In situ localization of the hepatocytic na+/taurocholate cotransporting polypeptide in rat liver

Stieger, Bruno; Hagenbuch, Bruno; Landmann, Lukas; Höchli, M.; Schroeder, Alice; Meier, Peter J.

doi:10.1016/0016-5085(94)90821-4

Cited by 206 publications

(136 citation statements)

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“…The anti-Ntcp antibody (K4) 6 was a gift from Dr. Stieger (Kantonsspital Zürich, Switzerland). The anti-Bsep antibody (K24) was raised in rabbit.…”

Section: Methodsmentioning

confidence: 99%

“…The sodium taurocholate cotransporting polypeptide (Ntcp/Slc10a1) is the major uptake system for conjugated bile salts from blood into liver parenchymal cells. 6 Together with several organic anion transporting polypeptides (Oatp1a1/ Slc21a1, Oatp1a4/Slc21a5, and Oatp1b2/Slc21a10), 7 it controls bile salt uptake at the sinusoidal membrane. Secretion of bile salts at the canalicular membrane is mediated by the bile salt export pump (Bsep, ABCB11) 8 and to a lesser extent by the multidrug resistance associated protein Mrp2 (ABCC2).…”

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confidence: 99%

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Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

et al. 2012

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The sodium taurocholate cotransporting polypeptide (Ntcp) is the major bile salt uptake transporter at the sinusoidal membrane of hepatocytes. Short-term feedback regulation of Ntcp by primary bile salts has not yet been investigated in vivo. Subcellular localization of Ntcp was analyzed in Ntcp-transfected HepG2-cells by flow cytometry and in immunofluorescence images from tissue sections by a new automated image analysis method. Net bile salt uptake was investigated in perfused rat liver by a pulse chase technique. In Flag-Ntcp-EGFP (enhanced green fluorescent protein) expressing HepG2-cells, taurochenodeoxycholate (TCDC), but not taurocholate (TC), induced endocytosis of Ntcp. TCDC, but not TC, caused significant internalization of Ntcp in perfused rat livers, as shown by an increase in intracellular Ntcp immunoreactivity, whereas Bsep distribution remained unchanged. These results correlate with functional studies. Rat livers were continuously perfused with 100 mu mol/L of TC. 25 mu mol/L of TCDC, taurodeoxycholate (TDC), tauroursodeoxycholate (TUDC), or TC were added for 30 minutes, washed out, followed by a pulse of (3)[H]-TC. TCDC, but not TDC, TUDC, or TC significantly increased the amount of (3)[H]-TC in the effluent, indicating a reduced sinusoidal net TC uptake. This effect was sensitive to chelerythrine (protein kinase C inhibitor) and cypermethrin (protein phosphatase 2B inhibitor). Phosphoinositide 3-kinase (PI3K) inhibitors had an additive effect, whereas Erk1/2 (extracellular signal activated kinase 1/2), p38MAPK, protein phosphatase 1/2A (PP1/2A), and reactive oxygen species (ROS) were not involved. Conclusion: TCDC regulates bile salt transport at the sinusoidal membrane by protein kinase C-and protein phosphatase 2B-mediated retrieval of Ntcp from the plasma membrane. During increased portal bile salt load this mechanism may adjust bile salt uptake along the acinus and protect periportal hepatocytes from harmful bile salt concentrations

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“…The anti-Ntcp antibody (K4) 6 was a gift from Dr. Stieger (Kantonsspital Zürich, Switzerland). The anti-Bsep antibody (K24) was raised in rabbit.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

et al. 2012

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“…Additionally, mouse Ntcp gene encodes a second, less abundant splice variant with 317 amino acids and a shorter C-terminal end (Cattori et al 1999). NTCP/Ntcps are exclusively expressed at the basolateral (sinusoidal) membrane of hepatocytes Stieger et al 1994;Kullak-Ublick et al 1997). Here, they mediate sodium-coupled uptake of taurocholate and other bile acids with a Na + :taurocholate stoichiometry of 2:1 Weinman 1997).…”

Section: Functional Properties and Expression Patterns Of The Individmentioning

confidence: 99%

“…Membrane insertion and sorting of NTCP and ASBT Based on bioinformatic predictions and experimental data, it has been shown that NTCP and ASBT have an extracellular N-terminus, an odd number of transmembrane helices (seven or nine) and a cytoplasmic Cterminus (Hagenbuch et al 1991;Hagenbuch and Meier 1994;Stieger et al 1994;Dawson and Oelkers 1995;Hallén et al 1999;Hallén et al 2002b;Zhang et al 2004). Several potential N-glycosylation sites are present in NTCP, ASBT and SOAT proteins, and site-directed mutagenesis has revealed that only N 5 and N 11 in rat Ntcp (Hagenbuch 1997), and N 10 in human ASBT (Zhang et al 2004) are glycosylated.…”

