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Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity
Non-alcoholic fatty liver disease is a continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9262951/ https://www.ncbi.nlm.nih.gov/pubmed/35798791 http://dx.doi.org/10.1038/s41598-022-15731-4 |
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author | Pérez-Schindler, Joaquín Vargas-Fernández, Elyzabeth Karrer-Cardel, Bettina Ritz, Danilo Schmidt, Alexander Handschin, Christoph |
author_facet | Pérez-Schindler, Joaquín Vargas-Fernández, Elyzabeth Karrer-Cardel, Bettina Ritz, Danilo Schmidt, Alexander Handschin, Christoph |
author_sort | Pérez-Schindler, Joaquín |
collection | PubMed |
description | Non-alcoholic fatty liver disease is a continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating this process are poorly understood. The main aim of this study was to dissect transcriptional mechanisms regulated by lipotoxicity in hepatocytes. We achieved this aim by combining transcriptomic, proteomic and chromatin accessibility analyses from human liver and mouse hepatocytes. This integrative approach revealed several transcription factor networks deregulated by NASH and lipotoxicity. To validate these predictions, genetic deletion of the transcription factors MAFK and TCF4 was performed, resulting in hepatocytes that were better protected against saturated fatty acid oversupply. MAFK- and TCF4-regulated gene expression profiles suggest a mitigating effect against cell stress, while promoting cell survival and growth. Moreover, in the context of lipotoxicity, some MAFK and TCF4 target genes were to the corresponding differentially regulated transcripts in human liver fibrosis. Collectively, our findings comprehensively profile the transcriptional response to lipotoxicity in hepatocytes, revealing new molecular insights and providing a valuable resource for future endeavours to tackle the molecular mechanisms of NASH. |
format | Online Article Text |
id | pubmed-9262951 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-92629512022-07-09 Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity Pérez-Schindler, Joaquín Vargas-Fernández, Elyzabeth Karrer-Cardel, Bettina Ritz, Danilo Schmidt, Alexander Handschin, Christoph Sci Rep Article Non-alcoholic fatty liver disease is a continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating this process are poorly understood. The main aim of this study was to dissect transcriptional mechanisms regulated by lipotoxicity in hepatocytes. We achieved this aim by combining transcriptomic, proteomic and chromatin accessibility analyses from human liver and mouse hepatocytes. This integrative approach revealed several transcription factor networks deregulated by NASH and lipotoxicity. To validate these predictions, genetic deletion of the transcription factors MAFK and TCF4 was performed, resulting in hepatocytes that were better protected against saturated fatty acid oversupply. MAFK- and TCF4-regulated gene expression profiles suggest a mitigating effect against cell stress, while promoting cell survival and growth. Moreover, in the context of lipotoxicity, some MAFK and TCF4 target genes were to the corresponding differentially regulated transcripts in human liver fibrosis. Collectively, our findings comprehensively profile the transcriptional response to lipotoxicity in hepatocytes, revealing new molecular insights and providing a valuable resource for future endeavours to tackle the molecular mechanisms of NASH. Nature Publishing Group UK 2022-07-07 /pmc/articles/PMC9262951/ /pubmed/35798791 http://dx.doi.org/10.1038/s41598-022-15731-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Pérez-Schindler, Joaquín Vargas-Fernández, Elyzabeth Karrer-Cardel, Bettina Ritz, Danilo Schmidt, Alexander Handschin, Christoph Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity |
title | Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity |
title_full | Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity |
title_fullStr | Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity |
title_full_unstemmed | Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity |
title_short | Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity |
title_sort | characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9262951/ https://www.ncbi.nlm.nih.gov/pubmed/35798791 http://dx.doi.org/10.1038/s41598-022-15731-4 |
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