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dc.contributor.author | López Vicario, Cristina |
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dc.contributor.author | Alcaraz-Quiles, José |
dc.contributor.author | García-Alonso, Verónica |
dc.contributor.author | Rius, Bibiana |
dc.contributor.author | Hwang, Sung H. |
dc.contributor.author | Titos Rodríguez, Esther |
dc.contributor.author | Lopategi, Aritz |
dc.contributor.author | Hammock, Bruce D. |
dc.contributor.author | Arroyo, Vicente |
dc.contributor.author | Clària i Enrich, Joan |
dc.date | 2018-04-03T15:07:58Z |
dc.date | 2018-04-03T15:07:58Z |
dc.date | 2015-01-13 |
dc.date | 2018-04-03T15:07:58Z |
dc.identifier | 0027-8424 |
dc.identifier | 645818 |
dc.identifier | 25550510 |
dc.identifier.uri | http://hdl.handle.net/2445/121234 |
dc.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. |
dc.format | 6 p. |
dc.format | application/pdf |
dc.language | eng |
dc.publisher | National Academy of Sciences |
dc.relation | Versió postprint del document publicat a: https://doi.org/10.1073/pnas.1422590112 |
dc.relation | Proceedings of the National Academy of Sciences of the United States of America - PNAS, 2014, vol. 112, num. 2, p. 536-541 |
dc.relation | https://doi.org/10.1073/pnas.1422590112 |
dc.rights | (c) López-Vicario, Cristina et al., 2014 |
dc.rights | info:eu-repo/semantics/openAccess |
dc.subject | Àcids grassos insaturats |
dc.subject | Àcids grassos omega-3 |
dc.subject | Inflamació |
dc.subject | Teixit adipós |
dc.subject | Malalties del fetge |
dc.subject | Autofàgia |
dc.subject | Obesitat |
dc.subject | Unsaturated fatty acids |
dc.subject | Omega-3 fatty acids |
dc.subject | Inflammation |
dc.subject | Adipose tissues |
dc.subject | Liver diseases |
dc.subject | Autophagy |
dc.subject | Obesity |
dc.title | Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver. Role for omega-3 epoxides |
dc.type | info:eu-repo/semantics/article |
dc.type | info:eu-repo/semantics/acceptedVersion |