Disease relevance of Abcb11

• CONCLUSIONS: p38(MAPK) regulates BSEP trafficking from the Golgi to the canalicular membrane, and the Golgi may serve as a BSEP pool in certain forms of cholestasis or when p38(MAPK) activity is inhibited [1].
• Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate [2].

High impact information on Abcb11

• In isolated rat hepatocytes with intact bile secretion, no colocalization of rat isoforms of the bile salt export pump (Bsep) and Golgi was found, but colocalization occurred after inhibition of p38(MAPK) and PKC, suggesting that Bsep trafficking to the canalicular membrane depends on the basal activity of these kinases in polarized cells [1].
• Also, tauroursodeoxycholate (TUDC), which activates p38(MAP) kinase (p38(MAPK), increased BSEP-positive pseudocanaliculi by more than 50% in rat sodium taurocholate cotransporting peptide (Ntcp)-transfected but not in untransfected HepG2 cells [1].
• Cycloheximide, an inhibitor of protein translation, induced a microtubule- and p38(MAP) kinase-dependent decrease of Golgi-associated BSEP, accompanied by a more than 2-fold increase in BSEP-positive pseudocanaliculi [1].
• Protein levels of the canalicular bile salt export pump (Bsep) were unchanged in diabetic rats, but basal biliary bile salt output and the SRm of taurocholate were increased by 260% and 130%, respectively, compared with controls [3].
• Protein expression, messenger RNA levels, and tissue distribution of the bile acid transporters sodium taurocholate cotransporting protein (ntcp) and bile salt export pump (bsep) were also analyzed [4].

Chemical compound and disease context of Abcb11

• CONCLUSIONS: These results provide a molecular basis for previous in vivo observations and identify Bsep as an important target for induction of drug- and estrogen-induced cholestasis in mammalian liver [5].
• The data show that oral supplementation of taurine induces Mrp2 and Bsep expression and may prevent LPS-induced cholestasis [6].
• Impaired localisation and transport function of canalicular Bsep in taurolithocholate induced cholestasis in the rat [7].

Biological context of Abcb11

• The maximal secretory rate (nmol/min/g liver) for TC in the single pass isolated perfused liver was also increased by 10%, 31%, and 24% at 2, 14, and 21 days postpartum and correlated with increased expression of Ntcp and Bsep mRNA and protein [8].
• Furthermore, Bsep and Mrp2 protein levels were maintained at about 50%, while the Mrp2 mRNA showed a transient up-regulation to 154% at 24 and 48 hours [9].
• In contrast, the maximum secretory rate of tauroursodeoxycholate as well as expression of Bsep protein detected by Western blotting were not affected [10].
• These results show that 1) expression (of mRNA and protein) of canalicular transporters is developmentally regulated by both transcriptional and posttranscriptional mechanisms and 2) Mrp2 and Bsep gene expression (mRNA) are differentially regulated [11].
• The 5' flanking region of the bile salt export pump (Bsep) gene was systematically analysed to provide the basis for understanding the mechanisms which regulate Bsep transcription [12].

Anatomical context of Abcb11

• Trafficking of the bile salt export pump (BSEP) to the canalicular membrane was investigated in HepG2 cells and rat hepatocytes [1].
• The short-term effects of anisoosmolarity and Ca(2+)-withdrawal on the localization of Bsep and the tight junction proteins Zo-1 and occludin were studied in perfused rat liver by immunohistochemistry, confocal microscopy, and densitometry [13].
• In isolated canalicular rat liver plasma membrane preparations, troglitazone competitively inhibited the ATP-dependent taurocholate transport (apparent K(i) value, 1.3 microM), mediated by the canalicular bile salt export pump (Bsep) [14].
• RESULTS: CLF and LLF, which like their natural nonsulfated bile acid congeners are expected to be handled by the canalicular bile salt export pump, were transferred into the bile canaliculus much faster than sLLF, a putative substrate for the canalicular multispecific organic anion transporter in both the in vivo and the in vitro models employed [15].
• TLCA (10 micromol/l for 50 min) decreased Bsep density in canalicular membranes to 31% of controls (P<0.05) when bile flow was reduced to 35% of controls (P<0.05) [16].

Associations of Abcb11 with chemical compounds

• Fusidate inhibited the ATP-dependent transport of the Mrp2 substrates 17beta-glucuronosyl estradiol and leukotriene C4, and the transport of cholyltaurine by Bsep with Ki values of 2.2+/-0.3, 7.6+/-1.3, and 5.5+/-0.8 microM, respectively [17].
• Estradiol-17beta-d-glucuronide (E(2)17G) and taurolithocholate (TLC) induce acute cholestasis-associated with retrieval of the bile salt export pump (Bsep), which parallels with alteration in transport activity. cAMP stimulates the apically directed vesicular trafficking of transporters, partially preventing these alterations [18].
• Sil (2.5microM) elevated by 40+/-3% intracellular cAMP, and mimicked the ability of dibutyryl-cAMP (10microM) to prevent internalisation of Bsep and the TLC (2.5microM)- and E(2)17G (50microM)-induced impairment in the capacity of IRHC to accumulate CLF apically [18].
• We aimed to assess the ability of silibinin (Sil), the silymarin active component, to prevent the retrieval of Bsep induced by TLC and E(2)17G, and the associated alteration in its transport function [18].
• Dexamethasone, hydrocortisone and phenobarbital had no effect on Bsep promoter activity [12].

Other interactions of Abcb11

• Infusion of ovine prolactin (oPRL) to ovariectomized rats increased expression of both Ntcp and Bsep mRNA and protein [8].
• Taurine supplementation induces multidrug resistance protein 2 and bile salt export pump expression in rats and prevents endotoxin-induced cholestasis [6].

Analytical, diagnostic and therapeutic context of Abcb11

• METHODS: Subcellular localization of BSEP was determined by confocal laser scanning microscopy using different BSEP antibodies [1].
• E217G (15 micromol/kg i.v.) impaired bile salt (BS) output and induced Bsep internalization, as assessed by confocal microscopy and Western blotting [19].
• In contrast, protein and mRNA expression of both the canalicular ATP-dependent bile salt export pump (Bsep) and the multiorganic anion transporter Mrp2 remained unchanged or were slightly increased during liver regeneration, but also returned to control values 7-14 days after partial hepatectomy [20].
• Coimmunoprecipitation experiments and immunoelectron microscopy using a double immunogold labeling of heat shock protein 70 (HSP70) and various hepatocyte transporters suggested colocalization with HSP70 for the canalicular bile acid transporter (Bsep) in the subcanalicular space [21].
• Immunoelectronmicroscopic analysis of Bsep density on canalicular membranes, microvilli, and pericanalicular area of hepatocytes was performed in rat liver tissue prepared after liver perfusion with bile acids or carrier medium only [16].

References