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Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: role for omega-3 epoxides.
Proc Natl Acad Sci U S A. 2015 Jan 13; 112(2):536-41.PN

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+Show Affiliations

Department of Biochemistry and Molecular Genetics.Department of Biochemistry and Molecular Genetics.Department of Biochemistry and Molecular Genetics.Department of Biochemistry and Molecular Genetics.Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616.Department of Biochemistry and Molecular Genetics, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, and.Department of Biochemistry and Molecular Genetics.Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616 jclaria@clinic.ub.es bdhammock@ucdavis.edu.Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, and Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS).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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25550510

Citation

López-Vicario, Cristina, et al. "Inhibition of Soluble Epoxide Hydrolase Modulates Inflammation and Autophagy in Obese Adipose Tissue and Liver: Role for Omega-3 Epoxides." Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 2, 2015, pp. 536-41.
López-Vicario C, Alcaraz-Quiles J, García-Alonso V, et al. Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: role for omega-3 epoxides. Proc Natl Acad Sci USA. 2015;112(2):536-41.
López-Vicario, C., Alcaraz-Quiles, J., García-Alonso, V., Rius, B., Hwang, S. H., Titos, E., Lopategi, A., Hammock, B. D., Arroyo, V., & Clària, J. (2015). Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: role for omega-3 epoxides. Proceedings of the National Academy of Sciences of the United States of America, 112(2), 536-41. https://doi.org/10.1073/pnas.1422590112
López-Vicario C, et al. Inhibition of Soluble Epoxide Hydrolase Modulates Inflammation and Autophagy in Obese Adipose Tissue and Liver: Role for Omega-3 Epoxides. Proc Natl Acad Sci USA. 2015 Jan 13;112(2):536-41. PubMed PMID: 25550510.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: role for omega-3 epoxides. AU - López-Vicario,Cristina, AU - Alcaraz-Quiles,José, AU - García-Alonso,Verónica, AU - Rius,Bibiana, AU - Hwang,Sung H, AU - Titos,Esther, AU - Lopategi,Aritz, AU - Hammock,Bruce D, AU - Arroyo,Vicente, AU - Clària,Joan, Y1 - 2014/12/30/ PY - 2015/1/1/entrez PY - 2015/1/1/pubmed PY - 2015/5/1/medline KW - autophagy KW - inflammation KW - obesity KW - omega-3–derived epoxides KW - soluble epoxide hydrolase SP - 536 EP - 41 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 112 IS - 2 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/25550510/Inhibition_of_soluble_epoxide_hydrolase_modulates_inflammation_and_autophagy_in_obese_adipose_tissue_and_liver:_role_for_omega_3_epoxides_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=25550510 DB - PRIME DP - Unbound Medicine ER -