TY - JOUR
T1 - p63 controls metabolic activation of hepatic stellate cells and fibrosis via an HER2-ACC1 pathway
AU - Fondevila, Marcos F
AU - Novoa, Eva
AU - Gonzalez-Rellan, Maria J
AU - Fernandez, Uxia
AU - Heras, Violeta
AU - Porteiro, Begoña
AU - Parracho, Tamara
AU - Dorta, Valentina
AU - Riobello, Cristina
AU - da Silva Lima, Natalia
AU - Seoane, Samuel
AU - Garcia-Vence, Maria
AU - Chantada-Vazquez, Maria P
AU - Bravo, Susana B
AU - Senra, Ana
AU - Leiva, Magdalena
AU - Marcos, Miguel
AU - Sabio, Guadalupe
AU - Perez-Fernandez, Roman
AU - Dieguez, Carlos
AU - Prevot, Vincent
AU - Schwaninger, Markus
AU - Woodhoo, Ashwin
AU - Martinez-Chantar, Maria L
AU - Schwabe, Robert
AU - Cubero, Francisco J
AU - Varela-Rey, Marta
AU - Crespo, Javier
AU - Iruzubieta, Paula
AU - Nogueiras, Ruben
N1 - Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2024/2/20
Y1 - 2024/2/20
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85185283740
UR - https://www.mendeley.com/catalogue/9c061126-a15f-3181-88df-9079d6b7297b/
U2 - 10.1016/j.xcrm.2024.101401
DO - 10.1016/j.xcrm.2024.101401
M3 - Journal articles
C2 - 38340725
SN - 2666-3791
VL - 5
SP - 101401
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 2
M1 - 101401
ER -
