title: Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: role for omega-3 epoxides.
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-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.
authors.affiliation: Department of Biochemistry and Molecular Genetics.
authors.forename: Cristina
authors.initials: C
authors.lastname: López-Vicario
authors.affiliation: Department of Biochemistry and Molecular Genetics.
authors.forename: José
authors.initials: J
authors.lastname: Alcaraz-Quiles
authors.affiliation: Department of Biochemistry and Molecular Genetics.
authors.forename: Verónica
authors.initials: V
authors.lastname: García-Alonso
authors.affiliation: Department of Biochemistry and Molecular Genetics.
authors.forename: Bibiana
authors.initials: B
authors.lastname: Rius
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616.
authors.forename: Sung H
authors.initials: SH
authors.lastname: Hwang
authors.affiliation: Department of Biochemistry and Molecular Genetics, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, and.
authors.forename: Esther
authors.initials: E
authors.lastname: Titos
authors.affiliation: Department of Biochemistry and Molecular Genetics.
authors.forename: Aritz
authors.initials: A
authors.lastname: Lopategi
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616 jclaria@clinic.ub.es bdhammock@ucdavis.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, and Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS).
authors.forename: Vicente
authors.initials: V
authors.lastname: Arroyo
authors.affiliation: 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; and jclaria@clinic.ub.es bdhammock@ucdavis.edu.
authors.forename: Joan
authors.initials: J
authors.lastname: Clària
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000502:physiology; D001565:Benzoates / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D004852:Epoxy Compounds / Q000378:metabolism; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology
chemical_list: C572961:4-(4-(3-(4-trifluoromethoxy-phenyl)ureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D015820:Cadherins; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D015525:Fatty Acids, Omega-3; D010671:Phenylurea Compounds; C502406:fat1 protein, mouse; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D019363:Cytochrome P-450 CYP1A1; D044943:Fatty Acid Desaturases; C078565:omega-3 fatty acid desaturase; D004851:Epoxide Hydrolases
keywords: autophagy; inflammation; obesity; omega-3–derived epoxides; soluble epoxide hydrolase