Acetaminophen-induced liver injury alters the Acyl ethanolamine-based anti-inflammatory signaling system in liver
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 i...
| Autores: | , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | Universitat Pompeu Fabra |
| Repositorio: | Repositorio Digital de la UPF |
| OAI Identifier: | oai:repositori.upf.edu:10230/34066 |
| Acceso en línea: | http://hdl.handle.net/10230/34066 http://dx.doi.org/10.3389/fphar.2017.00705 |
| Access Level: | acceso abierto |
| Palabra clave: | FAAH OEA PPARα Hepatic injury Paracetamol Toxicity |
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Acetaminophen-induced liver injury alters the Acyl ethanolamine-based anti-inflammatory signaling system in liverRivera, 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, JuanFAAHOEAPPARαHepatic injuryParacetamolToxicityProtective 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.Frontiers201820182017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/34066http://dx.doi.org/10.3389/fphar.2017.00705reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésFront Pharmacol. 2017 Oct 6;8:705© 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.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/340662026-06-12T07:21:37Z |
| dc.title.none.fl_str_mv |
Acetaminophen-induced liver injury alters the Acyl ethanolamine-based anti-inflammatory signaling system in liver |
| title |
Acetaminophen-induced liver injury alters the Acyl ethanolamine-based anti-inflammatory signaling system in liver |
| spellingShingle |
Acetaminophen-induced liver injury alters the Acyl ethanolamine-based anti-inflammatory signaling system in liver Rivera, Patricia FAAH OEA PPARα Hepatic injury Paracetamol Toxicity |
| title_short |
Acetaminophen-induced liver injury alters the Acyl ethanolamine-based anti-inflammatory signaling system in liver |
| title_full |
Acetaminophen-induced liver injury alters the Acyl ethanolamine-based anti-inflammatory signaling system in liver |
| title_fullStr |
Acetaminophen-induced liver injury alters the Acyl ethanolamine-based anti-inflammatory signaling system in liver |
| title_full_unstemmed |
Acetaminophen-induced liver injury alters the Acyl ethanolamine-based anti-inflammatory signaling system in liver |
| title_sort |
Acetaminophen-induced liver injury alters the Acyl ethanolamine-based anti-inflammatory signaling system in liver |
| dc.creator.none.fl_str_mv |
Rivera, Patricia Pastor, Antonio Arrabal, Sergio Decara, Juan M. Vargas, Antonio Sánchez-Marín, Laura Pavón, Francisco Javier Serrano, Antonia Bautista, Dolores Boronat Rigol, Anna, 1990- Torre Fornell, Rafael de la Baixeras, Elena Lucena, Maria Isabel Rodríguez de Fonseca, Fernando Suárez, Juan |
| author |
Rivera, Patricia |
| author_facet |
Rivera, Patricia Pastor, Antonio Arrabal, Sergio Decara, Juan M. Vargas, Antonio Sánchez-Marín, Laura Pavón, Francisco Javier Serrano, Antonia Bautista, Dolores Boronat Rigol, Anna, 1990- Torre Fornell, Rafael de la Baixeras, Elena Lucena, Maria Isabel Rodríguez de Fonseca, Fernando Suárez, Juan |
| author_role |
author |
| author2 |
Pastor, Antonio Arrabal, Sergio Decara, Juan M. Vargas, Antonio Sánchez-Marín, Laura Pavón, Francisco Javier Serrano, Antonia Bautista, Dolores Boronat Rigol, Anna, 1990- Torre Fornell, Rafael de la Baixeras, Elena Lucena, Maria Isabel Rodríguez de Fonseca, Fernando Suárez, Juan |
| author2_role |
author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
FAAH OEA PPARα Hepatic injury Paracetamol Toxicity |
| topic |
FAAH OEA PPARα Hepatic injury Paracetamol Toxicity |
| description |
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. |
| publishDate |
2017 |
| dc.date.none.fl_str_mv |
2017 2018 2018 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10230/34066 http://dx.doi.org/10.3389/fphar.2017.00705 |
| url |
http://hdl.handle.net/10230/34066 http://dx.doi.org/10.3389/fphar.2017.00705 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Front Pharmacol. 2017 Oct 6;8:705 |
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http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf application/pdf |
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Frontiers |
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Frontiers |
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reponame:Repositorio Digital de la UPF instname:Universitat Pompeu Fabra |
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Universitat Pompeu Fabra |
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