Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver. Role for omega-3 epoxides

Soluble epoxide hydrolase (sEH) is an emerging therapeutic target in a number of diseases that have inflammation as a common underlying cause. sEH limits tissue levels of cytochrome P450 (CYP) epoxides derived from omega-6 and omega-3 polyunsaturated fatty acids (PUFA) by converting these antiinflam...

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Autores: López Vicario, Cristina, Alcaraz-Quiles, José, García-Alonso, Verónica, Rius, Bibiana, Hwang, Sung H., Titos Rodríguez, Esther, Lopategi, Aritz, Hammock, Bruce D., Arroyo, Vicente, Clària i Enrich, Joan
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2015
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/121234
Acceso en línea:https://hdl.handle.net/2445/121234
Access Level:acceso abierto
Palabra clave:Àcids grassos insaturats
Àcids grassos omega-3
Inflamació
Teixit adipós
Malalties del fetge
Autofàgia
Obesitat
Unsaturated fatty acids
Omega-3 fatty acids
Inflammation
Adipose tissues
Liver diseases
Autophagy
Obesity
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repository_id_str
spelling Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver. Role for omega-3 epoxidesLópez Vicario, CristinaAlcaraz-Quiles, JoséGarcía-Alonso, VerónicaRius, BibianaHwang, Sung H.Titos Rodríguez, EstherLopategi, AritzHammock, Bruce D.Arroyo, VicenteClària i Enrich, JoanÀcids grassos insaturatsÀcids grassos omega-3InflamacióTeixit adipósMalalties del fetgeAutofàgiaObesitatUnsaturated fatty acidsOmega-3 fatty acidsInflammationAdipose tissuesLiver diseasesAutophagyObesitySoluble epoxide hydrolase (sEH) is an emerging therapeutic target in a number of diseases that have inflammation as a common underlying cause. sEH limits tissue levels of cytochrome P450 (CYP) epoxides derived from omega-6 and omega-3 polyunsaturated fatty acids (PUFA) by converting these antiinflammatory mediators into their less active diols. Here, we explored the metabolic effects of a sEH inhibitor (t-TUCB) in fat-1 mice with transgenic expression of an omega-3 desaturase capable of enriching tissues with endogenous omega-3 PUFA. These mice exhibited increased CYP1A1, CYP2E1, and CYP2U1 expression and abundant levels of the omega-3-derived epoxides 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic (19,20-EDP) in insulin-sensitive tissues, especially liver, as determined by LC-ESI-MS/MS. In obese fat-1 mice, t-TUCB raised hepatic 17,18-EEQ and 19,20-EDP levels and reinforced the omega-3-dependent reduction observed in tissue inflammation and lipid peroxidation. t-TUCB also produced a more intense antisteatotic action in obese fat-1 mice, as revealed by magnetic resonance spectroscopy. Notably, t-TUCB skewed macrophage polarization toward an antiinflammatory M2 phenotype and expanded the interscapular brown adipose tissue volume. Moreover, t-TUCB restored hepatic levels of Atg12-Atg5 and LC3-II conjugates and reduced p62 expression, indicating up-regulation of hepatic autophagy. t-TUCB consistently reduced endoplasmic reticulum stress demonstrated by the attenuation of IRE-1α and eIF2α phosphorylation. These actions were recapitulated in vitro in palmitate-primed hepatocytes and adipocytes incubated with 19,20-EDP or 17,18-EEQ. Relatively similar but less pronounced actions were observed with the omega-6 epoxide, 14,15-EET, and nonoxidized DHA. Together, these findings identify omega-3 epoxides as important regulators of inflammation and autophagy in insulin-sensitive tissues and postulate sEH as a druggable target in metabolic diseases.National Academy of Sciences2015info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/121234Articles publicats en revistes (Biomedicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1073/pnas.1422590112Proceedings of the National Academy of Sciences of the United States of America - PNAS, 2014, vol. 112, num. 2, p. 536-541https://doi.org/10.1073/pnas.1422590112(c) López-Vicario, Cristina et al., 2014info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1212342026-05-27T06:46:51Z
dc.title.none.fl_str_mv Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver. Role for omega-3 epoxides
title Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver. Role for omega-3 epoxides
spellingShingle Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver. Role for omega-3 epoxides
López Vicario, Cristina
Àcids grassos insaturats
Àcids grassos omega-3
Inflamació
Teixit adipós
Malalties del fetge
