RT Journal Article
T1 Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver.
A1 Rivera-González, Patricia
A1 Pastor, Antoni
A1 Arrabal, Sergio
A1 Decara, Juan Manuel
A1 Vargas, Antonio
A1 Sanchez, Laura
A1 Pavón, Francisco javier
A1 Serrano, Antonia
A1 Bautista, Dolores
A1 Boronat, Anna
A1 De la Torre, Rafael
A1 Baixeras-Llano, Elena
A1 Lucena-González, María Isabel
A1 Rodriguez de Fonseca, Fernando
A1 Suárez-Pérez, Juan
K1 Hepatotoxicidad
K1 Hígado - Heridas y lesiones
K1 Paracetamol - Toxicidad
AB Protective 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).
AB 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.
PB Frontiers
YR 2017
FD 2017-10-06
LK https://hdl.handle.net/10630/40268
UL https://hdl.handle.net/10630/40268
LA eng
NO Patricia Rivera, Antoni Pastor, Sergio Arrabal, Juan Decara, Antonio Vargas, Laura Sánchez-Marín, Francisco J Pavón, Antonia Serrano, Dolores Bautista, Anna Boronat, Rafael de la Torre, Elena Baixeras, M Isabel Lucena, Fernando R de Fonseca, Juan Suárez. 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.2017.00705
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 4 mar 2026