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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-01-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/2/832 |
| _version_ | 1797411041691303936 |
|---|---|
| author | Kaja Blagotinšek Cokan Žiga Urlep Miha Moškon Miha Mraz Xiang Yi Kong Winnie Eskild Damjana Rozman Peter Juvan Tadeja Režen |
| author_facet | Kaja Blagotinšek Cokan Žiga Urlep Miha Moškon Miha Mraz Xiang Yi Kong Winnie Eskild Damjana Rozman Peter Juvan Tadeja Režen |
| author_sort | Kaja Blagotinšek Cokan |
| collection | DOAJ |
| 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—<i>Cyp51</i>, notch signaling—<i>Rbpj</i>, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling—<i>Ikbkg</i>, and unknown lysosomal pathway—<i>Glmp</i>. 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. |
| first_indexed | 2024-03-09T04:39:14Z |
| format | Article |
| id | doaj.art-9ff6cf5bb655424ca1f5e758f321d63f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T04:39:14Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9ff6cf5bb655424ca1f5e758f321d63f2023-12-03T13:23:49ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-0122283210.3390/ijms22020832Common Transcriptional Program of Liver Fibrosis in Mouse Genetic Models and HumansKaja Blagotinšek Cokan0Žiga Urlep1Miha Moškon2Miha Mraz3Xiang Yi Kong4Winnie Eskild5Damjana Rozman6Peter Juvan7Tadeja Režen8Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, SloveniaCentre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, SloveniaComputational Biology Group, Faculty of Computer and Information Science, University of Ljubljana, 1000 Ljubljana, SloveniaComputational Biology Group, Faculty of Computer and Information Science, University of Ljubljana, 1000 Ljubljana, SloveniaResearch Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, 0372 Oslo, NorwaySection for Biochemistry and Molecular Biology, Department of Biosciences, Faculty of Mathematics and Natural Science, University of Oslo, 0315 Oslo, NorwayCentre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, SloveniaCentre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, SloveniaCentre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, SloveniaMultifactorial 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—<i>Cyp51</i>, notch signaling—<i>Rbpj</i>, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling—<i>Ikbkg</i>, and unknown lysosomal pathway—<i>Glmp</i>. 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.https://www.mdpi.com/1422-0067/22/2/832NAFLDNASHbile acidGEMfibrosisfatty acid |
| spellingShingle | Kaja Blagotinšek Cokan Žiga Urlep Miha Moškon Miha Mraz Xiang Yi Kong Winnie Eskild Damjana Rozman Peter Juvan Tadeja Režen Common Transcriptional Program of Liver Fibrosis in Mouse Genetic Models and Humans International Journal of Molecular Sciences NAFLD NASH bile acid GEM fibrosis fatty acid |
| 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 | NAFLD NASH bile acid GEM fibrosis fatty acid |
| url | https://www.mdpi.com/1422-0067/22/2/832 |
| work_keys_str_mv | AT kajablagotinsekcokan commontranscriptionalprogramofliverfibrosisinmousegeneticmodelsandhumans AT zigaurlep commontranscriptionalprogramofliverfibrosisinmousegeneticmodelsandhumans AT mihamoskon commontranscriptionalprogramofliverfibrosisinmousegeneticmodelsandhumans AT mihamraz commontranscriptionalprogramofliverfibrosisinmousegeneticmodelsandhumans AT xiangyikong commontranscriptionalprogramofliverfibrosisinmousegeneticmodelsandhumans AT winnieeskild commontranscriptionalprogramofliverfibrosisinmousegeneticmodelsandhumans AT damjanarozman commontranscriptionalprogramofliverfibrosisinmousegeneticmodelsandhumans AT peterjuvan commontranscriptionalprogramofliverfibrosisinmousegeneticmodelsandhumans AT tadejarezen commontranscriptionalprogramofliverfibrosisinmousegeneticmodelsandhumans |