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: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 2 Pg. 536-41 (Jan 13 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25550510 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(4-(3-(4-trifluoromethoxy-phenyl)ureido)cyclohexyloxy)benzoic acid
• Benzoates
• Cadherins
• Enzyme Inhibitors
• Epoxy Compounds
• Fatty Acids, Omega-3
• Phenylurea Compounds
• fat1 protein, mouse
• Cytochrome P-450 Enzyme System
• Cytochrome P-450 CYP2E1
• Cytochrome P-450 CYP1A1
• Fatty Acid Desaturases
• omega-3 fatty acid desaturase
• Epoxide Hydrolases

Topics

• 3T3-L1 Cells
• Adipose Tissue (drug effects, metabolism, pathology)
• Animals
• Autophagy (physiology)
• Benzoates (pharmacology)
• Cadherins (genetics, metabolism)
• Cytochrome P-450 CYP1A1 (metabolism)
• Cytochrome P-450 CYP2E1 (metabolism)
• Cytochrome P-450 Enzyme System (metabolism)
• Enzyme Inhibitors (pharmacology)
• Epoxide Hydrolases (antagonists & inhibitors)
• Epoxy Compounds (metabolism)
• Fatty Acid Desaturases (genetics, metabolism)
• Fatty Acids, Omega-3 (metabolism)
• Female
• Inflammation (metabolism, pathology)
• Liver (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Mice, Transgenic
• Obesity (metabolism, pathology)
• Phenylurea Compounds (pharmacology)