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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Alcaraz-quiles, José Hwang, Sung H. Titos, Esther Clària, Joan Rius, Bibiana García-alonso, Verónica Lopategi, Aritz Arroyo, Vicente Hammock, Bruce D. López-vicario, Cristina |
| Description | Author Affiliation: López-Vicario C ( Department of Biochemistry and Molecular Genetics.); Alcaraz-Quiles J ( Department of Biochemistry and Molecular Genetics.); García-Alonso V ( Department of Biochemistry and Molecular Genetics.); Rius B ( Department of Biochemistry and Molecular Genetics.); Hwang SH ( Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616.); Titos E ( Department of Biochemistry and Molecular Genetics, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, and.); Lopategi A ( Department of Biochemistry and Molecular Genetics.); Hammock BD ( Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616 jclaria@clinic.ub.es bdhammock@ucdavis.edu.); Arroyo V ( Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, and Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS).); Clària J ( Department of Biochemistry and Molecular Genetics, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, and Department of Physiological Sciences I, University of Barcelona, Barcelona 08036, Spain); |
| Abstract | 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-1 and eIF2 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 2 |
| Volume Number | 112 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2015-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Adipose Tissue Metabolism Epoxide Hydrolases Antagonists & Inhibitors Fatty Acids, Omega-3 Obesity 3T3-L1 Cells Drug Effects Pathology Animals Autophagy Physiology Benzoates Pharmacology Cadherins Genetics Cytochrome P-450 CYP1A1 Cytochrome P-450 CYP2E1 Cytochrome P-450 Enzyme System Enzyme Inhibitors Epoxy Compounds Fatty Acid Desaturases Inflammation Liver Mice Mice, Inbred C57BL Mice, Mutant Strains Mice, Transgenic Phenylurea Compounds Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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