AUTHOR=Rivera Patricia , Pastor Antoni , Arrabal Sergio , Decara Juan , Vargas Antonio , Sánchez-Marín Laura , Pavón Francisco J. , Serrano Antonia , Bautista Dolores , Boronat Anna , de la Torre Rafael , Baixeras Elena , Lucena M. Isabel , de Fonseca Fernando R. , Suárez Juan 

TITLE=Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver

JOURNAL=Frontiers in Pharmacology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00705

DOI=10.3389/fphar.2017.00705

ISSN=1663-9812

ABSTRACT=<p>Protective mechanisms against drug-induced liver injury are actively being searched to identify new therapeutic targets. Among them, the anti-inflammatory <italic>N</italic>-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 <italic>PPAR</italic>α expression after 6-h APAP incubation followed by a generalized increase of NAE-PPARα system-related components (<italic>PPAR</italic>α, <italic>NAPE-PLD</italic>, and <italic>FAAH</italic>), 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 <italic>Ppar</italic>α and <italic>Faah</italic> were decreased after 6 h of treatment and, after 24 h, the gene expression levels of <italic>Nape-pld</italic> and <italic>Faah</italic>, 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 (<italic>Cyp2e1, Caspase3</italic>, α<italic>Sma, Tnf</italic>α, and <italic>Mcp1</italic>)-related alterations observed after repeated APAP administration were aggravated in the liver of <italic>Ppar</italic>α-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.</p>