scholarly journals Hepatic uptake of conjugated bile acids is mediated by both sodium taurocholate cotransporting polypeptide and organic anion transporting polypeptides and modulated by intestinal sensing of plasma bile acid levels in mice

Hepatology ◽  
2017 ◽  
Vol 66 (5) ◽  
pp. 1631-1643 ◽  
Author(s):  
Davor Slijepcevic ◽  
Reinout L.P. Roscam Abbing ◽  
Takeshi Katafuchi ◽  
Antje Blank ◽  
Joanne M. Donkers ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Organic Anion ◽  
Sodium Taurocholate ◽  
Hepatic Uptake ◽  
Organic Anion Transporting Polypeptides ◽  
Conjugated Bile Acids

scholarly journals Bile Acid Uptake Transporters as Targets for Therapy

2017 ◽  
Vol 35 (3) ◽  
pp. 251-258 ◽  
Author(s):  
Davor Slijepcevic ◽  
Stan F.J. van de Graaf
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Energy Homeostasis ◽  
Sodium Taurocholate ◽  
Hepatic Uptake ◽  
Farnesoid X Receptor ◽  
Acid Uptake ◽  
Bile Acid Uptake ◽  
Uptake Transporters ◽  
Conjugated Bile Acids

Background: Bile acids are potent signaling molecules that regulate glucose, lipid and energy homeostasis predominantly via the bile acid receptors farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor 5 (TGR5). The sodium taurocholate cotransporting polypeptide (NTCP) and the apical sodium dependent bile acid transporter (ASBT) ensure an effective circulation of (conjugated) bile acids. The modulation of these transport proteins affects bile acid localization, dynamics and signaling. The NTCP-specific pharmacological inhibitor myrcludex B inhibits hepatic uptake of conjugated bile acids. Multiple ASBT-inhibitors are already in clinical trials to inhibit intestinal bile acid uptake. Here, we discuss current insights into the consequences of targeting bile acid uptake transporters on systemic and intestinal bile acid dynamics and discuss the possible therapeutic applications that evolve as a result.

scholarly journals Heterogeneous accumulation of fluorescent bile acids in primary rat hepatocytes does not correlate with their homogenous expression of ntcp

2011 ◽  
Vol 301 (1) ◽  
pp. G60-G68 ◽  
Author(s):  
John W. Murray ◽  
Amar J. Thosani ◽  
Pijun Wang ◽  
Allan W. Wolkoff
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Hela Cells ◽  
Organic Anion ◽  
Fluorescent Microscopy ◽  
Sodium Taurocholate ◽  
Rat Hepatocytes ◽  
Acid Uptake ◽  
Anion Transporter ◽  
Acid Accumulation

Sodium taurocholate-cotransporting polypeptide (ntcp) is considered to be a major determinant of bile acid uptake into hepatocytes. However, the regulation of ntcp and the degree that it participates in the accumulation of specific substrates are not well understood. We utilized fluorescent bile acid derivatives and direct quantitation of fluorescent microscopy images to examine the regulation of ntcp and its role in the cell-to-cell variability of fluorescent bile acid accumulation. Primary-cultured rat hepatocytes rapidly accumulated the fluorescent bile acids, chenodeoxycholylglycylamidofluorescein (CDCGamF), 7-β- nitrobenzoxadiazole 3-α hydroxy 5-β cholan-24-oic acid (NBD-CA), and cholyl-glycylamido-fluorescein (CGamF). However, in stably transfected HeLa cells, ntcp preferred CDCGamF, whereas the organic anion transporter, organic anion transporting polypeptide 1 (oatp1a1), preferred NBD-CA, and neither ntcp nor oatp1a1 showed strong accumulation of CGamF by these methods. Ntcp-mediated transport of CDCGamF was inhibited by taurocholate, cyclosporin, actin depolymerization, and an inhibitor of atypical PKC-ζ. The latter two agents altered the cellular distribution of ntcp as visualized in ntcp-green fluorescent protein-transfected cells. Although fluorescent bile acid accumulation was reproducible by the imaging assays, individual cells showed variable accumulation that was not attributable to changes in membrane permeability or cell viability. In HeLa cells, this was accounted for by variable levels of ntcp, whereas, in hepatocytes, ntcp expression was uniform, and low accumulation was seen in a large portion of cells despite the presence of ntcp. These studies indicate that single-cell imaging can provide insight into previously unrecognized details of anion transport in the complex environment of polarized hepatocytes.

scholarly journals Evaluating Hepatobiliary Transport with 18F-Labeled Bile Acids: The Effect of Radiolabel Position and Bile Acid Structure on Radiosynthesis and In Vitro and In Vivo Performance

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Stef De Lombaerde ◽  
Ken Kersemans ◽  
Sara Neyt ◽  
Jeroen Verhoeven ◽  
Christian Vanhove ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Membrane Vesicles ◽  
Hepatic Uptake ◽  
Hepatobiliary Transport ◽  
Bile Acid Transporters ◽  
Significant Difference ◽  
The Impact

