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BET Inhibition Improves NASH and Liver Fibrosis

Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a...

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Autores principales: Middleton, Sarah A., Rajpal, Neetu, Cutler, Leanne, Mander, Palwinder, Rioja, Inmaculada, Prinjha, Rab K., Rajpal, Deepak, Agarwal, Pankaj, Kumar, Vinod
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250695/
https://www.ncbi.nlm.nih.gov/pubmed/30467325
http://dx.doi.org/10.1038/s41598-018-35653-4
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author Middleton, Sarah A.
Rajpal, Neetu
Cutler, Leanne
Mander, Palwinder
Rioja, Inmaculada
Prinjha, Rab K.
Rajpal, Deepak
Agarwal, Pankaj
Kumar, Vinod
author_facet Middleton, Sarah A.
Rajpal, Neetu
Cutler, Leanne
Mander, Palwinder
Rioja, Inmaculada
Prinjha, Rab K.
Rajpal, Deepak
Agarwal, Pankaj
Kumar, Vinod
author_sort Middleton, Sarah A.
collection PubMed
description Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and progression to fibrosis). I-BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-γ expression. Transcriptional characterization of these mice through RNA-sequencing was consistent with predictions from the CMAP analysis of a human NASH signature and pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis.
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spelling pubmed-62506952018-11-29 BET Inhibition Improves NASH and Liver Fibrosis Middleton, Sarah A. Rajpal, Neetu Cutler, Leanne Mander, Palwinder Rioja, Inmaculada Prinjha, Rab K. Rajpal, Deepak Agarwal, Pankaj Kumar, Vinod Sci Rep Article Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and progression to fibrosis). I-BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-γ expression. Transcriptional characterization of these mice through RNA-sequencing was consistent with predictions from the CMAP analysis of a human NASH signature and pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis. Nature Publishing Group UK 2018-11-22 /pmc/articles/PMC6250695/ /pubmed/30467325 http://dx.doi.org/10.1038/s41598-018-35653-4 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Middleton, Sarah A.
Rajpal, Neetu
Cutler, Leanne
Mander, Palwinder
Rioja, Inmaculada
Prinjha, Rab K.
Rajpal, Deepak
Agarwal, Pankaj
Kumar, Vinod
BET Inhibition Improves NASH and Liver Fibrosis
title BET Inhibition Improves NASH and Liver Fibrosis
title_full BET Inhibition Improves NASH and Liver Fibrosis
title_fullStr BET Inhibition Improves NASH and Liver Fibrosis
title_full_unstemmed BET Inhibition Improves NASH and Liver Fibrosis
title_short BET Inhibition Improves NASH and Liver Fibrosis
title_sort bet inhibition improves nash and liver fibrosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250695/
https://www.ncbi.nlm.nih.gov/pubmed/30467325
http://dx.doi.org/10.1038/s41598-018-35653-4
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