Fatty acids homeostasis during fasting predicts protection from chemotherapy toxicity
Marta Barradas, Adrián Plaza, Gonzalo Colmenarejo, Iolanda Lázaro, Luis Filipe Costa‐Machado, Roberto Martín‐Hernández, Víctor Micó, José Luis López-Aceituno, Jesús Herránz, Cristina Pantoja, Héctor Tejero, Alberto Díaz‐Ruiz, Fátima Al‐Shahrour, Lidia Daimiel, Viviana Loria‐Kohen, Ana Ramı́rez de Molina, Alejo Efeyan, Manuel Serrano, Óscar J. Pozo, Aleix Sala‐Vila, Pablo J. Fernández-Marcos
Abstract
Fasting exerts beneficial effects in mice and humans, including protection from chemotherapy toxicity. To explore the involved mechanisms, we collect blood from humans and mice before and after 36 or 24 hours of fasting, respectively, and measure lipid composition of erythrocyte membranes, circulating micro RNAs (miRNAs), and RNA expression at peripheral blood mononuclear cells (PBMCs). Fasting coordinately affects the proportion of polyunsaturated versus saturated and monounsaturated fatty acids at the erythrocyte membrane; and reduces the expression of insulin signaling-related genes in PBMCs. When fasted for 24 hours before and 24 hours after administration of oxaliplatin or doxorubicin, mice show a strong protection from toxicity in several tissues. Erythrocyte membrane lipids and PBMC gene expression define two separate groups of individuals that accurately predict a differential protection from chemotherapy toxicity, with important clinical implications. Our results reveal a mechanism of fasting associated with lipid homeostasis, and provide biomarkers of fasting to predict fasting-mediated protection from chemotherapy toxicity.