Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver

Role for omega-3 epoxides

Cristina López-Vicario, José Alcaraz-Quiles, Verónica García-Alonso, Bibiana Rius, Sung H. Hwang, Esther Titos, Aritz Lopategi, Bruce D. Hammock, Vicente Arroyo, Joan Clària

Research output: Contribution to journalArticle

74 Citations (Scopus)

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 insulinsensitive 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.

Original languageEnglish (US)
Pages (from-to)536-541
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number2
DOIs
StatePublished - Jan 13 2015
Externally publishedYes

Fingerprint

Epoxide Hydrolases
Epoxy Compounds
Autophagy
Adipose Tissue
Inflammation
Liver
Fats
Omega-3 Fatty Acids
Unsaturated Fatty Acids
Anti-Inflammatory Agents
Cytochrome P-450 CYP2E1
Cytochrome P-450 CYP1A1
Endoplasmic Reticulum Stress
Brown Adipose Tissue
Palmitates
Metabolic Diseases
Adipocytes
Cytochrome P-450 Enzyme System
Transgenic Mice
Lipid Peroxidation

Keywords

  • Autophagy
  • Inflammation
  • Obesity
  • Omega-3-derived epoxides
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • General

Cite this

Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver : Role for omega-3 epoxides. / López-Vicario, Cristina; Alcaraz-Quiles, José; García-Alonso, Verónica; Rius, Bibiana; Hwang, Sung H.; Titos, Esther; Lopategi, Aritz; Hammock, Bruce D.; Arroyo, Vicente; Clària, Joan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 2, 13.01.2015, p. 536-541.

Research output: Contribution to journalArticle

López-Vicario, C, Alcaraz-Quiles, J, García-Alonso, V, Rius, B, Hwang, SH, Titos, E, Lopategi, A, Hammock, BD, 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, vol. 112, no. 2, pp. 536-541. https://doi.org/10.1073/pnas.1422590112
López-Vicario, Cristina ; Alcaraz-Quiles, José ; García-Alonso, Verónica ; Rius, Bibiana ; Hwang, Sung H. ; Titos, Esther ; Lopategi, Aritz ; Hammock, Bruce D. ; Arroyo, Vicente ; Clària, Joan. / Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver : Role for omega-3 epoxides. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 2. pp. 536-541.
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AU - Hwang, Sung H.

AU - Titos, Esther

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