p63 controls metabolic activation of hepatic stellate cells and fibrosis via an HER2-ACC1 pathway
Year: 2024
Type: article
Abstract: The p63 protein has pleiotropic functions and, in the liver, participates in the progression of nonalcoholic fatty liver disease (NAFLD). However, its functions in hepatic stellate cells (HSCs) have not yet been explored. TAp63 is induced in HSCs from animal models and patients with liver fibrosis and its levels positively correlate with NAFLD activity score and fibrosis stage. In mice, genetic depletion of TAp63 in HSCs reduces the diet-induced liver fibrosis. In vitro silencing of p63 blunts TGF-β1-induced HSCs activation by reducing mitochondrial respiration and glycolysis, as well as decreasing acetyl CoA carboxylase 1 (ACC1). Ectopic expression of TAp63 induces the activation of HSCs and increases the expression and activity of ACC1 by promoting the transcriptional activity of HER2. Genetic inhibition of both HER2 and ACC1 blunt TAp63-induced activation of HSCs. Thus, TAp63 induces HSC activation by stimulating the HER2-ACC1 axis and participates in the development of liver fibrosis.
Source: Cell Reports Medicine
Authors: Marcos F. Fondevila, Eva Novoa, Maria J. Gonzalez-Rellan, Uxia Fernandez, Violeta Heras, Begoña Porteiro, Tamara Parracho, Valentina Dorta, Cristina Riobello, Natalia da Silva Lima, Samuel Seoane, Maria Garcia-Vence, Maria P. Chantada-Vazquez, Susana B. Bravo, Ana Senra, Magdalena Leiva, Miguel Marcos, Guadalupe Sabio, Roman Perez-Fernandez, Carlos Dieguez, Vincent Prevot, Markus Schwaninger, Ashwin Woodhoo, Maria L. Martinez-Chantar, Robert Schwabe, Francisco J. Cubero, Marta Varela-Rey, Javier Crespo, Paula Iruzubieta, Ruben Nogueiras
Institutions: Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases, Centro de Investigación Biomédica en Red, Instituto de Investigación Sanitaria de Santiago, Universidad Complutense de Madrid, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca, Spanish National Centre for Cardiovascular Research, Inserm, Université de Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Lille Neurosciences & Cognition, University of Lübeck, CIC bioGUNE, Columbia University, Marqués de Valdecilla University Hospital, Instituto de Investigación Marqués de Valdecilla, Xunta de Galicia, Axencia Galega de Innovacion
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,460
Funders: Fundación BBVA, Ministerio de Ciencia, Innovación y Universidades, Fundacion Araucaria, European Foundation for the Study of Diabetes, Ministerio de Economía y Competitividad, Banco Bilbao Vizcaya Argentaria, Xunta de Galicia, Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición, Centro de Investigación Biomédica en Red de Cáncer, Centers for Disease Control and Prevention, Horizon 2020 Framework Programme, European Research Council, Instituto de Salud Carlos III, European Regional Development Fund, H2020 European Research Council, H2020 Marie Skłodowska-Curie Actions
OpenAlex ID: W4391684203