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An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis

The presence and stage of liver fibrosis in patients with nonalcoholic steatohepatitis (NASH) is strongly associated with mortality. Thus, both preventing and reversing fibrosis are critically important approaches to prevent death or the need for liver transplantation from NASH. Recently, fibrosis i...

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Autores principales: Ulmasov, Barbara, Noritake, Hidenao, Carmichael, Peter, Oshima, Kiyoko, Griggs, David W., Neuschwander‐Tetri, Brent A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357833/
https://www.ncbi.nlm.nih.gov/pubmed/30766962
http://dx.doi.org/10.1002/hep4.1298
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author Ulmasov, Barbara
Noritake, Hidenao
Carmichael, Peter
Oshima, Kiyoko
Griggs, David W.
Neuschwander‐Tetri, Brent A.
author_facet Ulmasov, Barbara
Noritake, Hidenao
Carmichael, Peter
Oshima, Kiyoko
Griggs, David W.
Neuschwander‐Tetri, Brent A.
author_sort Ulmasov, Barbara
collection PubMed
description The presence and stage of liver fibrosis in patients with nonalcoholic steatohepatitis (NASH) is strongly associated with mortality. Thus, both preventing and reversing fibrosis are critically important approaches to prevent death or the need for liver transplantation from NASH. Recently, fibrosis in several mouse models of organ injury was shown to be prevented and reversed with the potent small molecule, arginine‐glycine‐aspartic acid tripeptide (RGD)‐binding, integrin antagonist (3S)‐3‐(3‐bromo‐5‐(tert‐butyl)phenyl)‐3‐(2‐(3‐hydroxy‐5‐((5‐hydroxy‐1,4,5,6‐tetrahydropyrimidin‐2‐yl)amino)benzamido)acetamido)propanoic acid (Center for World Health and Medicine [CWHM]‐12). We hypothesized that RGD‐binding integrins may play an important role in fibrosis progression in NASH. We assessed the efficacy of CWHM‐12 in a choline deficient, amino‐acid defined, high‐fat diet (CDAHFD) mouse model of NASH. Mice were kept on the CDAHFD or a control diet for 10 weeks, and CWHM‐12 was delivered by continuous infusion for the final 4 weeks. The parameters of NASH and liver fibrosis were evaluated before and after drug treatment. Hepatic steatosis, liver injury, and inflammation were significantly induced by the CDAHFD at week 6 and did not change by week 10. Hepatic profibrogenic gene expression was induced by the CDAHFD at week 6, further increased at week 10, and decreased by CWHM‐12. Fibrosis measured by analysis of liver collagen was reduced by CWHM‐12 to levels significantly less than found at 6 weeks, demonstrating the possibility of reversing already established fibrosis despite ongoing injury. Demonstrated mechanisms of the antifibrotic effect of CWHM‐12 included loss of activated hepatic stellate cells through apoptosis and suppression of hepatic profibrotic signal transduction by transforming growth factor β. Conclusion: RGD‐binding integrins may be critical in the development of fibrosis in NASH and may represent potential targets for treating patients with NASH to reverse advanced liver fibrosis.
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spelling pubmed-63578332019-02-14 An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis Ulmasov, Barbara Noritake, Hidenao Carmichael, Peter Oshima, Kiyoko Griggs, David W. Neuschwander‐Tetri, Brent A. Hepatol Commun Original Articles The presence and stage of liver fibrosis in patients with nonalcoholic steatohepatitis (NASH) is strongly associated with mortality. Thus, both preventing and reversing fibrosis are critically important approaches to prevent death or the need for liver transplantation from NASH. Recently, fibrosis in several mouse models of organ injury was shown to be prevented and reversed with the potent small molecule, arginine‐glycine‐aspartic acid tripeptide (RGD)‐binding, integrin antagonist (3S)‐3‐(3‐bromo‐5‐(tert‐butyl)phenyl)‐3‐(2‐(3‐hydroxy‐5‐((5‐hydroxy‐1,4,5,6‐tetrahydropyrimidin‐2‐yl)amino)benzamido)acetamido)propanoic acid (Center for World Health and Medicine [CWHM]‐12). We hypothesized that RGD‐binding integrins may play an important role in fibrosis progression in NASH. We assessed the efficacy of CWHM‐12 in a choline deficient, amino‐acid defined, high‐fat diet (CDAHFD) mouse model of NASH. Mice were kept on the CDAHFD or a control diet for 10 weeks, and CWHM‐12 was delivered by continuous infusion for the final 4 weeks. The parameters of NASH and liver fibrosis were evaluated before and after drug treatment. Hepatic steatosis, liver injury, and inflammation were significantly induced by the CDAHFD at week 6 and did not change by week 10. Hepatic profibrogenic gene expression was induced by the CDAHFD at week 6, further increased at week 10, and decreased by CWHM‐12. Fibrosis measured by analysis of liver collagen was reduced by CWHM‐12 to levels significantly less than found at 6 weeks, demonstrating the possibility of reversing already established fibrosis despite ongoing injury. Demonstrated mechanisms of the antifibrotic effect of CWHM‐12 included loss of activated hepatic stellate cells through apoptosis and suppression of hepatic profibrotic signal transduction by transforming growth factor β. Conclusion: RGD‐binding integrins may be critical in the development of fibrosis in NASH and may represent potential targets for treating patients with NASH to reverse advanced liver fibrosis. John Wiley and Sons Inc. 2018-12-27 /pmc/articles/PMC6357833/ /pubmed/30766962 http://dx.doi.org/10.1002/hep4.1298 Text en © 2018 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the http://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
Ulmasov, Barbara
Noritake, Hidenao
Carmichael, Peter
Oshima, Kiyoko
Griggs, David W.
Neuschwander‐Tetri, Brent A.
An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis
title An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis
title_full An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis
title_fullStr An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis
title_full_unstemmed An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis
title_short An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis
title_sort inhibitor of arginine‐glycine‐aspartate‐binding integrins reverses fibrosis in a mouse model of nonalcoholic steatohepatitis
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357833/
https://www.ncbi.nlm.nih.gov/pubmed/30766962
http://dx.doi.org/10.1002/hep4.1298
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