GATA4 induces liver fibrosis regression by deactivating hepatic stellate cells

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  • dc.contributor.author Arroyo, Noelia
  • dc.contributor.author Villamayor, Laura
  • dc.contributor.author Díaz, Irene
  • dc.contributor.author Carmona, Rita
  • dc.contributor.author Ramos-Rodríguez, Mireia
  • dc.contributor.author Muñoz-Chápuli, Ramón
  • dc.contributor.author Pasquali, Lorenzo
  • dc.contributor.author Toscano, Miguel G.
  • dc.contributor.author Martín, Franz
  • dc.contributor.author Cano, David A.
  • dc.contributor.author Rojas, Anabel
  • dc.date.accessioned 2022-02-03T07:37:11Z
  • dc.date.available 2022-02-03T07:37:11Z
  • dc.date.issued 2021
  • dc.description.abstract In response to liver injury, hepatic stellate cells activate and acquire proliferative and contractile features. The regression of liver fibrosis appears to involve the clearance of activated hepatic stellate cells, either by apoptosis or by reversion toward a quiescent-like state, a process called deactivation. Thus, deactivation of active hepatic stellate cells has emerged as a novel and promising therapeutic approach for liver fibrosis. However, our knowledge of the master regulators involved in the deactivation and/or activation of fibrotic hepatic stellate cells is still limited. The transcription factor GATA4 has been previously shown to play an important role in embryonic hepatic stellate cell quiescence. In this work, we show that lack of GATA4 in adult mice caused hepatic stellate cell activation and, consequently, liver fibrosis. During regression of liver fibrosis, Gata4 was reexpressed in deactivated hepatic stellate cells. Overexpression of Gata4 in hepatic stellate cells promoted liver fibrosis regression in CCl4-treated mice. GATA4 induced changes in the expression of fibrogenic and antifibrogenic genes, promoting hepatic stellate cell deactivation. Finally, we show that GATA4 directly repressed EPAS1 transcription in hepatic stellate cells and that stabilization of the HIF2α protein in hepatic stellate cells leads to liver fibrosis.
  • dc.description.sponsorship This work was supported by grants from the Spanish Ministry of Economy and Innovation (MICIN/AEI/10.13039/501100011033/ FEDER) (BFU2017-82497-P-to AR and BFU2017-83907-P to RMC and RC); from Spanish Ministry of Science and Innovation (MICIN/AEI/10.13039/501100011033) (PID2020-114656RB-I00 to AR); from Agencia Andaluza del Conocimiento, Consejería de Transformación Económica, Industria, Conocimiento y Universidades (PY20_00850 to AR); and from ISCIII-Subdirección General de Evaluación y Fomento de la Investigación cofunded with Fondos FEDER (PI16/00175 to DAC). We thank Antonio Cárdenas and Ana Belén Hitos for their technical assistance and Eloisa Andújar and Mónica Pérez from their technical services in the Genomic Unit at CABIMER.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Arroyo N, Villamayor L, Díaz I, Carmona R, Ramos-Rodríguez M, Muñoz-Chápuli R, Pasquali L, Toscano MG, Martín F, Cano DA, Rojas A. GATA4 induces liver fibrosis regression by deactivating hepatic stellate cells. JCI Insight. 2021;6(23):e150059. DOI: 10.1172/jci.insight.150059
  • dc.identifier.doi http://dx.doi.org/10.1172/jci.insight.150059
  • dc.identifier.issn 2379-3708
  • dc.identifier.uri http://hdl.handle.net/10230/52412
  • dc.language.iso eng
  • dc.publisher American Society for Clinical Investigation
  • dc.relation.ispartof JCI Insight. 2021;6(23):e150059
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-82497-P
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-83907-P
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-114656RB-I00
  • dc.rights © 2021, Arroyo et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri https://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Cell Biology
  • dc.subject.keyword Fibrosis
  • dc.subject.keyword Gastroenterology
  • dc.subject.keyword Mouse models
  • dc.title GATA4 induces liver fibrosis regression by deactivating hepatic stellate cells
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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