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.

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.

scholarly journals Inhibition Requirements of the Human Apical Sodium-Dependent Bile Acid Transporter (hASBT) Using Aminopiperidine Conjugates of glutamyl-Bile Acids

2009 ◽  
Vol 26 (7) ◽  
pp. 1665-1678 ◽  
Author(s):  
Pablo M. González ◽  
Chayan Acharya ◽  
Alexander D. MacKerell ◽  
James E. Polli
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Sodium Dependent ◽  
Bile Acid Transporter ◽  
Acid Transporter

Substrate binding in the bile acid transporter ASBTYf from Yersinia frederiksenii

2021 ◽  
Vol 77 (1) ◽  
pp. 117-125
Author(s):  
Xiaodong Wang ◽  
Ying Lyu ◽  
Yujia Ji ◽  
Ziyi Sun ◽  
Xiaoming Zhou
Keyword(s):  
Bile Acid ◽  
Enterohepatic Circulation ◽  
Substrate Binding ◽  
Central Cavity ◽  
Neisseria Meningitides ◽  
Transport Cycle ◽  
Sodium Dependent ◽  
Bile Acid Transporter ◽  
Acid Transporter ◽  
Alternating Access

Apical sodium-dependent bile acid transporter (ASBT) retrieves bile acids from the small intestine and plays a pivotal role in enterohepatic circulation. Currently, high-resolution structures are available for two bacterial ASBT homologs (ASBTNM from Neisseria meningitides and ASBTYf from Yersinia frederiksenii), from which an elevator-style alternating-access mechanism has been proposed for substrate transport. A key concept in this model is that the substrate binds to the central cavity of the transporter so that the elevator-like motion can expose the bound substrate alternatingly to either side of the membrane during a transport cycle. However, no structure of an ASBT has been solved with a substrate bound in its central cavity, so how a substrate binds to ASBT remains to be defined. In this study, molecular docking, structure determination and functional analysis were combined to define and validate the details of substrate binding in ASBTYf. The findings provide coherent evidence to provide a clearer picture of how the substrate binds in the central cavity of ASBTYf that fits the alternating-access model.

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