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Glycine‐β‐muricholic acid antagonizes the intestinal farnesoid X receptor–ceramide axis and ameliorates NASH in mice
Nonalcoholic steatohepatitis (NASH) is a rapidly developing pathology around the world, with limited treatment options available. Some farnesoid X receptor (FXR) agonists have been applied in clinical trials for NASH, but side effects such as pruritus and low‐density lipoprotein elevation have been...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9701488/ https://www.ncbi.nlm.nih.gov/pubmed/36196594 http://dx.doi.org/10.1002/hep4.2099 |
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author | Jiang, Jie Ma, Yuandi Liu, Yameng Lu, Dasheng Gao, Xiaoxia Krausz, Kristopher W. Desai, Dhimant Amin, Shantu G. Patterson, Andrew D. Gonzalez, Frank J. Xie, Cen |
author_facet | Jiang, Jie Ma, Yuandi Liu, Yameng Lu, Dasheng Gao, Xiaoxia Krausz, Kristopher W. Desai, Dhimant Amin, Shantu G. Patterson, Andrew D. Gonzalez, Frank J. Xie, Cen |
author_sort | Jiang, Jie |
collection | PubMed |
description | Nonalcoholic steatohepatitis (NASH) is a rapidly developing pathology around the world, with limited treatment options available. Some farnesoid X receptor (FXR) agonists have been applied in clinical trials for NASH, but side effects such as pruritus and low‐density lipoprotein elevation have been reported. Intestinal FXR is recognized as a promising therapeutic target for metabolic diseases. Glycine‐β‐muricholic acid (Gly‐MCA) is an intestine‐specific FXR antagonist previously shown to have favorable metabolic effects on obesity and insulin resistance. Herein, we identify a role for Gly‐MCA in the pathogenesis of NASH, and explore the underlying molecular mechanism. Gly‐MCA improved lipid accumulation, inflammatory response, and collagen deposition in two different NASH models. Mechanistically, Gly‐MCA decreased intestine‐derived ceramides by suppressing ceramide synthesis–related genes via decreasing intestinal FXR signaling, leading to lower liver endoplasmic reticulum (ER) stress and proinflammatory cytokine production. The role of bile acid metabolism and adiposity was excluded in the suppression of NASH by Gly‐MCA, and a correlation was found between intestine‐derived ceramides and NASH severity. This study revealed that Gly‐MCA, an intestine‐specific FXR antagonist, has beneficial effects on NASH by reducing ceramide levels circulating to liver via lowering intestinal FXR signaling, and ceramide production, followed by decreased liver ER stress and NASH progression. Intestinal FXR is a promising drug target and Gly‐MCA a novel agent for the prevention and treatment of NASH. |
format | Online Article Text |
id | pubmed-9701488 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97014882022-11-28 Glycine‐β‐muricholic acid antagonizes the intestinal farnesoid X receptor–ceramide axis and ameliorates NASH in mice Jiang, Jie Ma, Yuandi Liu, Yameng Lu, Dasheng Gao, Xiaoxia Krausz, Kristopher W. Desai, Dhimant Amin, Shantu G. Patterson, Andrew D. Gonzalez, Frank J. Xie, Cen Hepatol Commun Original Articles Nonalcoholic steatohepatitis (NASH) is a rapidly developing pathology around the world, with limited treatment options available. Some farnesoid X receptor (FXR) agonists have been applied in clinical trials for NASH, but side effects such as pruritus and low‐density lipoprotein elevation have been reported. Intestinal FXR is recognized as a promising therapeutic target for metabolic diseases. Glycine‐β‐muricholic acid (Gly‐MCA) is an intestine‐specific FXR antagonist previously shown to have favorable metabolic effects on obesity and insulin resistance. Herein, we identify a role for Gly‐MCA in the pathogenesis of NASH, and explore the underlying molecular mechanism. Gly‐MCA improved lipid accumulation, inflammatory response, and collagen deposition in two different NASH models. Mechanistically, Gly‐MCA decreased intestine‐derived ceramides by suppressing ceramide synthesis–related genes via decreasing intestinal FXR signaling, leading to lower liver endoplasmic reticulum (ER) stress and proinflammatory cytokine production. The role of bile acid metabolism and adiposity was excluded in the suppression of NASH by Gly‐MCA, and a correlation was found between intestine‐derived ceramides and NASH severity. This study revealed that Gly‐MCA, an intestine‐specific FXR antagonist, has beneficial effects on NASH by reducing ceramide levels circulating to liver via lowering intestinal FXR signaling, and ceramide production, followed by decreased liver ER stress and NASH progression. Intestinal FXR is a promising drug target and Gly‐MCA a novel agent for the prevention and treatment of NASH. John Wiley and Sons Inc. 2022-10-05 /pmc/articles/PMC9701488/ /pubmed/36196594 http://dx.doi.org/10.1002/hep4.2099 Text en © 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Jiang, Jie Ma, Yuandi Liu, Yameng Lu, Dasheng Gao, Xiaoxia Krausz, Kristopher W. Desai, Dhimant Amin, Shantu G. Patterson, Andrew D. Gonzalez, Frank J. Xie, Cen Glycine‐β‐muricholic acid antagonizes the intestinal farnesoid X receptor–ceramide axis and ameliorates NASH in mice |
title | Glycine‐β‐muricholic acid antagonizes the intestinal farnesoid X receptor–ceramide axis and ameliorates NASH in mice |
title_full | Glycine‐β‐muricholic acid antagonizes the intestinal farnesoid X receptor–ceramide axis and ameliorates NASH in mice |
title_fullStr | Glycine‐β‐muricholic acid antagonizes the intestinal farnesoid X receptor–ceramide axis and ameliorates NASH in mice |
title_full_unstemmed | Glycine‐β‐muricholic acid antagonizes the intestinal farnesoid X receptor–ceramide axis and ameliorates NASH in mice |
title_short | Glycine‐β‐muricholic acid antagonizes the intestinal farnesoid X receptor–ceramide axis and ameliorates NASH in mice |
title_sort | glycine‐β‐muricholic acid antagonizes the intestinal farnesoid x receptor–ceramide axis and ameliorates nash in mice |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9701488/ https://www.ncbi.nlm.nih.gov/pubmed/36196594 http://dx.doi.org/10.1002/hep4.2099 |
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