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Tag: p63

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.

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.

Hepatic p63 regulates steatosis via IKKβ/ER stress

Begoña Porteiro, Marcos F. Fondevila, Teresa C. Delgado, Cristina Iglesias, Monica Imbernon, Paula Iruzubieta, Javier Crespo, Amaia Zabala-Letona, Johan Fernø, Bárbara González-Terán, Nuria Matesanz, Lourdes Hernández-Cosido, Miguel Marcos, Sulay Tovar, Anxo Vidal, Julia Sánchez-Ceinos, Maria M. Malagon, Celia Pombo, Juan Zalvide, Arkaitz Carracedo, Xabier Buque, Carlos Dieguez, Guadalupe Sabio, Miguel López, Patricia Aspichueta, María L. Martínez-Chantar & Ruben Nogueiras.

Pathway proposed to modulate lipid metabolism in liverp53 family members control several metabolic and cellular functions. The p53 ortholog p63 modulates cellular adaptations to stress and has a major role in cell maintenance and proliferation.

Here we show that p63 regulates hepatic lipid metabolism. Mice with liver-specific p53 deletion develop steatosis and show increased levels of p63. Down-regulation of p63 attenuates liver steatosis in p53 knockout mice and in diet-induced obese mice, whereas the activation of p63 induces lipid accumulation. Hepatic overexpression of N-terminal transactivation domain TAp63 induces liver steatosis through IKKβ activation and the induction of ER stress, the inhibition of which rescues the liver functions. Expression of TAp63, IKKβ and XBP1s is also increased in livers of obese patients with NAFLD. In cultured human hepatocytes, TAp63 inhibition protects against oleic acid-induced lipid accumulation, whereas TAp63 overexpression promotes lipid storage, an effect reversible by IKKβ silencing.

Our findings indicate an unexpected role of the p63/IKKβ/ER stress pathway in lipid metabolism and liver disease.

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