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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)
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Free by publisher: Verlagsversion online verfügbar 07/2022
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
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
Begutachtungsstatus Peer reviewed
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