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, 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.obesity | inflammation | autophagy | omega-3-derived epoxides | soluble epoxide hydrolase C ytochrome P450 (CYP) epoxygenases represent the third branch of polyunsaturated fatty acid (PUFA) metabolism (1). CYP epoxygenases add oxygen across one of the four double bonds of PUFA to generate three-membered ethers known as epoxides (1). In the case of arachidonic acid, CYP epoxygenases convert this omega-6 PUFA into epoxyeicosatrienoic acids (EETs), which act as autocrine or paracrine factors in the regulation of vascular tone, inflammation, hyperalgesia, and organ and tissue regeneration (2, 3). In addition to omega-6s, CYP epoxygenases also convert the omega-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into novel epoxyeicosatetraenoic (EEQs) and epoxydocosapentaenoic (EDPs) acids, respectively (4, 5). These omega-3-derived epoxides also exert salutary actions and are even more effective and potent than omega-6-derived EETs (4-8).Because the predicted in vivo half-lives of fatty acid epoxides (EpFA) are in the order of seconds (9), drugs that stabilize their levels by targeting the en...

Soluble epoxide hydrolase: a new therapeutic target for depression

“…5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET) [1][2][3][4][5]. In addition to omega-6 PUFAs, omega-3 PUFAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are common substrates used by the major catalyzing enzymes in the three branches of the arachidonate cascade (Figure 1) [4][5][6]. Epoxygenated PUFAs, which are lipid mediators produced by CYP epoxygenases from PUFAs, are important signaling molecules which control biological processes, such as anti-inflammation [4,5].…”

“…As described earlier, the CYP epoxygenases convert omega-3 PUFAs (EPA and DHA) to their epoxides, such as epoxyeicosatetraenoic acids (EEQs) and epoxydocosapentaenoic acids (EDPs), both of which exert potent anti-inflammatory actions [3][4][5][6]. Soluble epoxide hydrolase (sEH) also regulates tissue levels of omega-3 PUFA, by converting these omega-3 PUFA epoxides (e.g.…”

“…EEQs, EDPs) into their less active diols [3][4][5][6]. Interestingly, sEH inhibitors reduced the symptoms of diabetes in mice with enhanced levels of omega-3 PUFA [6]. Given the crucial contribution of omega-3 PUFA epoxides (e.g.…”

Effect of fish oil on monoepoxides derived from fatty acids during cardiac surgery

“…Our novel results indicate that the variability in plasma phospholipid response to n-3 PUFA supplementation may also be an important determinant of the availability of circulating MEFA following tissue injury. Given the potent anti-infl ammatory and cardiovascular-protective properties of MEFAs observed in experimental studies (25)(26)(27), our fi ndings suggest a potential explanation for variable cardiovascular effects of n-3 PUFA supplementation in different individuals and highlight the need for additional studies to determine biological and dietary determinants that may enhance or weaken MEFA production in response to n-3 PUFA consumption.…”

EPA and/or DHA? A test question on the principles and opportunities in utilizing the therapeutic potential of omega-3 fatty acids

“…17,18-EEQ appears to function as a highly potent mediator of cardioprotective and antiarrhythmic effects of EPA (13). As demonstrated in in vitro and animal studies, 17,18-EEQ also displays vasodilatory, anti-inflammatory, and anti-allergic properties that contribute to the beneficial effects of n-3 LC-PUFAs in diverse disease states ranging from bronchial disorders (16), fatty liver disease (17), and intraocular neovascularization (18) to allergic intestinal inflammation (19). The DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP alias 19,20-Ep-DPE) shares several of these properties but has attracted the most attention due to its capacity to inhibit tumor angiogenesis and proliferation (20).…”