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Endocrine Abstracts (2018) 56 GP156 | DOI: 10.1530/endoabs.56.GP156

ECE2018 Guided Posters Obesity (13 abstracts)

Pharmacological stimulation of p53 with low-dose doxorubicin ameliorates diet-induced nonalcoholic steatosis and steatohepatitis

María Jesús González Rellán 1, , Begoña Porteiro Couto 1, , Marcos Fernandez Fondevila 1, , Xabier Buque 3, , Uxía Fernández 1, , Alfonso Mora 5 , Daniel Beiroa 1, , Miguel López 1, , Guadalupe Sabioc 5 , Carlos Dieguez 1, , Patricia Aspichueta 3, & Rubén Nogueiras 1,


1CIMUS, Santiago de Compostela, Spain; 2CIBERobn, Madrid, Spain; 3Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Bilbao, Spain; 4Biocruces Research Institute, Bilbao, Spain; 5CNIC, Madrid, Spain.


Introduction: p53 is a transcription factor involved in many biological functions such as stress, ageing, and metabolism. Although there is a large body of evidence showing that p53 promotes fatty acid catabolism while it inhibits anabolism through the regulation of gene expression, the possible contribution of p53 to the pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains to be elucidated. Also, the anthracycline doxorubicin is an important chemotherapeutic agent, which therapeutic actions depends on p53, since p53 mutations are associated with resistance to this drug.

Objective: We hypothesized that the pharmacological activation of p53 with low-dose doxorubicin may have beneficial effects on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

Methods: We used long-term pharmacological activation of p53 by intraperitoneal injection 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 specifically in the liver.

Results: We demonstrate that chronic pharmacological stimulation of p53 with a low dose of doxorubicin (administered intraperitoneally and orally) improves liver injury in different models of diet-induced steatosis and NASH through stimulation of fatty acid oxidation and decrease of lipogenesis, inflammation, and ER stress. These effects did not occur when the drug was administered to mice with liver-specific ablation of p53.

Conclusion: Our results show that long-term pharmacological activation of p53 using intraperitoneal injection or oral administration of doxorubicin at much lower doses than those used in oncology ameliorates liver injury. The attenuation of liver injury was correlated with increased fatty acid oxidation, decreased de novo fatty acid synthesis, reduced inflammation, and lowered ER stress. We provide mechanistic insight evidence that these doxorubicin-mediated effects were dependent of p53, since they were not observed in mice where hepatic p53 expression was missing or reduced. These data provide new evidence for targeting p53 as a strategy to treat liver disease.

Acknowledgement: This work has been supported by a predoctoral grant from Programa Estatal de Promoción del Talento y su Empleabilidad en I+D+i 2016 financed by Ministerio de Industria, Economía y Competitividad and Fondo Social Europeo.

Volume 56

20th European Congress of Endocrinology

Barcelona, Spain
19 May 2018 - 22 May 2018

European Society of Endocrinology 

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