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 and Ruben Nogueiras ()
Additional contact information
Begoña Porteiro: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Marcos F. Fondevila: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Teresa C. Delgado: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
Cristina Iglesias: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Monica Imbernon: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Paula Iruzubieta: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
Javier Crespo: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
Amaia Zabala-Letona: CIC bioGUNE, Centro de Investigación Biomédica en Red de Cáncer (CIBERonc)
Johan Fernø: KG Jebsen Center for Diabetes Research, University of Bergen
Bárbara González-Terán: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Nuria Matesanz: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Lourdes Hernández-Cosido: Bariatric Surgery Unit, University Hospital of Salamanca, University of Salamanca
Miguel Marcos: University Hospital of Salamanca-IBSAL, University of Salamanca
Sulay Tovar: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Anxo Vidal: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Julia Sánchez-Ceinos: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)
Maria M. Malagon: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)
Celia Pombo: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Juan Zalvide: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Arkaitz Carracedo: CIC bioGUNE, Centro de Investigación Biomédica en Red de Cáncer (CIBERonc)
Xabier Buque: University of the Basque Country (UPV/EHU)
Carlos Dieguez: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Guadalupe Sabio: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Miguel López: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Patricia Aspichueta: University of the Basque Country (UPV/EHU)
María L. Martínez-Chantar: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
Ruben Nogueiras: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria

Nature Communications, 2017, vol. 8, issue 1, 1-19

Abstract: Abstract p53 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.

Date: 2017
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DOI: 10.1038/ncomms15111

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