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

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, Stephan Herzig

Research output: Contribution to journalJournal articleResearchpeer-review

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.
Original languageEnglish
JournalCell Metabolism
Volume33
Issue number8
Pages (from-to)1685-1700.e9
ISSN1550-4131
DOIs
Publication statusPublished - 3. Aug 2021

Keywords

  • Cell type-specific profiling
  • ELF3
  • GLIS2
  • genomic reprogramming
  • hepatocytes
  • liver fibrosis
  • metabolic-associated fatty liver disease
  • nonalcoholic steatohepatitis
  • transcription factor networks

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