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The role of FXR and TGR5 in reversing and preventing progression of Western diet–induced hepatic steatosis, inflammation, and fibrosis in mice
Nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease in the US, partly due to the increasing incidence of metabolic syndrome, obesity, and type 2 diabetes. The roles of bile acids and their receptors, such as the nuclear receptor farnesoid X receptor (FXR) and the G protein-c...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9638804/ https://www.ncbi.nlm.nih.gov/pubmed/36209823 http://dx.doi.org/10.1016/j.jbc.2022.102530 |
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author | Wang, Xiaoxin X. Xie, Cen Libby, Andrew E. Ranjit, Suman Levi, Jonathan Myakala, Komuraiah Bhasin, Kanchan Jones, Bryce A. Orlicky, David J. Takahashi, Shogo Dvornikov, Alexander Kleiner, David E. Hewitt, Stephen M. Adorini, Luciano Kopp, Jeffrey B. Krausz, Kristopher W. Rosenberg, Avi McManaman, James L. Robertson, Charles E. Ir, Diana Frank, Daniel N. Luo, Yuhuan Gonzalez, Frank J. Gratton, Enrico Levi, Moshe |
author_facet | Wang, Xiaoxin X. Xie, Cen Libby, Andrew E. Ranjit, Suman Levi, Jonathan Myakala, Komuraiah Bhasin, Kanchan Jones, Bryce A. Orlicky, David J. Takahashi, Shogo Dvornikov, Alexander Kleiner, David E. Hewitt, Stephen M. Adorini, Luciano Kopp, Jeffrey B. Krausz, Kristopher W. Rosenberg, Avi McManaman, James L. Robertson, Charles E. Ir, Diana Frank, Daniel N. Luo, Yuhuan Gonzalez, Frank J. Gratton, Enrico Levi, Moshe |
author_sort | Wang, Xiaoxin X. |
collection | PubMed |
description | Nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease in the US, partly due to the increasing incidence of metabolic syndrome, obesity, and type 2 diabetes. The roles of bile acids and their receptors, such as the nuclear receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, on the development of NASH are not fully clear. C57BL/6J male mice fed a Western diet (WD) develop characteristics of NASH, allowing determination of the effects of FXR and TGR5 agonists on this disease. Here we show that the FXR-TGR5 dual agonist INT-767 prevents progression of WD-induced hepatic steatosis, inflammation, and fibrosis, as determined by histological and biochemical assays and novel label-free microscopy imaging techniques, including third harmonic generation, second harmonic generation, and fluorescence lifetime imaging microscopy. Furthermore, we show INT-767 decreases liver fatty acid synthesis and fatty acid and cholesterol uptake, as well as liver inflammation. INT-767 markedly changed bile acid composition in the liver and intestine, leading to notable decreases in the hydrophobicity index of bile acids, known to limit cholesterol and lipid absorption. In addition, INT-767 upregulated expression of liver p-AMPK, SIRT1, PGC-1α, and SIRT3, which are master regulators of mitochondrial function. Finally, we found INT-767 treatment reduced WD-induced dysbiosis of gut microbiota. Interestingly, the effects of INT-767 in attenuating NASH were absent in FXR-null mice, but still present in TGR5-null mice. Our findings support treatment and prevention protocols with the dual FXR-TGR5 agonist INT-767 arrest progression of WD-induced NASH in mice mediated by FXR-dependent, TGR5-independent mechanisms. |
format | Online Article Text |
