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

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

doi:10.1016/j.xcrm.2024.101401

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

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 DieguezVincent Prevot, Markus Schwaninger, Ashwin Woodhoo, Maria L Martinez-Chantar, Robert Schwabe, Francisco J Cubero, Marta Varela-Rey, Javier Crespo, Paula Iruzubieta, Ruben Nogueiras

Institute of Experimental and Clinical Pharmacology and Toxicology

15 Citations (Scopus)

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.

Original language	English
Article number	101401
Journal	Cell Reports Medicine
Volume	5
Issue number	2
Pages (from-to)	101401
DOIs	https://doi.org/10.1016/j.xcrm.2024.101401
Publication status	Published - 20.02.2024

Funding

Funders	Funder number
European Community's H2020 Framework Programme
European Community's H2020 Framework Programme
Ministerio de Ciencia , Innovación y Universidades-Agencia Estatal de Investigación	PID2020-119486RB-100, PID2021-126096NB-I00, SAF2017-87301-R, PID2020-116628GB-100, PID2021-127169OB-I00, RED2018-102379-T, RTC2019-007125-1
Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación	RTC2019-007125-1and SAF2017-87301-R
Fundación BBVA	DTS20/00138
Fundación BBVA
H2020 Marie Skłodowska-Curie Actions	101073094
H2020 Marie Skłodowska-Curie Actions
Fundacion Araucaria
European Research Council	2019-WATCH- 810331, 865157
European Research Council
European Foundation for the Study of Diabetes
Ministerio de Economía y Competitividad	SEV-2016-0644
Ministerio de Economía y Competitividad
Instituto de Salud Carlos III
European Regional Development Fund
Xunta de Galicia	2021-CP085, 2020-PG015
Xunta de Galicia
Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición
Centro de Investigación Biomédica en Red de Cáncer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

DFG Research Classification Scheme

2.22-17 Endocrinology, Diabetology, Metabolism

Access to Document

10.1016/j.xcrm.2024.101401

Cite this

Fondevila, M. F., Novoa, E., Gonzalez-Rellan, M. J., Fernandez, U., Heras, V., Porteiro, B., Parracho, T., Dorta, V., Riobello, C., da Silva Lima, N., Seoane, S., Garcia-Vence, M., Chantada-Vazquez, M. P., Bravo, S. B., Senra, A., Leiva, M., Marcos, M., Sabio, G., Perez-Fernandez, R., ... Nogueiras, R. (2024). p63 controls metabolic activation of hepatic stellate cells and fibrosis via an HER2-ACC1 pathway. Cell Reports Medicine, 5(2), 101401. Article 101401. https://doi.org/10.1016/j.xcrm.2024.101401

@article{7e1b63844df745f9bffe2c91b71c8d5f,

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

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.",

author = "Fondevila, \{Marcos F\} and Eva Novoa and Gonzalez-Rellan, \{Maria J\} and Uxia Fernandez and Violeta Heras and Bego{\~n}a Porteiro and Tamara Parracho and Valentina Dorta and Cristina Riobello and \{da Silva Lima\}, Natalia and Samuel Seoane and Maria Garcia-Vence and Chantada-Vazquez, \{Maria P\} and Bravo, \{Susana B\} and Ana Senra and Magdalena Leiva and Miguel Marcos and Guadalupe Sabio and Roman Perez-Fernandez and Carlos Dieguez and Vincent Prevot and Markus Schwaninger and Ashwin Woodhoo and Martinez-Chantar, \{Maria L\} and Robert Schwabe and Cubero, \{Francisco J\} and Marta Varela-Rey and Javier Crespo and Paula Iruzubieta and Ruben Nogueiras",

year = "2024",

month = feb,

day = "20",

doi = "10.1016/j.xcrm.2024.101401",

language = "English",

volume = "5",

pages = "101401",

journal = "Cell Reports Medicine",

issn = "2666-3791",

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Fondevila, MF, Novoa, E, Gonzalez-Rellan, MJ, Fernandez, U, Heras, V, Porteiro, B, Parracho, T, Dorta, V, Riobello, C, da Silva Lima, N, Seoane, S, Garcia-Vence, M, Chantada-Vazquez, MP, Bravo, SB, Senra, A, Leiva, M, Marcos, M, Sabio, G, Perez-Fernandez, R, Dieguez, C, Prevot, V, Schwaninger, M, Woodhoo, A, Martinez-Chantar, ML, Schwabe, R, Cubero, FJ, Varela-Rey, M, Crespo, J, Iruzubieta, P & Nogueiras, R 2024, 'p63 controls metabolic activation of hepatic stellate cells and fibrosis via an HER2-ACC1 pathway', Cell Reports Medicine, vol. 5, no. 2, 101401, pp. 101401. https://doi.org/10.1016/j.xcrm.2024.101401

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

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 -

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

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

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