2026-06-14T03:40:59Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/173372024-02-09T16:12:39Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16927col_20.500.12105_16983
Repisalud
author
Rivera, Patricia
author
Pastor, Antoni
author
Arrabal, Sergio
author
Decara, Juan
author
Vargas, Antonio
author
Sánchez-Marín, Laura
author
Pavón, Francisco-Javier
author
Serrano, Antonia
author
Bautista, Dolores
author
Boronat, Anna
author
de la Torre, Rafael
author
Baixeras, Elena
author
Lucena, M Isabel
author
de Fonseca, Fernando R
author
Suárez, Juan
2024-01-23T20:13:10Z
2024-01-23T20:13:10Z
2017-10-06
10.3389/fphar.2017.00705
1663-9812
Frontiers in pharmacology
http://hdl.handle.net/10668/11713
29056914
http://hdl.handle.net/20.500.12105/17337
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). 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.
eng
FAAH
OEA
PPARα
hepatic injury
paracetamol
toxicity
Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver.
research article