scholarly journals The ileal bile acid transporter inhibitor A4250 decreases serum bile acids by interrupting the enterohepatic circulation

2015 ◽  
Vol 43 (2) ◽  
pp. 303-310 ◽  
Author(s):  
H. Graffner ◽  
P.-G. Gillberg ◽  
L. Rikner ◽  
H.-U. Marschall
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Enterohepatic Circulation ◽  
Serum Bile Acids ◽  
Bile Acid Transporter ◽  
Acid Transporter

scholarly journals The inhibitors of the apical sodium-dependent bile acid transporter (ASBT) as promising drugs

2020 ◽  
Vol 66 (3) ◽  
pp. 185-195
Author(s):  
E.E. Saveleva ◽  
E.S. Tyutrina ◽  
T. Nakanishi ◽  
I. Tamai ◽  
A.B. Salmina
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Enterohepatic Circulation ◽  
Alcoholic Fatty Liver ◽  
Good Tolerance ◽  
Current Trends ◽  
Sodium Dependent ◽  
Bile Acid Transporter ◽  
Acid Transporter

Inhibition of the apical sodium-dependent bile acid transporter (ASBT, also known as IBAT — ileal bile acid transporter, SLC10A2) leads to disruption of the enterohepatic circulation of bile acids and their excretion with fecal masses. This is accompanied by cholesterol utilization for synthesis of new bile acids. ASBT inhibitors are promising drugs for the treatment of such diseases as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, type 2 diabetes mellitus, necrotic enterocolitis, chronic constipation, atherosclerosis. To date the most known chemically synthesized inhibitors are: A3309, SHP626, A4250, 264W94, GSK2330672, SC-435. All of them are at different stages of clinical trials, which confirm the high efficacy and good tolerance of these inhibitors. Current trends in this field also include directed chemical synthesis of ASBT inhibitors, as well as their search among substances of plant origin.

scholarly journals Metabolic consequences of ileal interruption of the enterohepatic circulation of bile acids

2020 ◽  
Vol 319 (5) ◽  
pp. G619-G625
Author(s):  
Ivo P. van de Peppel ◽  
Henkjan J. Verkade ◽  
Johan W. Jonker
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Enterohepatic Circulation ◽  
Current Knowledge ◽  
Whole Body ◽  
Novel Studies ◽  
Sodium Dependent ◽  
Bile Acid Transporter ◽  
Bile Acid Secretion ◽  
Different Levels

The enterohepatic circulation of bile acids comprises a tightly regulated process of hepatic bile acid secretion, intestinal reabsorption and transport back to the liver. Disruption of this process has significant consequences for gastrointestinal, liver and whole body homeostasis and therefore offers opportunities for therapeutic intervention. In this review we discuss the effects of (pharmacological) interruption of the enterohepatic circulation at different levels. Recently, several studies have been published on ileal interruption of the enterohepatic circulation of bile acids, targeting the apical-sodium dependent bile acid transporter (ASBT, SLC10A2), as therapy for various diseases. However, ambiguous results have been reported and in-depth mechanistic insights are lacking. Here we discuss these novel studies and review the current knowledge on the consequences of ASBT inhibition and its potential effects on physiology and metabolism.

Sa1715 ELOBIXIBAT, ILEAL BILE ACID TRANSPORTER INHIBITOR, INCREASES FECAL BILE ACIDS IN PATIENTS WITH CHRONIC CONSTIPATION

2020 ◽  
Vol 158 (6) ◽  
pp. S-394-S-395
Author(s):  
Atsushi Nakajima ◽  
Sonoko Ishizaki ◽  
Shinsuke Kurosu ◽  
Shinya Taniguchi ◽  
Per-Göran Gillberg ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Chronic Constipation ◽  
Fecal Bile Acids ◽  
Bile Acid Transporter ◽  
Acid Transporter

Effect of cholestasis on ileal absorption of bile acids and on ileal bile acid transporter in rat

1998 ◽  
Vol 114 ◽  
pp. A1334
Author(s):  
P. Sauer ◽  
A. Stiehl ◽  
P. Kloeters-Plachky ◽  
BA Fitscher ◽  
HD Riedel ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Bile Acid Transporter ◽  
Ileal Absorption ◽  
Acid Transporter

Electrostatic and potential cation-π forces may guide the interaction of extracellular loop III with Na+ and bile acids for human apical Na+-dependent bile acid transporter