Autofàgia
Obesitat
Unsaturated fatty acids
Omega-3 fatty acids
Inflammation
Adipose tissues
Liver diseases
Autophagy
Obesity
title_short Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver. Role for omega-3 epoxides
title_full Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver. Role for omega-3 epoxides
title_fullStr Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver. Role for omega-3 epoxides
title_full_unstemmed Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver. Role for omega-3 epoxides
title_sort Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver. Role for omega-3 epoxides
dc.creator.none.fl_str_mv López Vicario, Cristina
Alcaraz-Quiles, José
García-Alonso, Verónica
Rius, Bibiana
Hwang, Sung H.
Titos Rodríguez, Esther
Lopategi, Aritz
Hammock, Bruce D.
Arroyo, Vicente
Clària i Enrich, Joan
author López Vicario, Cristina
author_facet López Vicario, Cristina
Alcaraz-Quiles, José
García-Alonso, Verónica
Rius, Bibiana
Hwang, Sung H.
Titos Rodríguez, Esther
Lopategi, Aritz
Hammock, Bruce D.
Arroyo, Vicente
Clària i Enrich, Joan
author_role author
author2 Alcaraz-Quiles, José
García-Alonso, Verónica
Rius, Bibiana
Hwang, Sung H.
Titos Rodríguez, Esther
Lopategi, Aritz
Hammock, Bruce D.
Arroyo, Vicente
Clària i Enrich, Joan
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Àcids grassos insaturats
Àcids grassos omega-3
Inflamació
Teixit adipós
Malalties del fetge
Autofàgia
Obesitat
Unsaturated fatty acids
Omega-3 fatty acids
Inflammation
Adipose tissues
Liver diseases
Autophagy
Obesity
topic Àcids grassos insaturats
Àcids grassos omega-3
Inflamació
Teixit adipós
Malalties del fetge
Autofàgia
Obesitat
Unsaturated fatty acids
Omega-3 fatty acids
Inflammation
Adipose tissues
Liver diseases
Autophagy
Obesity
description Soluble epoxide hydrolase (sEH) is an emerging therapeutic target in a number of diseases that have inflammation as a common underlying cause. sEH limits tissue levels of cytochrome P450 (CYP) epoxides derived from omega-6 and omega-3 polyunsaturated fatty acids (PUFA) by converting these antiinflammatory mediators into their less active diols. Here, we explored the metabolic effects of a sEH inhibitor (t-TUCB) in fat-1 mice with transgenic expression of an omega-3 desaturase capable of enriching tissues with endogenous omega-3 PUFA. These mice exhibited increased CYP1A1, CYP2E1, and CYP2U1 expression and abundant levels of the omega-3-derived epoxides 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic (19,20-EDP) in insulin-sensitive tissues, especially liver, as determined by LC-ESI-MS/MS. In obese fat-1 mice, t-TUCB raised hepatic 17,18-EEQ and 19,20-EDP levels and reinforced the omega-3-dependent reduction observed in tissue inflammation and lipid peroxidation. t-TUCB also produced a more intense antisteatotic action in obese fat-1 mice, as revealed by magnetic resonance spectroscopy. Notably, t-TUCB skewed macrophage polarization toward an antiinflammatory M2 phenotype and expanded the interscapular brown adipose tissue volume. Moreover, t-TUCB restored hepatic levels of Atg12-Atg5 and LC3-II conjugates and reduced p62 expression, indicating up-regulation of hepatic autophagy. t-TUCB consistently reduced endoplasmic reticulum stress demonstrated by the attenuation of IRE-1α and eIF2α phosphorylation. These actions were recapitulated in vitro in palmitate-primed hepatocytes and adipocytes incubated with 19,20-EDP or 17,18-EEQ. Relatively similar but less pronounced actions were observed with the omega-6 epoxide, 14,15-EET, and nonoxidized DHA. Together, these findings identify omega-3 epoxides as important regulators of inflammation and autophagy in insulin-sensitive tissues and postulate sEH as a druggable target in metabolic diseases.
publishDate 2015
dc.date.none.fl_str_mv 2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/121234
url https://hdl.handle.net/2445/121234
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1073/pnas.1422590112
Proceedings of the National Academy of Sciences of the United States of America - PNAS, 2014, vol. 112, num. 2, p. 536-541
https://doi.org/10.1073/pnas.1422590112
dc.rights.none.fl_str_mv (c) López-Vicario, Cristina et al., 2014
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) López-Vicario, Cristina et al., 2014
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
dc.source.none.fl_str_mv Articles publicats en revistes (Biomedicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300724

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