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Córdoba-Jover BAuthorRibera JAuthorPortolés IAuthorRodríguez-Vita JAuthorMannara FAuthorSolsona-Vilarrasa EAuthorGarcia-Ruiz CAuthorFernandez-Checa JcAuthorCasals GAuthorRodriguez-Revenga LAuthorAlvarez-Mora MiAuthorCalvo RAuthorPinyol RAuthorHuguet-Pradell JAuthorMelgar-Lesmes PAuthorJimenez WAuthorMorales-Ruiz MCorresponding Author
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Article

Tcf20 deficiency is associated with increased liver fibrogenesis and alterations in mitochondrial metabolism in mice and humans

Publicated to:Liver International. 43 (8): 1822-1836 - 2023-08-01 43(8), DOI: 10.1111/liv.15640

Authors: Cordoba-Jover, Bernat; Ribera, Jordi; Portoles, Irene; Lecue, Elena; Rodriguez-Vita, Juan; Perez-Sisques, Leticia; Mannara, Francesco; Solsona-Vilarrasa, Estel; Garcia-Ruiz, Carmen; Fernandez-Checa, Jose C; Casals, Gregori; Rodriguez-Revenga, Laia; alvarez-Mora, Maria Isabel; Arteche-Lopez, Ana; de Bustamante, Aranzazu Diaz; Calvo, Rosa; Pujol, Anna; Azkargorta, Mikel; Elortza, Felix; Malagelada, Cristina; Pinyol, Roser; Huguet-Pradell, Julia; Melgar-Lesmes, Pedro; Jimenez, Wladimiro; Morales-Ruiz, Manuel

Affiliations

12 Octubre Univ Hosp, Genet Dept, Madrid, Spain - Author
12 Octubre Univ Hosp, UDISGEN Unidad Dismorfol & Genet, Madrid, Spain - Author
Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. - Author
CIBERehd, Instituto de Salud Carlos III, Madrid, Spain. - Author
CIBERehd, Prote Platform, CIC bioGUNE, Basque Res & Technol Alliance BRTA, Derio, Spain - Author
Ctr Invest Principe Felipe, Tumour Stroma Commun Lab, Valencia, Spain - Author
Department of Biomedicine-Biochemistry Unit, School of Medicine University of Barcelona, Barcelona, Spain. - Author
Hosp Clin Barcelona, Inst Invest Biomed August Pi i Sunyer IDIBAPS, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Biochem & Mol Genet Dept, Barcelona, Spain - Author
Hosp Univ Mostoles, Unidad Genet, Madrid, Spain - Author
Inst Invest Biomed August Pi i Sunyer IDIBAPS, Barcelona, Spain - Author
Inst Salud Carlos III, CIBERehd, Madrid, Spain - Author
Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain. - Author
Keck Sch Med, USC Res Ctr ALPD, Los Angeles, CA USA - Author
Univ Autonoma Barcelona, Unidad Anim Transgenicos UAT, CBATEG, Cerdanyola Del Valles, Spain - Author
Univ Barcelona, Barcelona Clin Hosp, Liver Unit, Translat Res Hepat Oncol Grp,IDIBAPS, Barcelona, Spain - Author
Univ Barcelona, Dept Biomed, Biochem Unit, Sch Med, Barcelona, Spain - Author
Univ Barcelona, Hosp Clin Barcelona, Ctr Invest Biomed Red Salud Mental CIBERSAM, Sch Med,Dept Child & Adolescent Psychiat & Psycho, Madrid, Spain - Author
Univ Barcelona, Hosp Clin, Inst Biomed Res Barcelona IIBB,Liver Unit,IDIBAPS, Consejo Super Invest Cient CSIC,Cell Death & Prol, Barcelona, Spain - Author
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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. © 2023 The Authors. Liver International published by John Wiley & Sons Ltd.

Keywords
AnimalAnimal experimentAnimal modelAnimal tissueAnimalsArticleBiological markerCitric acid cycleCollagenControlled studyDifferential gene expressionExtracellular matrixFibroblastFibroblastsFibrogenesisGene expressionGene knockoutGeneticsGenotypingHaploinsufficiencyHeterozygoteHomeostasisHomologous recombinationHumanHumansKnockout mouseLiverLiver cirrhosisLiver fibrosisMaleMass fragmentographyMetabolic diseaseMiceMitochondriaMitochondrial respirationMitochondrionMouseNewborn lethalityNonhumanOxidative phosphorylationPathologyProteomeStructural proteinSuccinateSuccinic acidTcf20Tcf20 protein, humanTranscription co activator factor 20Transcription factorTranscription factorsUnclassified drugWild type

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Liver International due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2023, it was in position 20/143, thus managing to position itself as a Q1 (Primer Cuartil), in the category Gastroenterology & Hepatology.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 4.37, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-19, the following number of citations:

  • WoS: 3
  • Scopus: 4
  • OpenCitations: 2
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-19:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 10.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 10 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 4.
  • The number of mentions on the social network X (formerly Twitter): 5 (Altmetric).
Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Córdoba Jover, Bernat) and Last Author (Morales Ruiz, Manuel).

the author responsible for correspondence tasks has been Morales Ruiz, Manuel.