2. Academic Validation
  3. p63 controls metabolic activation of hepatic stellate cells and fibrosis via an HER2-ACC1 pathway

p63 controls metabolic activation of hepatic stellate cells and fibrosis via an HER2-ACC1 pathway

  • Cell Rep Med. 2024 Feb 20;5(2):101401. doi: 10.1016/j.xcrm.2024.101401.
Marcos F Fondevila 1,  Eva Novoa 2,  Maria J Gonzalez-Rellan 3,  Uxia Fernandez 2,  Violeta Heras 3,  Begoña Porteiro 3,  Tamara Parracho 3,  Valentina Dorta 3,  Cristina Riobello 4,  Natalia da Silva Lima 3,  Samuel Seoane 3,  Maria Garcia-Vence 5,  Maria P Chantada-Vazquez 5,  Susana B Bravo 5,  Ana Senra 3,  Magdalena Leiva 6,  Miguel Marcos 7,  Guadalupe Sabio 8,  Roman Perez-Fernandez 3,  Carlos Dieguez 3,  Vincent Prevot 9,  Markus Schwaninger 10,  Ashwin Woodhoo 4,  Maria L Martinez-Chantar 11,  Robert Schwabe 12,  Francisco J Cubero 6,  Marta Varela-Rey 4,  Javier Crespo 13,  Paula Iruzubieta 13,  Ruben Nogueiras 14
Affiliations

Affiliations

  • 1 Department of Physiology, CIMUS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), 15782 Santiago de Compostela, Spain. Electronic address: marcos.fernandez.fondevila@gmail.com.
  • 2 Department of Physiology, CIMUS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), 15782 Santiago de Compostela, Spain.
  • 3 Department of Physiology, CIMUS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
  • 4 Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
  • 5 Proteomic Unit, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), 15705 Santiago de Compostela, Spain.
  • 6 Department of Immunology, Ophthalmology, & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; Health Research Institute Gregorio Marañón (IiSGM), 28007 Madrid, Spain; CIBER Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain.
  • 7 University of Salamanca, Department of Internal Medicine, University Hospital of Salamanca-IBSAL, 37008 Salamanca, Spain.
  • 8 Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
  • 9 University Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, European Genomic Institute for Diabetes (EGID), 59000 Lille, France.
  • 10 University of Lübeck, Institute for Experimental and Clinical Pharmacology and Toxicology, 23562 Lübeck, Germany.
  • 11 Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain.
  • 12 Department of Medicine, Columbia University, New York, NY 10027, USA.
  • 13 Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL, 39008 Santander, Spain.
  • 14 Department of Physiology, CIMUS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), 15782 Santiago de Compostela, Spain; Galicia Agency of Innovation (GAIN), Xunta de Galicia, 15702 Santiago de Compostela, Spain. Electronic address: ruben.nogueiras@usc.es.
PMID: 38340725 DOI: 10.1016/j.xcrm.2024.101401
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.

Keywords

ACC1; HER2; NASH; fibrosis; hepatic stellate cell; lipid metabolism; p63.

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