RT Journal Article
T1 Pharmacological stimulation of p53 with low-dose doxorubicin ameliorates diet-induced nonalcoholic steatosis and steatohepatitis
A1 Porteiro Couto, Begoña
A1 Fernández Fondevila, Marcos
A1 Buque García, Xabier
A1 González Rellán, María Jesús
A1 Fernández Paz, Uxía
A1 Mora Corral, Alfonso
A1 Beiroa Tarrío, Daniel
A1 Senra, Ana
A1 Gallego Gómez, Rosalía
A1 Fernø, Johan
A1 López Pérez, Miguel A.
A1 Sabio, Guadalupe
A1 García Diéguez, Carlos
A1 Aspichueta Celaá, Patricia
A1 Nogueiras Pozo, Rubén
K1 Inflammation
K1 Lipid metabolism
K1 Obesity
AB ObjectiveRecent 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).MethodsWe 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).ResultsThe 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.ConclusionThese data provide new evidence for targeting p53 as a strategy to treat liver disease
PB Elsevier
YR 2018
FD 2018-02
LK https://hdl.handle.net/10347/45197
UL https://hdl.handle.net/10347/45197
LA eng
NO Begoña 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.2017.12.005
NO This work has been supported by grants from Ministerio de Economia y Competitividad (CD: BFU2014-55871; RN: BFU2015-70664-R; GS: SAF2016-79126-R; ML: SAF2015-71026-R; PA: SAF2015-64352-R), Xunta de Galicia (ML: 2015-CP079; RN: 2015-CP080 and PIE13/00024), Helse Vest RHF (JF: Western Norway Regional Health Authority), Comunidad de Madrid (GS: S2010/BMD-2326); Govierno Vasco (PA: 2016-IT-336-10) and Fundación AstraZeneca (R.N.) Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds. The research leading to these results has also received funding from the European Community's Seventh Framework Programme under the following grant: RN: ERC StG-281408 and GS: ERC StG-260464
DS Minerva
RD 23 may 2026