the diminished expression of a bile salt export pump in the latter [22].
• Administration IL-1beta caused an increase in both mdr1b mRNA and protein expression, however, mRNA levels of mdr1a, mdr2 and spgp were significantly reduced [18].

Analytical, diagnostic and therapeutic context of Abcb11

• Molecular cloning and characterization of the murine bile salt export pump [23].
• The radiation hybrid results also provided the highest resolution of the area containing the two candidate genes, which both mapped in the Lith1 region with close linkage, being separated by a distance of only 15 cR(3000) [24].

References