Porteiro Couto, BegoñaFernández Fondevila, MarcosBuque García, XabierGonzález Rellán, María JesúsFernández Paz, UxíaMora Corral, AlfonsoBeiroa Tarrío, DanielSenra, AnaGallego Gómez, RosalíaFernø, JohanLópez Pérez, Miguel A.Sabio, GuadalupeGarcía Diéguez, CarlosAspichueta Celaá, PatriciaNogueiras Pozo, Rubén2026-01-152026-01-152018-02Begoña Porteiro, Marcos F. Fondevila, Xabier Buque, Maria J. Gonzalez-Rellan, Uxia Fernandez, Alfonso Mora, Daniel Beiroa, Ana Senra, Rosalia Gallego, Johan Fernø, Miguel López, Guadalupe Sabio, Carlos Dieguez, Patricia Aspichueta, Rubén Nogueiras, Pharmacological stimulation of p53 with low-dose doxorubicin ameliorates diet-induced nonalcoholic steatosis and steatohepatitis, Molecular Metabolism, Volume 8, 2018, Pages 132-143, ISSN 2212-8778, https://doi.org/10.1016/j.molmet.2017.12.005https://hdl.handle.net/10347/45197Objective Recent reports have implicated the p53 tumor suppressor in the regulation of lipid metabolism. We hypothesized that the pharmacological activation of p53 with low-dose doxorubicin, which is widely used to treat several types of cancer, may have beneficial effects on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Methods We used long-term pharmacological activation of p53 by i.p. or oral administration of low-dose doxorubicin in different animal models of NAFLD (high fat diet containing 45% and 60% kcal fat) and NASH (methionine- and choline-deficient diet and choline deficiency combined with high fat diet). We also administered doxorubicin in mice lacking p53 in the liver and in two human hepatic cells lines (HepG2 and THLE2). Results The attenuation of liver damage was accompanied by the stimulation of fatty acid oxidation and decrease of lipogenesis, inflammation, and ER stress. The effects of doxorubicin were abrogated in mice with liver-specific ablation of p53. Finally, the effects of doxorubicin on lipid metabolism found in animal models were also present in two human hepatic cells lines, in which the drug stimulated fatty acid oxidation and inhibited de novo lipogenesis at doses that did not cause changes in apoptosis or cell viability. Conclusion These data provide new evidence for targeting p53 as a strategy to treat liver diseaseeng© 2017 The Authors. Published by Elsevier GmbH. This article is available under the Creative Commons CC-BY-NC-ND licenseAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/InflammationLipid metabolismObesityjournal article10.1016/j.molmet.2017.12.0052212-8778open access