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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Published in:Cell metabolism Vol. 33; no. 8; p. 1685
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 03.08.2021
Subjects:
Communication
Gene Regulatory Networks
Hepatocytes - metabolism
Humans
Liver - metabolism
Liver Cirrhosis - metabolism
Non-alcoholic Fatty Liver Disease - metabolism
nonalcoholic steatohepatitis
genomic reprogramming
liver fibrosis
ELF3
Cell type-specific profiling
transcription factor networks
metabolic-associated fatty liver disease
hepatocytes
GLIS2
ISSN:1932-7420, 1932-7420
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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.
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ISSN:1932-7420
1932-7420
DOI:10.1016/j.cmet.2021.06.005