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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.P. ; Ravnskjaer, K.* ; Diaz, M.B. ; Blagoev, B.* ; Herzig, S.

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

Cell Metab. 33, 1685-1700.e9 (2021)
Verlagsversion Forschungsdaten DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Cell Type-specific Profiling ; Elf3 ; Glis2 ; Genomic Reprogramming ; Hepatocytes ; Liver Fibrosis ; Metabolic-associated Fatty Liver Disease ; Nonalcoholic Steatohepatitis ; Transcription Factor Networks; Gene-expression; Cell Identity; Mouse Model; Steatohepatitis; Osteopontin; Distinct; Inflammation; Association; Homeostasis; Macrophage
ISSN (print) / ISBN 1550-4131
e-ISSN 1932-7420
Zeitschrift Cell Metabolism
Quellenangaben Band: 33, Heft: 8, Seiten: 1685-1700.e9 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Research Unit Analytical Pathology (AAP)
Institute of Neurogenomics (ING)
Förderungen NNF
DZD grant NEXT
EMBO Long-Term Fellowship
Danish Independent Research Council | Natural Sciences
Novo Nordisk Foundation (NNF)
Danish National Research Foundation
Deutsche Forschungsge-meinschaft (DFG, German Research Foundation) through the Collaborative Research Center (CRC) 1118