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

Anne Loft1, Ana Jimena Alfaro2, Søren Fisker Schmidt3, Felix Boel Pedersen4, Mike Krogh Terkelsen4, Michele Puglia5, Kan Kau Chow2, Annette Feuchtinger6, Maria Troullinaki2, Adriano Maida2, Gretchen Wolff2, Minako Sakurai2, Riccardo Berutti7, Bilgen Ekim Üstünel2, Peter Nawroth8, Kim Ravnskjaer4, Mauricio Berriel Diaz2, Blagoy Blagoev4, Stephan Herzig9

  1. Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg 69120, Germany; Molecular Metabolic Control, Medical Faculty, Technical University Munich, München 80333, Germany; German Center for Diabetes Research (DZD), Neuherberg 85764, Germany; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense 5230, Denmark. Electronic address: anne.loft@helmholtz-muenchen.de.
  2. Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg 69120, Germany; Molecular Metabolic Control, Medical Faculty, Technical University Munich, München 80333, Germany; German Center for Diabetes Research (DZD), Neuherberg 85764, Germany.
  3. Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg 69120, Germany; Molecular Metabolic Control, Medical Faculty, Technical University Munich, München 80333, Germany; German Center for Diabetes Research (DZD), Neuherberg 85764, Germany; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense 5230, Denmark.
  4. Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense 5230, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, Odense 5230, Denmark.
  5. Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense 5230, Denmark.
  6. Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg 85764, Germany.
  7. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany.
  8. Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg 69120, Germany; German Center for Diabetes Research (DZD), Neuherberg 85764, Germany; Department of Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg 69120, Germany.
  9. Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg 69120, Germany; Molecular Metabolic Control, Medical Faculty, Technical University Munich, München 80333, Germany; German Center for Diabetes Research (DZD), Neuherberg 85764, Germany. Electronic address: stephan.herzig@helmholtz-muenchen.de.

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.

Presented By Anne Loft | ORCID iD

Metabolism, Biochemistry, MedicineNicholas Liao2021-08 (Aug)