1. Hepatic p63 regulates steatosis via IKKβ/ER stress
- Author
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Arkaitz Carracedo, Lourdes Hernández-Cosido, Nuria Matesanz, Miguel López, Anxo Vidal, Patricia Aspichueta, Miguel Marcos, Javier Crespo, Amaia Zabala-Letona, Sulay Tovar, Rubén Nogueiras, Begoña Porteiro, Xabier Buqué, Paula Iruzubieta, María M. Malagón, Bárbara González-Terán, Celia M. Pombo, Guadalupe Sabio, Johan Fernø, Teresa C. Delgado, Carlos Dieguez, Marcos F. Fondevila, Monica Imbernon, María L. Martínez-Chantar, Cristina Iglesias, Julia Sánchez-Ceinos, Juan Zalvide, Ministerio de Economía y Competitividad (España), Xunta de Galicia (España), Comunidad de Madrid (España), Fundación Sociedad Española se Endocrinología y Nutrición, Instituto de Salud Carlos III, Asociación Española Contra el Cáncer, Basque Government (España), Fundación BBVA, Fundación AstraZeneca, Centro de Investigación Biomédica en Red - CIBEROBN (Fisiopatología de la Obesidad y Nutrición), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), and Unión Europea
- Subjects
Male ,X-Box Binding Protein 1 ,0301 basic medicine ,General Physics and Astronomy ,Mice ,Transactivation ,Liver disease ,liver physiology ,ENDOPLASMIC-RETICULUM STRESS ,IN-VIVO ,Mice, Knockout ,Multidisciplinary ,UNFOLDED PROTEIN RESPONSE ,Chemistry ,MOUSE MODEL ,Middle Aged ,ER STRESS ,Endoplasmic Reticulum Stress ,I-kappa B Kinase ,Cell biology ,Liver ,Knockout mouse ,Female ,Adult ,Science ,p63 steatosis ,KAPPA-B ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,B-KINASE-BETA ,LIPID-METABOLISM ,medicine ,Animals ,Humans ,Gene silencing ,FATTY LIVER-DISEASE ,P53 ,Tumor Suppressor Proteins ,Lipid metabolism ,General Chemistry ,Metabolism ,Lipid Metabolism ,Phosphoproteins ,medicine.disease ,Fatty Liver ,Mice, Inbred C57BL ,030104 developmental biology ,Hepatocytes ,Trans-Activators ,Unfolded protein response ,Steatosis ,Transcription Factors - 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 IKK beta activation and the induction of ER stress, the inhibition of which rescues the liver functions. Expression of TAp63, IKK beta 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 IKK beta silencing. Our findings indicate an unexpected role of the p63/IKK beta/ER stress pathway in lipid metabolism and liver disease. We deeply thank Dr Manuel Serrano (Spanish National Cancer Research Center, CNIO, Spain) for kindly providing p53 null mice and critically reading the article. This work has been supported by grants from Ministerio de Economia y Competitividad (C.D.: BFU2014-55,871; R.N.: BFU2015-70,664-R; M.M.M.: BFU2013-44229-R; A.C.: SAF2016-79381-R, FEDER/UE; GS: SAF2013-43506-R; M.L.M.-C.: SAF2014-54658-R; M.L.: SAF2015-71026-R; P.A.: SAF2015-64352-R; B.G.-T.: FPI Severo Ochoa CNIC program SVP-2013-067639), Xunta de Galicia (M.L.: 2015-CP079; R.N.: 2015-CP080 and PIE13/00024), Comunidad de Madrid (G.S.: S2010/BMD-2326); Fondo de Investigaciones Sanitarias (M.M.: PI10/01692), Fundacion SEEN (R.N.), GV-Departamento de Salud-2013111114 (to M.L.M.-C.), ISCIII: PIE14/00031 (to M.L.M.-C.), Junta Provincial de Bizkaia-AECC (to M.L.M.-C.), AECC (T.C.D.); Basque Department of Industry, Tourism and Trade (Etortek) (A.C.), the BBVA foundation (A.C.), Fundacion AstraZeneca (R.N.) Centro de Investigacion Biomedica en Red (CIBER) de Fisiopatologia de la Obesidad y Nutricion (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds. The participation of A.C. and A.Z.-L. as part of CIBERONC was co-funded with FEDER funds. The research leading to these results has also received funding from the European Community's Seventh Framework Programme under the following grant: A.C.: ERC StG-336343; R.N.: ERC StG-281408 and G.S.: ERC StG-260464. Sí
- Published
- 2017
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