RT Journal Article
T1 Inhibition of hepatic p63 ameliorates steatohepatitis with fibrosis in mice
A1 Fernández Fondevila, Marcos
A1 Eva Nóvoa Deaño, 
A1 Uxía Fernández Paz, 
A1 Dorta Bouza, Valentina
A1 Parracho Martínez, Tamara
A1 Kreimeyer, Henriette
A1 García Vence, María
A1 Chantada Vázquez, María del Pilar
A1 Bravo López, Susana Belén
A1 Porteiro Couto, Begoña
A1 López Cabaleiro, Alba
A1 Koning, Mijra
A1 Ana Senra, 
A1 Yara Souto Becerra, 
A1 Verheij, Joanne
A1 Guallar Artal, Diana
A1 Fidalgo Pérez, Miguel Ángel
A1 Meijnikman, Abraham S.
A1 da Silva Lima, Natalia
A1 Diéguez González, Carlos
A1 González Rellán, María Jesús
A1 Nogueiras Pozo, Rubén
K1 p63
K1 TAp63
K1 MASLD
K1 NAFLD
K1 MASH
K1 NASH
K1 Metabolism
K1 Steatosis
K1 Fibrosis
K1 Liver
AB Objectivep63 is a transcription factor involved in multiple biological functions. In the liver, the TAp63 isoform induces lipid accumulation in hepatocytes. However, the role of liver TAp63 in the progression of metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis is unknown.MethodsWe evaluated the hepatic p63 levels in different mouse models of steatohepatitis with fibrosis induced by diet. Next, we used virogenetic approaches to manipulate the expression of TAp63 in adult mice under diet-induced steatohepatitis with fibrosis and characterized the disease condition. Finally, we performed proteomics analysis in mice with overexpression and knockdown of hepatic TAp63.ResultsLevels of TAp63, but not of ΔN isoform, are increased in the liver of mice with diet-induced steatohepatitis with fibrosis. Both preventive and interventional strategies for the knockdown of hepatic TAp63 significantly ameliorated diet-induced steatohepatitis with fibrosis in mice fed a methionine- and choline-deficient diet (MCDD) and choline deficient and high fat diet (CDHFD). The overexpression of hepatic TAp63 in mice aggravated the liver condition in mice fed a CDHFD. Proteomic analysis in the liver of these mice revealed alteration in multiple proteins and pathways, such as oxidative phosphorylation, antioxidant activity, peroxisome function and LDL clearance.ConclusionsThese results indicate that liver TAp63 plays a critical role in the progression of diet-induced steatohepatitis with fibrosis, and its inhibition ameliorates the disease
PB Elsevier
YR 2024
FD 2024-06-02
LK https://hdl.handle.net/10347/43538
UL https://hdl.handle.net/10347/43538
LA eng
NO Marcos F. Fondevila, Eva Novoa, Uxia Fernandez, Valentina Dorta, Tamara Parracho, Henriette Kreimeyer, Maria Garcia-Vence, Maria P. Chantada-Vazquez, Susana B. Bravo, Begoña Porteiro, Alba Cabaleiro, Mijra Koning, Ana Senra, Yara Souto, Joanne Verheij, Diana Guallar, Miguel Fidalgo, Abraham S. Meijnikman, Natalia da Silva Lima, Carlos Dieguez, Maria J. Gonzalez-Rellan, Ruben Nogueiras, Inhibition of hepatic p63 ameliorates steatohepatitis with fibrosis in mice, Molecular Metabolism, Volume 85, 2024, 101962, ISSN 2212-8778, https://doi.org/10.1016/j.molmet.2024.101962
NO This work has been supported by grants from FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (RN: PID2021-126096NB-I00 and RED2018-102379-T), Xunta de Galicia (RN: 2021-CP085 and 2020-PG015), Fundación BBVA (RN), Fundación Atresmedia (RN) and European Foundation for the Study of Diabetes (RN). This research also received funding from the European Community's H2020 Framework Programme (ERC Synergy Grant-2019-WATCH-810331). MJGR and MF are supported by the Xunta de Galicia & Fulbright Postdoctoral Fellowship (MF) 2022 (ED481B-2022-030). HK is supported by the Walter-Benjamin-Fellowship of the Deutsche Forschungsgemeinschaft (KR 5843 1-1)
DS Minerva
RD 3 may 2026