2008 ◽  
Vol 410 (2) ◽  
pp. 391-400 ◽  
Author(s):  
Antara Banerjee ◽  
Naissan Hussainzada ◽  
Akash Khandelwal ◽  
Peter W. Swaan
Keyword(s):  
Amino Acids ◽  
Bile Acid ◽  
Bile Acids ◽  
Conformational Changes ◽  
Electrostatic Interactions ◽  
Extracellular Loop ◽  
Membrane Expression ◽  
Ligand Interaction ◽  
Bile Acid Transporter ◽  
Acid Transporter

The hASBT (human apical Na+-dependent bile acid transporter) constitutes a key target of anti-hypercholesterolaemic therapies and pro-drug approaches; physiologically, hASBT actively reclaims bile acids along the terminal ileum via Na+ co-transport. Previously, TM (transmembrane segment) 7 was identified as part of the putative substrate permeation pathway using SCAM (substitute cysteine accessibility mutagenesis). In the present study, SCAM was extended through EL3 (extracellular loop 3; residues Arg254–Val286) that leads into TM7 from the exofacial matrix. Activity of most EL3 mutants was significantly hampered upon cysteine substitution, whereas ten (out of 31) were functionally inactive (<10% activity). Since only E282C lacked plasma membrane expression, EL3 amino acids predominantly fulfill critical functional roles during transport. Oppositely charged membrane-impermeant MTS (methanethiosulfonate) reagents {MTSET [(2-trimethylammonium) ethyl MTS] and MTSES [(2-sulfonatoethyl) MTS]} produced mostly similar inhibition profiles wherein only middle and descending loop segments (residues Thr267–Val286) displayed significant MTS sensitivity. The presence of bile acid substrate significantly reduced the rates of MTS modification for all MTS-sensitive mutants, suggesting a functional association between EL3 residues and bile acids. Activity assessments at equilibrative [Na+] revealed numerous Na+-sensitive residues, possibly performing auxiliary functions during transport such as transduction of protein conformational changes during translocation. Integration of these data suggests ligand interaction points along EL3 via electrostatic interactions with Arg256, Glu261 and probably Glu282 and a potential cation-π interaction with Phe278. We conclude that EL3 amino acids are essential for hASBT activity, probably as primary substrate interaction points using long-range electrostatic attractive forces.

scholarly journals A novel bioluminescence-based method to investigate uptake of bile acids in living cells

2018 ◽  
Vol 315 (4) ◽  
pp. G529-G537 ◽  
Author(s):  
Alexander L. Ticho ◽  
Hyunjin Lee ◽  
Ravinder K. Gill ◽  
Pradeep K. Dudeja ◽  
Seema Saksena ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Real Time ◽  
Sodium Taurocholate ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Bile Acid Transporters ◽  
Sodium Dependent ◽  
Bile Acid Transporter ◽  
Acid Transporter

Bile acid transporters, including the ileal apical sodium-dependent bile acid transporter (ASBT) and the hepatic sodium-taurocholate cotransporting polypeptide (NTCP), are crucial for the enterohepatic circulation of bile acids. Our objective was to develop a method for measuring bile acid transporter activity in real time to precisely evaluate rapid changes in their function. We designed a reporter system relying on a novel probe: cholic acid attached to luciferin via a disulfide-containing, self-immolating linker (CA-SS-Luc). Incubation of human embryonic kidney-293 cells coexpressing luciferase and ASBT with different concentrations of CA-SS-Luc (0.01–1 μM) resulted in bioluminescence with an intensity that was concentration- and time-dependent. The bioluminescence measured during incubation with 1 μM CA-SS-Luc was dependent on the levels of ASBT or NTCP expressed in the cells. Coincubation of CA-SS-Luc with natural bile acids enhanced the bioluminescence in a concentration-dependent manner with kinetic parameters for ASBT similar to those previously reported using conventional methods. These findings suggest that this method faithfully assesses ASBT function. Further, incubation with tyrosine phosphatase inhibitor III (PTPIII) led to significantly increased bioluminescence in cells expressing ASBT, consistent with previous studies showing an increase in ASBT function by PTPIII. We then investigated CA-SS-Luc in isolated mouse intestinal epithelial cells. Ileal enterocytes displayed significantly higher luminescence compared with jejunal enterocytes, indicating a transport process mediated by ileal ASBT. In conclusion, we have developed a novel method to monitor the activity of bile acid transporters in real time that has potential applications both for in vitro and in vivo studies.NEW & NOTEWORTHY This article reports the development of a real-time method for measuring the uptake of bile acids using a bioluminescent bile acid-based probe. This method has been validated for measuring uptake via the apical sodium-dependent bile acid transporter and the sodium-taurocholate cotransporting polypeptide in cell culture and ex vivo intestinal models.

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