Introduction. An in vivo determination of bile acid hepatobiliary transport efficiency can be of use in liver disease and preclinical drug development. Given the increased interest in bile acid Positron Emission Tomography- (PET-) imaging, a further understanding of the impact of 18-fluorine substitution on bile acid handling in vitro and in vivo can be of significance. Methods. A number of bile acid analogues were conceived for nucleophilic substitution with [18F]fluoride: cholic acid analogues of which the 3-, 7-, or 12-OH function is substituted with a fluorine atom (3α-[18F]FCA; 7β-[18F]FCA; 12β-[18F]FCA); a glycocholic and chenodeoxycholic acid analogue, substituted on the 3-position (3β-[18F]FGCA and 3β-[18F]FCDCA, resp.). Uptake by the bile acid transporters NTCP and OATP1B1 was evaluated with competition assays in transfected CHO and HEK cell lines and efflux by BSEP in membrane vesicles. PET-scans with the tracers were performed in wild-type mice (n=3 per group): hepatobiliary transport was monitored and compared to a reference tracer, namely, 3β-[18F]FCA. Results. Compounds 3α-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA were synthesized in moderate radiochemical yields (4–10% n.d.c.) and high radiochemical purity (>99%); 7β-[18F]FCA and 12β-[18F]FCA could not be synthesized and included further in this study. In vitro evaluation showed that 3α-FCA, 3β-FGCA, and 3β-FCDCA all had a low micromolar Ki-value for NTCP, OATP1B1, and BSEP. In vivo, 3α-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA displayed hepatobiliary transport with varying efficiency. A slight yet significant difference in uptake and efflux rate was noticed between the 3α-[18F]FCA and 3β-[18F]FCA epimers. Conjugation of 3β-[18F]FCA with glycine had no significant effect in vivo. Compound 3β-[18F]FCDCA showed a significantly slower hepatic uptake and efflux towards gallbladder and intestines. Conclusion. A set of 18F labeled bile acids was synthesized that are substrates of the bile acid transporters in vitro and in vivo and can serve as PET-biomarkers for hepatobiliary transport of bile acids.

Interaction of bumetanide derivatives with hepatocellular bile acid uptake

1993 ◽  
Vol 265 (5) ◽  
pp. G942-G954
Author(s):  
E. Petzinger ◽  
W. Follmann ◽  
M. Blumrich ◽  
R. Schermuly ◽  
S. Schulz ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Model Building ◽  
Organic Anion ◽  
Rat Hepatocytes ◽  
Salt Transport ◽  
Acid Uptake ◽  
Ligand Interaction ◽  
Isolated Rat Hepatocytes ◽  
Bile Acid Uptake

The loop diuretic bumetanide is an organic monocarboxylic organic anion assumed to be transported into hepatocytes by a transport system for bile acids. The structural requirements of 22 bumetanide analogues were analyzed for an interaction with bile acid uptake into isolated rat hepatocytes. Whereas bumetanide inhibited the hepatocellular uptake of [14C]cholate to the same degree as its own uptake, derivatization altered affinity and specificity and yielded compounds that selectively inhibited either cholate or taurocholate uptake or uptake of both. No correlation was found between the diuretic potency of bumetanide derivatives, reflecting the affinity to the Na(+)-K(+)-Cl- cotransporter, and their affinity to hepatic bile salt transport. Computer-aided model building combined with the calculation of potential energy maps showed a strictly amphipathic charge separation in bumetanide analogues as in bile acids. Ranking bumetanide compounds by their mean inhibitory concentration values, inhibition constants, and their type of competition, we conclude that at least three binding domains in the proteins are essential for recognition by bile acid transporters, namely two hydrophobic and an anionic side, and that for the anionic binding region a carbonyl atom in the ligands as an electron donor group is sufficient for ligand interaction.

Bile Acid Synthesis in the Developing Sheep Liver

1973 ◽  
Vol 45 (3) ◽  
pp. 403-406
Author(s):  
R. A. Smallwood ◽  
P. Jablonski ◽  
J. McK. Watts
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Placental Transfer ◽  
Umbilical Vein ◽  
Acid Synthesis ◽  
Taurocholic Acid ◽  
Secondary Bile Acid ◽  
Radioactive Label ◽  
Sheep Liver ◽  
Conjugated Bile Acids

1. [14C]Cholesterol was administered intravenously via the umbilical vein to foetal sheep in the latter half of gestation, and the incorporation of radioactive label into foetal bile acids was assessed. 2. After 4 days, 0·5–2% of the radioactive label was found in foetal bile. Seventy to eighty per cent of the radioactive label in foetal bile was present as [14C]taurocholic acid and [14C]taurochenodeoxycholic acid. The remainder was [14C]cholesterol. No radioactive label was found in taurodeoxycholic acid, or in any of the glycine-conjugated bile acids. 3. It is concluded that the foetal sheep liver in the second half of gestation synthesizes taurocholic acid and taurochenodeoxycholic acid. However, the secondary bile acid taurodeoxycholic acid and the glycine-conjugated bile acids, present in foetal bile, have been acquired by placental transfer from the mother.

Involvement of Organic Anion-Transporting Polypeptides in the Hepatic Uptake of Dioscin in Rats and Humans

2013 ◽  
Vol 41 (5) ◽  
pp. 994-1003 ◽  
Author(s):  
Aijie Zhang ◽  
Changyuan Wang ◽  
Qi Liu ◽  
Qiang Meng ◽  
Jinyong Peng ◽  
...  
Keyword(s):  
Organic Anion ◽  
Hepatic Uptake ◽  
Organic Anion Transporting Polypeptides

scholarly journals Organic anion transporting polypeptides in the hepatic uptake of PBDE congeners in mice

2011 ◽  
Vol 257 (1) ◽  
pp. 23-31 ◽  
Author(s):  
Erik Pacyniak ◽  
Bruno Hagenbuch ◽  
Curtis D. Klaassen ◽  
Lois Lehman-McKeeman ◽  
Grace L. Guo
Keyword(s):  
Organic Anion ◽  
Hepatic Uptake ◽  
Organic Anion Transporting Polypeptides
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