Bile salt transporters

Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, 8091 Switzerland.
Annual Review of Physiology (Impact Factor: 18.51). 02/2002; 64:635-61. DOI: 10.1146/annurev.physiol.64.082201.100300
Source: PubMed


Bile salts are the major organic solutes in bile and undergo extensive enterohepatic circulation. Hepatocellular bile salt uptake is mediated predominantly by the Na(+)-taurocholate cotransport proteins Ntcp (rodents) and NTCP (humans) and by the Na(+)-independent organic anion-transporting polypeptides Oatp1, Oatp2, and Oatp4 (rodents) and OATP-C (humans). After diffusion (bound by intracellular bile salt-binding proteins) to the canalicular membrane, monoanionic bile salts are secreted into bile canaliculi by the bile salt export pump Bsep (rodents) or BSEP (humans). Both belong to the ATP-binding cassette (ABC) transporter superfamily. Dianionic conjugated bile salts are secreted into bile by the multidrug-resistance-associated proteins Mrp2/MRP2. In bile ductules, a minor portion of protonated bile acids and monomeric bile salts are reabsorbed by non-ionic diffusion and the apical sodium-dependent bile salt transporter Asbt/ASBT, transported back into the periductular capillary plexus by Mrp3/MRP3 [and/or a truncated form of Asbt (tAsbt)], and subjected to cholehepatic shunting. The major portion of biliary bile salts is aggregated into mixed micelles and transported into the intestine, where they are reabsorbed by apical Oatp3, the apical sodium-dependent bile salt transporter (ASBT), cytosolic intestinal bile acid-binding protein (IBABP), and basolateral Mrp3/MRP3 and tAsbt. Transcriptional and posttranscriptional regulation of these enterohepatic bile salt transporters is closely related to the regulation of lipid and cholesterol homeostasis. Furthermore, defective expression and function of bile salt transporters have been recognized as important causes for various cholestatic liver diseases.

