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Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication
Open accessAbstract
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.
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Metadata
- Authors
- 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., Ekim Üstünel, B., Nawroth, P., Ravnskjaer, K., Diaz, M. B., Blagoev, B., & Herzig, S.
- Affiliations
- University of Southern Denmark (DK)
- Heidelberg University (DE)
- Helmholtz Munich (DE)
- University Hospital Heidelberg (DE)
- Corresponding author
- Loft, Anne
- Herzig, Stephan
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2021-08
- Volume
- 33
- Issue
- 8
- Pages
- 1685-1700.e9
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W3180909105
- Cited by
- 129
- References
- 80
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 38 · 2023: 36 · 2022: 22 · 2021: 4
- FWCI
- 18.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 367 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Site cant be reached (submittedVersion, other-oa)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Funders
- International Design Centre
- Deutsche Forschungsgemeinschaft (CRC) 1118)
- Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences (DFF-6110-00265)
- Danmarks Grundforskningsfond (DNRF141)
- Shanxi Datong University
- Danmarks Frie Forskningsfond
- Novo Nordisk Fonden (NNF16OC0020742, NNF18OC0052768, NNFOC150019050)
- European Molecular Biology Organization (ALTF 897-2015)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- liver fibrosis, nonalcoholic steatohepatitis, metabolic-associated fatty liver disease, hepatocyte reprogramming, ELF3, GLIS2, transcriptional regulatory networks, hepatokines, hepatic stellate cells
- MeSH terms
- Communication, Humans, Liver, Liver Cirrhosis, Hepatocytes, Gene Regulatory Networks, Non-alcoholic Fatty Liver Disease
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