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Common Transcriptional Program of Liver Fibrosis in Mouse Genetic Models and Humans

Multifactorial metabolic diseases, such as non-alcoholic fatty liver disease, are a major burden to modern societies, and frequently present with no clearly defined molecular biomarkers. Herein we used system medicine approaches to decipher signatures of liver fibrosis in mouse models with malfuncti...

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Autores principales: Blagotinšek Cokan, Kaja, Urlep, Žiga, Moškon, Miha, Mraz, Miha, Kong, Xiang Yi, Eskild, Winnie, Rozman, Damjana, Juvan, Peter, Režen, Tadeja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830925/
https://www.ncbi.nlm.nih.gov/pubmed/33467660
http://dx.doi.org/10.3390/ijms22020832
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author Blagotinšek Cokan, Kaja
Urlep, Žiga
Moškon, Miha
Mraz, Miha
Kong, Xiang Yi
Eskild, Winnie
Rozman, Damjana
Juvan, Peter
Režen, Tadeja
author_facet Blagotinšek Cokan, Kaja
Urlep, Žiga
Moškon, Miha
Mraz, Miha
Kong, Xiang Yi
Eskild, Winnie
Rozman, Damjana
Juvan, Peter
Režen, Tadeja
author_sort Blagotinšek Cokan, Kaja
collection PubMed
description Multifactorial metabolic diseases, such as non-alcoholic fatty liver disease, are a major burden to modern societies, and frequently present with no clearly defined molecular biomarkers. Herein we used system medicine approaches to decipher signatures of liver fibrosis in mouse models with malfunction in genes from unrelated biological pathways: cholesterol synthesis—Cyp51, notch signaling—Rbpj, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling—Ikbkg, and unknown lysosomal pathway—Glmp. Enrichment analyses of Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome and TRANScription FACtor (TRANSFAC) databases complemented with genome-scale metabolic modeling revealed fibrotic signatures highly similar to liver pathologies in humans. The diverse genetic models of liver fibrosis exposed a common transcriptional program with activated estrogen receptor alpha (ERα) signaling, and a network of interactions between regulators of lipid metabolism and transcription factors from cancer pathways and the immune system. The novel hallmarks of fibrosis are downregulated lipid pathways, including fatty acid, bile acid, and steroid hormone metabolism. Moreover, distinct metabolic subtypes of liver fibrosis were proposed, supported by unique enrichment of transcription factors based on the type of insult, disease stage, or potentially, also sex. The discovered novel features of multifactorial liver fibrotic pathologies could aid also in improved stratification of other fibrosis related pathologies.
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spelling pubmed-78309252021-01-26 Common Transcriptional Program of Liver Fibrosis in Mouse Genetic Models and Humans Blagotinšek Cokan, Kaja Urlep, Žiga Moškon, Miha Mraz, Miha Kong, Xiang Yi Eskild, Winnie Rozman, Damjana Juvan, Peter Režen, Tadeja Int J Mol Sci Article Multifactorial metabolic diseases, such as non-alcoholic fatty liver disease, are a major burden to modern societies, and frequently present with no clearly defined molecular biomarkers. Herein we used system medicine approaches to decipher signatures of liver fibrosis in mouse models with malfunction in genes from unrelated biological pathways: cholesterol synthesis—Cyp51, notch signaling—Rbpj, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling—Ikbkg, and unknown lysosomal pathway—Glmp. Enrichment analyses of Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome and TRANScription FACtor (TRANSFAC) databases complemented with genome-scale metabolic modeling revealed fibrotic signatures highly similar to liver pathologies in humans. The diverse genetic models of liver fibrosis exposed a common transcriptional program with activated estrogen receptor alpha (ERα) signaling, and a network of interactions between regulators of lipid metabolism and transcription factors from cancer pathways and the immune system. The novel hallmarks of fibrosis are downregulated lipid pathways, including fatty acid, bile acid, and steroid hormone metabolism. Moreover, distinct metabolic subtypes of liver fibrosis were proposed, supported by unique enrichment of transcription factors based on the type of insult, disease stage, or potentially, also sex. The discovered novel features of multifactorial liver fibrotic pathologies could aid also in improved stratification of other fibrosis related pathologies. MDPI 2021-01-15 /pmc/articles/PMC7830925/ /pubmed/33467660 http://dx.doi.org/10.3390/ijms22020832 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Blagotinšek Cokan, Kaja
Urlep, Žiga
Moškon, Miha
Mraz, Miha
Kong, Xiang Yi
Eskild, Winnie
Rozman, Damjana
Juvan, Peter
Režen, Tadeja
Common Transcriptional Program of Liver Fibrosis in Mouse Genetic Models and Humans
title Common Transcriptional Program of Liver Fibrosis in Mouse Genetic Models and Humans
title_full Common Transcriptional Program of Liver Fibrosis in Mouse Genetic Models and Humans
title_fullStr Common Transcriptional Program of Liver Fibrosis in Mouse Genetic Models and Humans
title_full_unstemmed Common Transcriptional Program of Liver Fibrosis in Mouse Genetic Models and Humans
title_short Common Transcriptional Program of Liver Fibrosis in Mouse Genetic Models and Humans
title_sort common transcriptional program of liver fibrosis in mouse genetic models and humans
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830925/
https://www.ncbi.nlm.nih.gov/pubmed/33467660
http://dx.doi.org/10.3390/ijms22020832
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