Tcf20 deficiency is associated with increased liver fibrogenesis and alterations in mitochondrial metabolism in mice and humans
Year: 2023
Type: article
Abstract: Background & Aims Transcription co‐activator factor 20 (TCF20) is a regulator of transcription factors involved in extracellular matrix remodelling. In addition, TCF20 genomic variants in humans have been associated with impaired intellectual disability. Therefore, we hypothesized that TCF20 has several functions beyond those described in neurogenesis, including the regulation of fibrogenesis. Methods Tcf20 knock‐out (Tcf20−/−) and Tcf20 heterozygous mice were generated by homologous recombination. TCF20 gene genotyping and expression was assessed in patients with pathogenic variants in the TCF20 gene. Neural development was investigated by immufluorescense. Mitochondrial metabolic activity was evaluated with the Seahorse analyser. The proteome analysis was carried out by gas chromatography mass‐spectrometry. Results Characterization of Tcf20−/− newborn mice showed impaired neural development and death after birth. In contrast, heterozygous mice were viable but showed higher CCl4‐induced liver fibrosis and a differential expression of genes involved in extracellular matrix homeostasis compared to wild‐type mice, along with abnormal behavioural patterns compatible with autism‐like phenotypes. Tcf20−/− embryonic livers and mouse embryonic fibroblast (MEF) cells revealed differential expression of structural proteins involved in the mitochondrial oxidative phosphorylation chain, increased rates of mitochondrial metabolic activity and alterations in metabolites of the citric acid cycle. These results parallel to those found in patients with TCF20 pathogenic variants, including alterations of the fibrosis scores (ELF and APRI) and the elevation of succinate concentration in plasma. Conclusions We demonstrated a new role of Tcf20 in fibrogenesis and mitochondria metabolism in mice and showed the association of TCF20 deficiency with fibrosis and metabolic biomarkers in humans.
Source: Liver International
DOI: 10.1111/liv.15640
Authors: Bernat Córdoba‐Jover, Jordi Ribera, Irene Portolés, Elena Lecue, Juan Rodriguez‐Vita, Leticia Pérez‐Sisqués, Francesco Mannara, Estel Solsona‐Vilarrasa, Carmen García‐Ruiz, José C. Fernández‐Checa, Gregori Casals, Laia Rodríguez‐Revenga, María Isabel Álvarez‐Mora, Ana Arteche‐López, Aranzazu Díaz de Bustamante, Rosa Calvo, Anna Pujol, Mikel Azkargorta, Felix Elortza, Cristina Malagelada, Roser Pinyol, Júlia Huguet‐Pradell, Pedro Melgar‐Lesmes, Wladimiro Jiménez, Manuel Morales‐Ruiz
Institutions: Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Centro de Investigacion Principe Felipe, Universitat de Barcelona, Consejo Superior de Investigaciones Científicas, Institut d'Investigacions Biomèdiques de Barcelona, University of Southern California, Centre for Biomedical Network Research on Rare Diseases, Hospital Universitario 12 De Octubre, Hospital Universitario de Móstoles, Centro de Investigación Biomédica en Red de Salud Mental, Centro de Investigación Biomédica en Red, Universitat Autònoma de Barcelona, CIC bioGUNE
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,740
OpenAlex ID: W4380577649