Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity
Abstract 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 re...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-15731-4 |
| _version_ | 1828186760740339712 |
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| author | Joaquín Pérez-Schindler Elyzabeth Vargas-Fernández Bettina Karrer-Cardel Danilo Ritz Alexander Schmidt Christoph Handschin |
| author_facet | Joaquín Pérez-Schindler Elyzabeth Vargas-Fernández Bettina Karrer-Cardel Danilo Ritz Alexander Schmidt Christoph Handschin |
| author_sort | Joaquín Pérez-Schindler |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-12T07:24:19Z |
| format | Article |
| id | doaj.art-e18bf436ca0e4e619575d2c907d59d22 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T07:24:19Z |
| publishDate | 2022-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-e18bf436ca0e4e619575d2c907d59d222022-12-22T03:42:15ZengNature PortfolioScientific Reports2045-23222022-07-0112111610.1038/s41598-022-15731-4Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicityJoaquín Pérez-Schindler0Elyzabeth Vargas-Fernández1Bettina Karrer-Cardel2Danilo Ritz3Alexander Schmidt4Christoph Handschin5Biozentrum, University of BaselBiozentrum, University of BaselBiozentrum, University of BaselBiozentrum, University of BaselBiozentrum, University of BaselBiozentrum, University of BaselAbstract 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.https://doi.org/10.1038/s41598-022-15731-4 |
| spellingShingle | Joaquín Pérez-Schindler Elyzabeth Vargas-Fernández Bettina Karrer-Cardel Danilo Ritz Alexander Schmidt Christoph Handschin Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity Scientific Reports |
| 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 |
| url | https://doi.org/10.1038/s41598-022-15731-4 |
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