RT Journal Article
T1 Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver.
A1 Rivera, Patricia
A1 Pastor, Antoni
A1 Arrabal, Sergio
A1 Decara, Juan
A1 Vargas, Antonio
A1 Sanchez-Marin, Laura
A1 Pavon, Francisco J
A1 Serrano, Antonia
A1 Bautista, Dolores
A1 Boronat, Anna
A1 de-la-Torre, Rafael
A1 Baixeras, Elena
A1 Lucena, M Isabel
A1 de-Fonseca, Fernando R
A1 Suarez, Juan
K1 FAAH
K1 OEA
K1 PPARα
K1 Hepatic injury
K1 Paracetamol
K1 Toxicity
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). 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 Research Foundation
SN 1663-9812
YR 2017
FD 2017-10-06
LK http://hdl.handle.net/10668/11713
UL http://hdl.handle.net/10668/11713
LA en
NO Rivera 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
NO This work was supported by Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad (MINECO) co-funded by UE-ERDF program (JS: PI16/01374; FdF: PI16/01698 and RD16/0017/0001); Ministerio de Sanidad, Servicios Sociales e Igualdad and Plan Nacional sobre Drogas (JS: PNSD2015/047); Consejería de Economía, Innovación y Ciencia, Junta deAndalucía, UE-ERDF (FdF: CTS-8221); Consejería de Salud, Junta de Andalucía, UE-ERDF (FdF: SAS111224; PR: PI-0337-2012); and DIUE, Generalitat de Catalunya (RdT: 2014 SGR 680). FP (CP14/00212), AS (CP14/00173), and JS (CP12/03109) are recipients of a research contract from “Miguel Servet” Program of ISCIII and EU-ERDF. PR holds a “Sara Borrel” research contract from the National System of Health, ISCIII (CD16/00067).
DS RISalud
RD Apr 5, 2025