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

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 incompletel...

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Main Authors: Loft, Anne (Author) , Alfaro Nunez, Ana Jimena (Author) , Schmidt, Søren Fisker (Author) , Pedersen, Felix Boel (Author) , Terkelsen, Mike Krogh (Author) , Puglia, Michele (Author) , Chow, Kan Kau (Author) , Feuchtinger, Annette (Author) , Troullinaki, Maria (Author) , Maida, Adriano (Author) , Wolff, Gretchen (Author) , Sakurai, Minako (Author) , Berutti, Riccardo (Author) , Üstünel, Bilgen Ekim (Author) , Nawroth, Peter Paul (Author) , Ravnskjaer, Kim (Author) , Berriel Diaz, Mauricio (Author) , Blagoev, Blagoy (Author) , Herzig, Stephan (Author)
Format: Article (Journal)
Language:English
Published: 7 July 2021
In: Cell metabolism
Year: 2021, Volume: 33, Issue: 8, Pages: 1685-1700.e1-e9
ISSN:1932-7420
DOI:10.1016/j.cmet.2021.06.005
Online Access:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.cmet.2021.06.005
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1550413121002758
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Author Notes:Anne Loft, Ana Jimena Alfaro, Søren Fisker Schmidt, Felix Boel Pedersen, Mike Krogh Terkelsen, Michele Puglia, Kan Kau Chow, Annette Feuchtinger, Maria Troullinaki, Adriano Maida, Gretchen Wolff, Minako Sakurai, Riccardo Berutti, Bilgen Ekim Üstünel, Peter Nawroth, Kim Ravnskjaer, Mauricio Berriel Diaz, Blagoy Blagoev, and Stephan Herzig
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Summary: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.
Item Description:Gesehen am 15.07.2021
Physical Description:Online Resource
ISSN:1932-7420
DOI:10.1016/j.cmet.2021.06.005

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