Perfluoroalkyl Carboxylic Acids Interact with the Human Bile Acid Transporter NTCP

Na+/taurocholate cotransporting polypeptide (NTCP) is important for the enterohepatic circulation of bile acids, which has been suggested to contribute to the long serum elimination half-lives of perfluoroalkyl substances in humans. We demonstrated that some perfluoroalkyl sulfonates are transported by NTCP; however, little was known about carboxylates. The purpose of this study was to determine if perfluoroalkyl carboxylates would interact with NTCP and potentially act as substrates. Sodium-dependent transport of [3H]-taurocholate was measured in human embryonic kidney cells (HEK293) stably expressing NTCP in the absence or presence of perfluoroalkyl carboxylates with varying chain lengths. PFCAs with 8 (PFOA), 9 (PFNA), and 10 (PFDA) carbons were the strongest inhibitors. Inhibition kinetics demonstrated competitive inhibition and indicated that PFNA was the strongest inhibitor followed by PFDA and PFOA. All three compounds are transported by NTCP, and kinetics experiments revealed that PFOA had the highest affinity for NTCP with a Km value of 1.8 ± 0.4 mM. The Km value PFNA was estimated to be 5.3 ± 3.5 mM and the value for PFDA could not be determined due to limited solubility. In conclusion, our results suggest that, in addition to sulfonates, perfluorinated carboxylates are substrates of NTCP and have the potential to interact with NTCP-mediated transport.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00308.2020 ◽

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.

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Recent advances in understanding and managing cholestasis

F1000Research ◽

10.12688/f1000research.8012.1 ◽

2016 ◽

Vol 5 ◽

pp. 705 ◽

Cited By ~ 27

Author(s):

Martin Wagner ◽

Michael Trauner

Keyword(s):

Bile Acids ◽

Drug Targets ◽

Molecular Mechanisms ◽

Enterohepatic Circulation ◽

Farnesoid X Receptor ◽

Regulatory Mechanisms ◽

Cholestatic Liver Disease ◽

Sodium Dependent ◽

Bile Acid Transporter ◽

Fibroblast Growth Factor 19

Cholestatic liver diseases are hereditary or acquired disorders with impaired hepatic excretion and enterohepatic circulation of bile acids and other cholephiles. The distinct pathological mechanisms, particularly for the acquired forms of cholestasis, are not fully revealed, but advances in the understanding of the molecular mechanisms and identification of key regulatory mechanisms of the enterohepatic circulation of bile acids have unraveled common and central mechanisms, which can be pharmacologically targeted. This overview focuses on the central roles of farnesoid X receptor, fibroblast growth factor 19, and apical sodium-dependent bile acid transporter for the enterohepatic circulation of bile acids and their potential as new drug targets for the treatment of cholestatic liver disease.

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Substrate binding in the bile acid transporter ASBTYf from Yersinia frederiksenii

Acta Crystallographica Section D Structural Biology ◽

10.1107/s2059798320015004 ◽

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

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20206603185 ◽

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.

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