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Dynamics of compartment-specific proteomic landscapes of hepatotoxic and cholestatic models of liver fibrosis.
eLife 13:29 (2025)
Accumulation of extracellular matrix (ECM) in liver fibrosis is associated with changes in protein abundance and composition depending upon etiology of the underlying liver disease. Current efforts to unravel etiology-specific mechanisms and pharmacological targets rely on several models of experimental fibrosis. Here, we characterize and compare dynamics of hepatic proteome remodeling during fibrosis development and spontaneous healing in experimental mouse models of hepatotoxic (carbon tetrachloride [CCl4] intoxication) and cholestatic (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] feeding) injury. Using detergent-based tissue extraction and mass spectrometry, we identified compartment-specific changes in the liver proteome with detailed attention to ECM composition and changes in protein solubility. Our analysis revealed distinct time-resolved CCl4 and DDC signatures, with identified signaling pathways suggesting limited healing and a potential for carcinogenesis associated with cholestasis. Correlation of protein abundance profiles with fibrous deposits revealed extracellular chaperone clusterin with implicated role in fibrosis resolution. Dynamics of clusterin expression was validated in the context of human liver fibrosis. Atomic force microscopy of fibrotic livers complemented proteomics with profiles of disease-associated changes in local liver tissue mechanics. This study determined compartment-specific proteomic landscapes of liver fibrosis and delineated etiology-specific ECM components, providing thus a foundation for future antifibrotic therapies.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Atomic Force Microscopy ; Clusterin ; Collagen Deposits ; Human ; Mass Spectrometry ; Matrisome ; Medicine ; Mouse; Growth-factor; Extracellular-matrix; Gene-expression; Clusterin; Cell; Target; Identification; Deposition; Pathways; Disease
ISSN (print) / ISBN
2050-084X
e-ISSN
2050-084X
Zeitschrift
eLife
Quellenangaben
Band: 13,
Artikelnummer: 29
Verlag
eLife Sciences Publications
Verlagsort
95 Regent Street, Cambridge, England
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Research Unit Precision Regenerative Medicine (PRM)
Förderungen
European Regional Development Fund-Project 'Innovation of Czech Infrastructure for Integrative Structural Biology'
esk Republiky
Grant Agency of the Czech Republic
Grant Agency of the Ministry of Health of the Czech Republic
Institutional Research Project of the Czech Academy of Sciences
National Institute for Cancer Research
European Union - Next Generation EU
Grant Agency of Charles University
MEYS CR projects
MEYS CR
Grantov Agentura Ccaron
esk Republiky
Grant Agency of the Czech Republic
Grant Agency of the Ministry of Health of the Czech Republic
Institutional Research Project of the Czech Academy of Sciences
National Institute for Cancer Research
European Union - Next Generation EU
Grant Agency of Charles University
MEYS CR projects
MEYS CR
Grantov Agentura Ccaron