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Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice
The pronounced choleretic properties of 24-norUrsodeoxycholic acid (norUDCA) to induce bicarbonate-rich bile secretion have been attributed to its ability to undergo cholehepatic shunting. The goal of this study was to identify the mechanisms underlying the choleretic actions of norUDCA and the role...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070106/ https://www.ncbi.nlm.nih.gov/pubmed/36787187 http://dx.doi.org/10.1172/jci.insight.149360 |
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author | Truong, Jennifer K. Li, Jianing Li, Qin Pachura, Kimberly Rao, Anuradha Gumber, Sanjeev Fuchs, Claudia Daniela Feranchak, Andrew P. Karpen, Saul J. Trauner, Michael Dawson, Paul A. |
author_facet | Truong, Jennifer K. Li, Jianing Li, Qin Pachura, Kimberly Rao, Anuradha Gumber, Sanjeev Fuchs, Claudia Daniela Feranchak, Andrew P. Karpen, Saul J. Trauner, Michael Dawson, Paul A. |
author_sort | Truong, Jennifer K. |
collection | PubMed |
description | The pronounced choleretic properties of 24-norUrsodeoxycholic acid (norUDCA) to induce bicarbonate-rich bile secretion have been attributed to its ability to undergo cholehepatic shunting. The goal of this study was to identify the mechanisms underlying the choleretic actions of norUDCA and the role of the bile acid transporters. Here, we show that the apical sodium-dependent bile acid transporter (ASBT), organic solute transporter-α (OSTα), and organic anion transporting polypeptide 1a/1b (OATP1a/1b) transporters are dispensable for the norUDCA stimulation of bile flow and biliary bicarbonate secretion. Chloride channels in biliary epithelial cells provide the driving force for biliary secretion. In mouse large cholangiocytes, norUDCA potently stimulated chloride currents that were blocked by siRNA silencing and pharmacological inhibition of calcium-activated chloride channel transmembrane member 16A (TMEM16A) but unaffected by ASBT inhibition. In agreement, blocking intestinal bile acid reabsorption by coadministration of an ASBT inhibitor or bile acid sequestrant did not impact norUDCA stimulation of bile flow in WT mice. The results indicate that these major bile acid transporters are not directly involved in the absorption, cholehepatic shunting, or choleretic actions of norUDCA. Additionally, the findings support further investigation of the therapeutic synergy between norUDCA and ASBT inhibitors or bile acid sequestrants for cholestatic liver disease. |
format | Online Article Text |
id | pubmed-10070106 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-100701062023-04-05 Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice Truong, Jennifer K. Li, Jianing Li, Qin Pachura, Kimberly Rao, Anuradha Gumber, Sanjeev Fuchs, Claudia Daniela Feranchak, Andrew P. Karpen, Saul J. Trauner, Michael Dawson, Paul A. JCI Insight Research Article The pronounced choleretic properties of 24-norUrsodeoxycholic acid (norUDCA) to induce bicarbonate-rich bile secretion have been attributed to its ability to undergo cholehepatic shunting. The goal of this study was to identify the mechanisms underlying the choleretic actions of norUDCA and the role of the bile acid transporters. Here, we show that the apical sodium-dependent bile acid transporter (ASBT), organic solute transporter-α (OSTα), and organic anion transporting polypeptide 1a/1b (OATP1a/1b) transporters are dispensable for the norUDCA stimulation of bile flow and biliary bicarbonate secretion. Chloride channels in biliary epithelial cells provide the driving force for biliary secretion. In mouse large cholangiocytes, norUDCA potently stimulated chloride currents that were blocked by siRNA silencing and pharmacological inhibition of calcium-activated chloride channel transmembrane member 16A (TMEM16A) but unaffected by ASBT inhibition. In agreement, blocking intestinal bile acid reabsorption by coadministration of an ASBT inhibitor or bile acid sequestrant did not impact norUDCA stimulation of bile flow in WT mice. The results indicate that these major bile acid transporters are not directly involved in the absorption, cholehepatic shunting, or choleretic actions of norUDCA. Additionally, the findings support further investigation of the therapeutic synergy between norUDCA and ASBT inhibitors or bile acid sequestrants for cholestatic liver disease. American Society for Clinical Investigation 2023-03-22 /pmc/articles/PMC10070106/ /pubmed/36787187 http://dx.doi.org/10.1172/jci.insight.149360 Text en © 2023 Truong et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Truong, Jennifer K. Li, Jianing Li, Qin Pachura, Kimberly Rao, Anuradha Gumber, Sanjeev Fuchs, Claudia Daniela Feranchak, Andrew P. Karpen, Saul J. Trauner, Michael Dawson, Paul A. Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice |
title | Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice |
title_full | Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice |
title_fullStr | Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice |
title_full_unstemmed | Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice |
title_short | Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice |
title_sort | active enterohepatic cycling is not required for the choleretic actions of 24-norursodeoxycholic acid in mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070106/ https://www.ncbi.nlm.nih.gov/pubmed/36787187 http://dx.doi.org/10.1172/jci.insight.149360 |
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