id | pubmed-9638804 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-96388042022-11-14 The role of FXR and TGR5 in reversing and preventing progression of Western diet–induced hepatic steatosis, inflammation, and fibrosis in mice Wang, Xiaoxin X. Xie, Cen Libby, Andrew E. Ranjit, Suman Levi, Jonathan Myakala, Komuraiah Bhasin, Kanchan Jones, Bryce A. Orlicky, David J. Takahashi, Shogo Dvornikov, Alexander Kleiner, David E. Hewitt, Stephen M. Adorini, Luciano Kopp, Jeffrey B. Krausz, Kristopher W. Rosenberg, Avi McManaman, James L. Robertson, Charles E. Ir, Diana Frank, Daniel N. Luo, Yuhuan Gonzalez, Frank J. Gratton, Enrico Levi, Moshe J Biol Chem Research Article Nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease in the US, partly due to the increasing incidence of metabolic syndrome, obesity, and type 2 diabetes. The roles of bile acids and their receptors, such as the nuclear receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, on the development of NASH are not fully clear. C57BL/6J male mice fed a Western diet (WD) develop characteristics of NASH, allowing determination of the effects of FXR and TGR5 agonists on this disease. Here we show that the FXR-TGR5 dual agonist INT-767 prevents progression of WD-induced hepatic steatosis, inflammation, and fibrosis, as determined by histological and biochemical assays and novel label-free microscopy imaging techniques, including third harmonic generation, second harmonic generation, and fluorescence lifetime imaging microscopy. Furthermore, we show INT-767 decreases liver fatty acid synthesis and fatty acid and cholesterol uptake, as well as liver inflammation. INT-767 markedly changed bile acid composition in the liver and intestine, leading to notable decreases in the hydrophobicity index of bile acids, known to limit cholesterol and lipid absorption. In addition, INT-767 upregulated expression of liver p-AMPK, SIRT1, PGC-1α, and SIRT3, which are master regulators of mitochondrial function. Finally, we found INT-767 treatment reduced WD-induced dysbiosis of gut microbiota. Interestingly, the effects of INT-767 in attenuating NASH were absent in FXR-null mice, but still present in TGR5-null mice. Our findings support treatment and prevention protocols with the dual FXR-TGR5 agonist INT-767 arrest progression of WD-induced NASH in mice mediated by FXR-dependent, TGR5-independent mechanisms. American Society for Biochemistry and Molecular Biology 2022-10-07 /pmc/articles/PMC9638804/ /pubmed/36209823 http://dx.doi.org/10.1016/j.jbc.2022.102530 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Wang, Xiaoxin X. Xie, Cen Libby, Andrew E. Ranjit, Suman Levi, Jonathan Myakala, Komuraiah Bhasin, Kanchan Jones, Bryce A. Orlicky, David J. Takahashi, Shogo Dvornikov, Alexander Kleiner, David E. Hewitt, Stephen M. Adorini, Luciano Kopp, Jeffrey B. Krausz, Kristopher W. Rosenberg, Avi McManaman, James L. Robertson, Charles E. Ir, Diana Frank, Daniel N. Luo, Yuhuan Gonzalez, Frank J. Gratton, Enrico Levi, Moshe The role of FXR and TGR5 in reversing and preventing progression of Western diet–induced hepatic steatosis, inflammation, and fibrosis in mice |
title | The role of FXR and TGR5 in reversing and preventing progression of Western diet–induced hepatic steatosis, inflammation, and fibrosis in mice |
title_full | The role of FXR and TGR5 in reversing and preventing progression of Western diet–induced hepatic steatosis, inflammation, and fibrosis in mice |
title_fullStr | The role of FXR and TGR5 in reversing and preventing progression of Western diet–induced hepatic steatosis, inflammation, and fibrosis in mice |
title_full_unstemmed | The role of FXR and TGR5 in reversing and preventing progression of Western diet–induced hepatic steatosis, inflammation, and fibrosis in mice |
title_short | The role of FXR and TGR5 in reversing and preventing progression of Western diet–induced hepatic steatosis, inflammation, and fibrosis in mice |
title_sort | role of fxr and tgr5 in reversing and preventing progression of western diet–induced hepatic steatosis, inflammation, and fibrosis in mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9638804/ https://www.ncbi.nlm.nih.gov/pubmed/36209823 http://dx.doi.org/10.1016/j.jbc.2022.102530 |
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