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Cited by 130Liver Disease Diagnosis and TreatmentLiver physiology and pathologyLiver Diseases and Immunity

The DOI matches its Crossref record; 80 of the 80 references it cites were found in a registry or an index.

Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication

Open access
Loft, Anne, Alfaro, Ana Jimena, Schmidt, Søren Fisker, Pedersen, Felix Boel, Terkelsen, Mike Krogh, Puglia, Michele, Chow, Kan Kau, Feuchtinger, Annette, Troullinaki, Maria, Maida, Adriano, Wolff, Gretchen, Sakurai, Minako, Berutti, Riccardo, Ekim Üstünel, Bilgen, Nawroth, Peter, Ravnskjaer, Kim, Diaz, Mauricio Berriel, Blagoev, Blagoy, Herzig, Stephan·2021·Cell Metabolism
DOI 10.1016/j.cmet.2021.06.005
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Abstract

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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Crossref · 10.1016/j.cmet.2021.06.005

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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)
DOI
10.1016/j.cmet.2021.06.005
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
Licence
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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