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: | , , , , , , , , , , , , , , |
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| Formato: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Recursos: | Universitat Pompeu Fabra |
| Repositorio: | Repositorio Digital de la UPF |
| OAI Identifier: | oai:repositori.upf.edu:10230/34066 |
| Acesso em linha: | http://hdl.handle.net/10230/34066 http://dx.doi.org/10.3389/fphar.2017.00705 |
| Access Level: | acceso abierto |
| Palavra-chave: | FAAH OEA PPARα Hepatic injury Paracetamol Toxicity |
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oai:repositori.upf.edu:10230/34066 |
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España |
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Acetaminophen-induced liver injury alters the Acyl ethanolamine-based anti-inflammatory signaling system in liver 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 FAAH OEA PPARα Hepatic injury Paracetamol Toxicity 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. Frontiers http://hdl.handle.net/10230/34066 http://dx.doi.org/10.3389/fphar.2017.00705 |
| 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 |
| 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 |
| topic |
FAAH OEA PPARα Hepatic injury Paracetamol Toxicity |
| topic_facet |
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 |
| format |
article |
| status_str |
publishedVersion |
| url |
http://hdl.handle.net/10230/34066 http://dx.doi.org/10.3389/fphar.2017.00705 |
| eu_rights_str_mv |
openAccess |
| publisher |
Frontiers |
| institution |
Universitat Pompeu Fabra |
| collection |
Repositorio Digital de la UPF |
| reponame_str |
Repositorio Digital de la UPF |
| instname_str |
Universitat Pompeu Fabra |
| _version_ |
1878436835939581953 |
| publishDateSort |
2017 |
| author_browse |
Arrabal, Sergio Baixeras, Elena Bautista, Dolores Boronat Rigol, Anna, 1990- Decara, Juan M. Lucena, Maria Isabel Pastor, Antonio Pavón, Francisco Javier Rivera, Patricia Rodríguez de Fonseca, Fernando Serrano, Antonia Suárez, Juan Sánchez-Marín, Laura Torre Fornell, Rafael de la Vargas, Antonio |
| publisherStr |
Frontiers |
| score |
6,924472 |