Rivera, PatriciaPastor, AntonioArrabal, SergioDecara, Juan M.Vargas, AntonioSánchez-Marín, LauraPavón, Francisco JavierSerrano, AntoniaBautista, DoloresBoronat Rigol, Anna, 1990-Torre Fornell, Rafael de laBaixeras, ElenaLucena, Maria IsabelRodríguez de Fonseca, FernandoSuárez, Juan2018-03-082018-03-082017Rivera P, Pastor A, Arrabal S, Decara J, Vargas A, Sánchez-Marín L et al. Acetaminophen-induced liver injury alters the Acyl ethanolamine-based anti-inflammatory signaling system in liver. Front Pharmacol. 2017 Oct 6;8:705. DOI: 10.3389/fphar.2017.007051663-9812http://hdl.handle.net/10230/34066Protective mechanisms against drug-induced liver injury are actively being searched to identify new therapeutic targets. Among them, the anti-inflammatory N-acyl ethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system has gained much interest after the identification of its protective role in steatohepatitis and liver fibrosis. An overdose of paracetamol (APAP), a commonly used analgesic/antipyretic drug, causes hepatotoxicity, and it is being used as a liver model. In the present study, we have analyzed the impact of APAP on the liver NAE-PPARα system. A dose-response (0.5-5-10-20 mM) and time-course (2-6-24 h) study in human HepG2 cells showed a biphasic response, with a decreased PPARα expression after 6-h APAP incubation followed by a generalized increase of NAE-PPARα system-related components (PPARα, NAPE-PLD, and FAAH), including the NAEs oleoyl ethanolamide (OEA) and docosahexaenoyl ethanolamide, after a 24-h exposure to APAP. These results were partially confirmed in a time-course study of mice exposed to an acute dose of APAP (750 mg/kg). The gene expression levels of Pparα and Faah were decreased after 6 h of treatment and, after 24 h, the gene expression levels of Nape-pld and Faah, as well as the liver levels of OEA and palmitoyl ethanolamide, were increased. Repeated APAP administration (750 mg/kg/day) up to 4 days also decreased the expression levels of PPARα and FAAH, and increased the liver levels of NAEs. A resting period of 15 days completely restored these impairments. Liver immunohistochemistry in a well-characterized human case of APAP hepatotoxicity confirmed PPARα and FAAH decrements. Histopathological and hepatic damage (Cyp2e1, Caspase3, αSma, Tnfα, and Mcp1)-related alterations observed after repeated APAP administration were aggravated in the liver of Pparα-deficient mice. Our results demonstrate that the anti-inflammatory NAE-PPARα signaling system is implicated in liver toxicity after exposure to APAP overdose, and may contribute to its recovery through a long-term time-dependent response.application/pdfeng© 2017 Rivera, Pastor, Arrabal, Decara, Vargas, Sánchez-Marín, Pavón, Serrano, Bautista, Boronat, de la Torre, Baixeras, Lucena, de Fonseca and Suárez. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.info:eu-repo/semantics/articlehttp://dx.doi.org/10.3389/fphar.2017.00705FAAHOEAPPARαHepatic injuryParacetamolToxicityinfo:eu-repo/semantics/openAccess