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oai:repisalud.isciii.es:20.500.12105/51182024-09-27T07:59:12Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Porteiro, Begona author Fondevila, Marcos F. author Delgado, Teresa C. author Iglesias, Cristina author Imbernon, Monica author Iruzubieta, Paula author Crespo, Javier author Zabala-Letona, Amaia author Ferno, Johan author Gonzalez-Teran, Barbara author Matesanz, Nuria author Hernandez-Cosido, Lourdes author Marcos, Miguel author Tovar, Sulay author Vidal, Anxo author Sanchez-Ceinos, Julia author Malagon, Maria M. author Pombo, Celia author Zalvide, Juan author Carracedo, Arkaitz author Buque, Xabier author Dieguez, Carlos author Sabio, Guadalupe author Lopez, Miguel author Aspichueta, Patricia author Martinez-Chantar, Maria L. author Nogueiras, Ruben author 2017 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. Nat Commun. 2017; 8:15111 10.1038/ncomms15111 2041-1723 Nature Communications 28480888 http://hdl.handle.net/20.500.12105/5118 FATTY LIVER-DISEASE ENDOPLASMIC-RETICULUM STRESS UNFOLDED PROTEIN RESPONSE B-KINASE-BETA ER STRESS KAPPA-B LIPID-METABOLISM MOUSE MODEL IN-VIVO P53 Hepatic p63 regulates steatosis via IKK beta/ER stress