Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication
| Autor: | Annette Feuchtinger, Gretchen Wolff, Bilgen Ekim Üstünel, Minako Sakurai, Anne Loft, Felix B. Pedersen, Kan Kau Chow, Peter P. Nawroth, Maria Troullinaki, Mauricio Berriel Diaz, Søren Fisker Schmidt, Mike Krogh Terkelsen, Stephan Herzig, Michele Puglia, Ana Jimena Alfaro, Riccardo Berutti, Blagoy Blagoev, Kim Ravnskjaer, Adriano Maida |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Liver Cirrhosis
Physiology transcription factor networks Biology GLIS2 Non-alcoholic Fatty Liver Disease Fibrosis Cell type-specific profiling medicine Humans Gene Regulatory Networks nonalcoholic steatohepatitis Molecular Biology Transcription factor liver fibrosis Communication Fatty liver Cell Biology medicine.disease ELF3 medicine.anatomical_structure Liver Hepatocyte metabolic-associated fatty liver disease Hepatocytes Hepatic stellate cell Cancer research genomic reprogramming Cell Type-specific Profiling Elf3 Glis2 Genomic Reprogramming Liver Fibrosis Metabolic-associated Fatty Liver Disease Nonalcoholic Steatohepatitis Transcription Factor Networks hepatocytes Steatohepatitis Reprogramming |
| Zdroj: | Loft, A, Alfaro, A J, Schmidt, S F, Pedersen, F B, Terkelsen, M K, Puglia, M, Chow, K K, Feuchtinger, A, Troullinaki, M, Maida, A, Wolff, G, Sakurai, M, Berutti, R, Üstünel, B E, Nawroth, P, Ravnskjaer, K, Diaz, M B, Blagoev, B & Herzig, S 2021, ' Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication ', Cell Metabolism, vol. 33, no. 8, pp. 1685-1700.e9 . https://doi.org/10.1016/j.cmet.2021.06.005 Cell Metab. 33, 1685-1700.e9 (2021) |
| DOI: | 10.1016/j.cmet.2021.06.005 |
| Popis: | Liver fibrosis is a strong predictor of long-term mortality in individuals with metabolic-associated fatty liver disease; yet, the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely understood. Using cell-type-resolved genomics, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a network of fibrosis-activated transcription factors, as exemplified by the transcription factor Elf-3 (ELF3) and zinc finger protein GLIS2 (GLIS2). Indeed, ELF3- and GLIS2-controlled fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell gene programs. Thus, interconnected transcription factor networks not only promoted hepatocyte dysfunction but also directed the intra-hepatic crosstalk necessary for NASH and fibrosis progression, implying that molecular "hub-centered" targeting strategies are superior to existing mono-target approaches as currently used in NASH therapy. |
| Databáze: | OpenAIRE |
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