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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)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords 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
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 1550-4131
e-ISSN 1932-7420
Journal Cell Metabolism
Quellenangaben Volume: 33, Issue: 8, Pages: 1685-1700.e9 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)
CF Pathology & Tissue Analytics (CF-PTA)
Institute of Neurogenomics (ING)
Research Unit Analytical Pathology (AAP)
POF-Topic(s) 90000 - German Center for Diabetes Research
30505 - New Technologies for Biomedical Discoveries
30205 - Bioengineering and Digital Health
Research field(s) Helmholtz Diabetes Center
Enabling and Novel Technologies
Genetics and Epidemiology
PSP Element(s) G-501900-251
G-501900-253
A-630600-001
G-503292-001
G-500390-001
Grants 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
DOI 10.1016/j.cmet.2021.06.005
WOS ID WOS:000684259900004
Scopus ID 85111313175
PubMed ID 34237252
Erfassungsdatum 2021-07-30
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