Hepatic p63 regulates steatosis via IKK beta/ER stress

作者：Porteiro Begona; Fondevila Marcos F; Delgado Teresa C; Iglesias Cristina; Imbernon Monica; Iruzubieta Paula; Crespo Javier; Zabala Letona Amaia; Ferno Johan; Gonzalez Teran Barbara; Matesanz Nuria; Hernandez Cosido Lourdes; Marcos Miguel; Tovar Sulay; Vidal Anxo; Sanchez Ceinos Julia; Malagon Maria M; Pombo Celia; Zalvide Juan; Carracedo Arkaitz; Buque Xabier; Dieguez Carlos; Sabio Guadalupe; Lopez Miguel; Aspichueta Patricia; Martinez Chantar Maria L

来源：Nature Communications, 2017, 8(1): 15111.

DOI：10.1038/ncomms15111

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.

• 出版日期2017-5-8