Section: Functional Properties and Expression Patterns Of The Individmentioning

confidence: 99%

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

Geyer

Wilke

Petzinger

2006

Naunyn Schmied Arch Pharmacol

158

138

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The solute carrier family 10 (SLC10) comprises two sodium-dependent bile acid transporters, i.e. the Na + / taurocholate cotransporting polypeptide (NTCP; SLC10A1) and the apical sodium-dependent bile acid transporter (ASBT; SLC10A2). These carriers are essentially involved in the maintenance of the enterohepatic circulation of bile acids mediating the first step of active bile acid transport through the membrane barriers in the liver (NTCP) and intestine (ASBT). Recently, four new members of the SLC10 family were described and referred to as P3 (SLC10A3), P4 (SLC10A4), P5 (SLC10A5) and sodium-dependent organic anion transporter (SOAT; SLC10A6). Experimental data supporting carrier function of P3, P4, and P5 is currently not available. However, as demonstrated for SOAT, not all members of the SLC10 family are bile acid transporters. SOAT specifically transports steroid sulfates such as oestrone-3-sulfate and dehydroepiandrosterone sulfate in a sodium-dependent manner, and is considered to play an important role for the cellular delivery of these prohormones in testes, placenta, adrenal gland and probably other peripheral tissues. ASBT and SOAT are the most homologous members of the SLC10 family, with high sequence similarity (∼70%) and almost identical gene structures. Phylogenetic analyses of the SLC10 family revealed that ASBT and SOAT genes emerged from a common ancestor gene. Structure-activity relationships of NTCP, ASBT and SOAT are discussed at the amino acid sequence level.Based on the high structural homology between ASBT and SOAT, pharmacological inhibitors of the ASBT, which are currently being tested in clinical trials for cholesterollowering therapy, should be evaluated for their crossreactivity with SOAT.

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“…Different proteins were tively, the apparent molecular weight of the native Ntcp is 51 kd, as was determined by Ntcp-specific antibodies. 26 With labeled: the dianionic bile salt is preferentially bound to subunit 1 of the glutathione-S-transferases (M r 26 kd) and to a the same antibodies, Ntcp can be localized to the basolateral membrane. Ntcp is only expressed in livers of mammalian polypeptide with a relative molecular mass of 14 kd identified as the cytosolic hepatic fatty acid binding protein.…”

mentioning

confidence: 99%

Second International Ringberg Conference: ?Cell Biology and Molecular Basis of Liver Transport?

Wehner

Kinne²,

Petzinger³

1996

Hepatology

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In the 7 years since the 1st Ringberg conference on ''He-observed system is a Cif-transporter, which means that it is patic Transport of Organic Substances'' was held at Ringberg-specific for purines and uridine. The transporter was cloned Castle near Tegernsee in Bavaria, Germany, the molecular very recently by expression cloning in Xenopus laevis oobasis of transport in the liver has been investigated with cytes. 2 The 2.9-kb complementary DNA of the Na / -dependent great success. Several carrier proteins could be cloned and purine nucleoside transporter SPNT encodes a protein of 659 the molecular properties of hepatic transport systems are amino acid residues and an estimated molecular mass of 72 now better understood, e.g., their function, architecture, kd. Hydropathy analysis reveals 14 putative membrane spanmembrane insertion, expression, and subcellular localization. ning segments. In addition, new insights into the cell biology of hepatocelluMdr transporters, synonym P-glycoproteins, were discovlar membrane transport were obtained, including transport ered as plasma membrane transport ATPases that are overregulation by signal-transduction cascades and the involve-expressed in multidrug-resistant tumor cells. Mdr2 is a phosment of transport systems in pH homeostasis and cell volume pholipid translocator, whereas mdr1 and mdr3 confer the regulation. These items were the topics of the 2nd Interna-transport of drugs into bile. S. Ruetz (Montréal, Quebec, Cantional Ringberg Conference on ''Cell Biology and Molecular ada) presented results regarding the detailed characterizaBasis of Liver Transport.'' tion of mdr2-mediated phosphatidylcholine (PC) translocation in the canalicular membrane. Yeast mutants of the sec BIOCHEMISTRY AND MOLECULAR BIOLOGY6-4 strain, which expressed the mdr2 protein in the mem- OF TRANSPORTbrane of yeast secretory vesicles, were generated. By use of the fluorescent PC label 7-nitrobenzoxa-1,3-diazol phosphatiThe recent discovery of canalicular primary active trans-dylcholine, he finds that the mdr2 protein translocates specifport systems that are involved in the vectorial transport of ically PC but not phosphatidylethanolamine or phosphatidylcholephilic compounds into bile has markedly stimulated the serine from the outer leaflet to the inner leaflet of the vesicles. understanding of bile formation. Previous to this era, the This translocation is affected by vanadate and verapamil, but adenosine triphosphatase (ATPase) activity of canalicular it is insensitive to vesicle acidification or membrane depolarmembranes was mainly attributed to a Ca 2/ Mg 2/ -ATPase, ization. 3 When the vesicles accumulate taurocholate, PC an ectoenzyme cloned in 1989 by Lin and Guidotti. 1 As re-translocation is stimulated. Fifty micromoles of the bile acid viewed by I. M. Arias (Boston, MA), these enzymes degrade can act as a potential lipid solubilizer, extracting 7-nitroextracellular (intraluminal) adenosine triphosphate (ATP) to benzoxa-1,3-diazol phosphatidylcholine molecules from the adenosine diphosp...

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In situ localization of the hepatocytic na+/taurocholate cotransporting polypeptide in rat liver

Cited by 206 publications

References 17 publications

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

Second International Ringberg Conference: ?Cell Biology and Molecular Basis of Liver Transport?

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