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    • "Hepaticuptakeofbiliaryconstituentsatthesinusoidaldomainofhepatocytesismediatedby bothsodium-dependentandindependentmechanisms(NathansonandBoyer,1991).While sodium-independentuptakeofbilesaltsiscarriedbymembersoftheorganicaniontransporting polypeptidefamily(OATPs/SLCOs),sodium-dependentuptakeismediatedbytheNa +- taurocholatecotransportingpolypeptide(NTCP/SLC10A1)thatrepresentsthemostrelevant uptakesystem.Itaccountsfortheuptakeofthemajorpartofconjugatedbileacidsandlessthan halfofunconjugatedbileacids(Kullak-Ublicketal.,2000;MeierandStieger,2002).Bilesalts arethencarriedacrossthehepatocyteandsecretedintobileviacanaliculartransporters. "
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    ABSTRACT: The role of hepatobiliary transporters in drug-induced liver injury remains poorly understood. Various in vivo and in vitro biological approaches are currently used for studying hepatic transporters; however, appropriate localization and functional activity of these transporters are essential for normal biliary flow and drug transport. Human hepatocytes (HH) are considered as the most suitable in vitro cell model but erratic availability and inter-donor functional variations limit their use. In the present work, we aimed to compare localization of influx and efflux transporters and their functional activity in differentiated human HepaRG hepatocytes with fresh HH in conventional (CCHH) and sandwich (SCHH) cultures. All tested influx and efflux transporters were correctly localized to canalicular (BSEP, MRP2, MDR1, MDR3) or basolateral (NTCP, MRP3) membrane domains and were functional in all models. Contrary to other transporters, NTCP and BSEP were less abundant and active in HepaRG cells, cellular uptake of taurocholate was 2.2- and 1.4-fold and bile excretion index 2.8-and 2.6- fold lower, than in SCHH and CCHH respectively. However, when taurocholate canalicular efflux was evaluated in standard and divalent cation-free conditions in buffers or cell lysates, the difference between the three models did not exceed 9.3%. Interestingly, cell imaging showed higher bile canaliculi contraction/relaxation activity in HepaRG hepatocytes and larger bile canaliculi networks in SCHH. Altogether, our results bring new insights in mechanisms involved in bile acids accumulation and excretion in HH and suggest that HepaRG cells represent a suitable model for studying hepatobiliary transporters and drug-induced cholestasis. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email:
    Full-text · Article · Feb 2015 · Toxicological Sciences
    • "However, the carriers involved are still unknown. The two carriers Na + -taurocholate cotransporting polypeptide NTCP (SLC10A1) and the apical sodium-dependent bile acid transporter ASBT (SLC10A2) are known to maintain the enterohepatic circulation of bile acids (Shneider et al. 1995; Meier and Stieger 2002; Trauner and Boyer 2003) and, therefore, represent promising candidate transporters for IF conjugates. NTCP transports bile acids, sulfoconjugated bile acids, and sulfoconjugated steroid hormones and is mainly expressed in the liver, whereas ASBT is expressed in the brush-border membrane of ileocytes, the apical membrane of cholangiocytes in the liver and in the apical domain of the proximal tubules in the kidney with a substrate pattern restricted to bile acids (Hagenbuch and Meier 1994; Wong et al. 1995; Craddock et al. 1998; Schroeder et al. 1998; Kramer et al. 1999). "
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    ABSTRACT: Soy isoflavones (IF) are phytoestrogens, which interact with estrogen receptors. They are extensively metabolized by glucuronosyltransferases and sulfotransferases, leading to the modulation of their estrogenic activity. It can be assumed that this biotransformation also has a crucial impact on the uptake of IF by active or passive cellular transport mechanisms, but little is known about the transport of IF phase II metabolites into the cell. Therefore, transport assays for phase II metabolites of daidzein (DAI) were carried out using HEK293 cell lines transfected with five human candidate carriers, i.e., organic anion transporter OAT4, sodium-dependent organic anion transporter (SOAT), Na(+)-taurocholate cotransporting polypeptide (NTCP), apical sodium-dependent bile acid transporter ASBT, and organic anion transporting polypeptide OATP2B1. Cellular uptake was monitored by UHPLC-DAD. DAI monosulfates were transported by the carriers NTCP and SOAT in a sodium-dependent manner, while OAT4-HEK293 cells revealed a partly sodium-dependent transport for these compounds. In contrast, DAI-7,4'-disulfate was only taken up by NTCP-HEK293 cells. DAI-7-glucuronide, but not DAI-4'-glucuronide, was transported exclusively by OATP2B1 in a sodium-independent manner. DAI-7-glucuronide-4'-sulfate, DAI-7-glucoside, and DAI were no substrate of any of the tested carriers. In addition, the inhibitory potency of the DAI metabolites toward estrone-sulfate (E1S) uptake of the above-mentioned carriers was determined. In conclusion, human SOAT, NTCP, OATP2B1, and OAT4 were identified as carriers for the DAI metabolites. Several metabolites were able to inhibit carrier-dependent E1S uptake. These findings might contribute to a better understanding of the bioactivity of IF especially in case of hormone-related cancers.
    No preview · Article · Oct 2014 · Archive für Toxikologie
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    • "Consistent with our hepatic mRNA expression data, the protein levels of CYP8B1 and AKR1D1 were reduced in all-trans RA-treated mice. In addition, the protein level of ABCB11, a bile acid transporter [23], and SLC27A5, a very longchain acyl–CoA synthetase [37], was also reduced by all-trans RA Fig. 1. The effect of all-trans RA in regulating the expression of genes that control bile acid homeostasis. "
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    ABSTRACT: Retinoic acid (RA) and bile acids share common roles in regulating lipid homeostasis and insulin sensitivity. In addition, the receptor for RA (retinoid x receptor) is a permissive partner of the receptor for bile acids, farnesoid x receptor (FXR/NR1H4). Thus, RA can activate the FXR-mediated pathway as well. The current study was designed to understand the effect of all-trans RA on bile acid homeostasis. Mice were fed an all-trans RA-supplemented diet and the expression of 46 genes that participate in regulating bile acid homeostasis was studied. The data showed that all-trans RA has a profound effect in regulating genes involved in synthesis and transport of bile acids. All-trans RA treatment reduced the gene expression levels of Cyp7a1, Cyp8b1, and Akr1d1, which are involved in bile acid synthesis. All-trans RA also decreased the hepatic mRNA levels of Lrh-1 (Nr5a2) and Hnf4α (Nr2a1), which positively regulate the gene expression of Cyp7a1 and Cyp8b1. Moreover, all-trans RA induced the gene expression levels of negative regulators of bile acid synthesis including hepatic Fgfr4, Fxr, and Shp (Nr0b2) as well as ileal Fgf15. All-trans RA also decreased the expression of Abcb11 and Slc51b, which have a role in bile acid transport. Consistently, all-trans RA reduced hepatic bile acid levels and the ratio of CA/CDCA, as demonstrated by liquid chromatography-mass spectrometry. The data suggest that all-trans RA-induced SHP may contribute to the inhibition of CYP7A1 and CYP8B1, which in turn reduces bile acid synthesis and affects lipid absorption in the gastrointestinal tract.
    Full-text · Article · Aug 2014 · Biochemical Pharmacology
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