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Hepatic p63 regulates steatosis via IKKβ/ER stress

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  • Begoña Porteiro

    (CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn))

  • Marcos F. Fondevila

    (CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn))

  • 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
    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn))

  • 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
    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn))

  • Anxo Vidal

    (CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria)

  • Julia Sánchez-Ceinos

    (CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)
    Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Hospital Universitario Reina Sofía)

  • Maria M. Malagon

    (CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)
    Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Hospital Universitario Reina Sofía)

  • 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)
    IKERBASQUE, Basque foundation for science
    University of the Basque Country (UPV/EHU))

  • Xabier Buque

    (University of the Basque Country (UPV/EHU)
    Biocruces Research Institute)

  • Carlos Dieguez

    (CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn))

  • Guadalupe Sabio

    (Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC))

  • Miguel López

    (CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn))

  • Patricia Aspichueta

    (University of the Basque Country (UPV/EHU)
    Biocruces Research Institute)

  • 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
    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn))

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.

Suggested Citation

  • 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 , 2017. "Hepatic p63 regulates steatosis via IKKβ/ER stress," Nature Communications, Nature, vol. 8(1), pages 1-19, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15111
    DOI: 10.1038/ncomms15111
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