RT Journal Article
T1 Hepatic p63 regulates steatosis via IKKβ/ER stress.
A1 Porteiro, Begoña
A1 Fondevila, Marcos F
A1 Delgado, Teresa C
A1 Iglesias, Cristina
A1 Imbernon, Monica
A1 Iruzubieta, Paula
A1 Crespo, Javier
A1 Zabala-Letona, Amaia
A1 Fernø, Johan
A1 Gonzalez-Teran, Barbara
A1 Matesanz, Nuria
A1 Hernandez-Cosido, Lourdes
A1 Marcos, Miguel
A1 Tovar, Sulay
A1 Vidal, Anxo
A1 Sanchez-Ceinos, Julia
A1 Malagon, Maria M
A1 Pombo, Celia
A1 Zalvide, Juan
A1 Carracedo, Arkaitz
A1 Buque, Xabier
A1 Dieguez, Carlos
A1 Sabio, Guadalupe
A1 Lopez, Miguel
A1 Aspichueta, Patricia
A1 Martinez-Chantar, Maria L
A1 Nogueiras, Ruben
K1 Adult
K1 Animals
K1 Endoplasmic reticulum stress
K1 Fatty liver
K1 Hepatocytes
AB 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.
PB Nature Publishing Group
YR 2017
FD 2017-03-01
LK http://hdl.handle.net/10668/11180
UL http://hdl.handle.net/10668/11180
LA en
NO Porteiro B, Fondevila MF, Delgado TC, Iglesias C, Imbernon M, Iruzubieta P, et al. Hepatic p63 regulates steatosis via IKKβ/ER stress. Nat Commun. 2017 May 8;8:15111. doi: 10.1038/ncomms15111. Erratum in: Nat Commun. 2017 Jun 16;8:16059
NO 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 andPIE13/00024), Comunidad de Madrid (G.S.: S2010/BMD-2326); Fondo de Investigaciones Sanitarias (M.M.: PI10/01692), Fundacio´n 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.), Fundación AstraZeneca (R.N.) Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad yNutrición (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.
DS RISalud
RD Apr 17, 2025