Expression and characterization of an epoxide hydrolase from Anopheles gambiae with high activity on epoxy fatty acids

In Euphorbia lagascae the major fatty acid in triacylglycerol is the epoxidated fatty acid vernolic acid (cis- 12-epoxyoctadeca-cis-9-enoic acid). The enzymic reactions occurring during the catabolism of epoxidated fatty acids during germination are not known, but it seems likely that the degradation requires the activity of an epoxide hydrolase. Epoxide hydrolases are a group of functionally related enzymes that catalyse the cofactor-independent hydrolysis of epoxides to their corresponding vicinal diols by the addition of a water molecule. Here we report the cloning and characterization of an epoxide hydrolase gene from E. lagascae. The structure of the gene is unusual since it lacks introns. A detailed investigation of the transcription pattern of the epoxide hydrolase gene shows that the gene is induced during germination. We have used in situ hybridization to identify in which tissues the gene is expressed during germination. We speculate that this epoxide hydrolase enzyme is involved in the catabolism of epoxidated fatty acids during germination of E. lagascae seeds.

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Soluble Epoxide Hydrolase Deletion Limits High-Fat Diet-Induced Inflammation

Frontiers in Pharmacology ◽

10.3389/fphar.2021.778470 ◽

2021 ◽

Vol 12 ◽

Author(s):

Karen M. Wagner ◽

Jun Yang ◽

Christophe Morisseau ◽

Bruce D. Hammock

Keyword(s):

Fatty Acids ◽

High Fat Diet ◽

Epoxide Hydrolase ◽

Biological Effects ◽

Soluble Epoxide Hydrolase ◽

Bioactive Lipids ◽

High Fat ◽

Female Mice ◽

Epoxy Fatty Acids ◽

Fat Diets

The soluble epoxide hydrolase (sEH) enzyme is a major regulator of bioactive lipids. The enzyme is highly expressed in liver and kidney and modulates levels of endogenous epoxy-fatty acids, which have pleiotropic biological effects including limiting inflammation, neuroinflammation, and hypertension. It has been hypothesized that inhibiting sEH has beneficial effects on limiting obesity and metabolic disease as well. There is a body of literature published on these effects, but typically only male subjects have been included. Here, we investigate the role of sEH in both male and female mice and use a global sEH knockout mouse model to compare the effects of diet and diet-induced obesity. The results demonstrate that sEH activity in the liver is modulated by high-fat diets more in male than in female mice. In addition, we characterized the sEH activity in high fat content tissues and demonstrated the influence of diet on levels of bioactive epoxy-fatty acids. The sEH KO animals had generally increased epoxy-fatty acids compared to wild-type mice but gained less body weight on higher-fat diets. Generally, proinflammatory prostaglandins and triglycerides were also lower in livers of sEH KO mice fed HFD. Thus, sEH activity, prostaglandins, and triglycerides increase in male mice on high-fat diet but are all limited by sEH ablation. Additionally, these changes also occur in female mice though at a different magnitude and are also improved by knockout of the sEH enzyme.

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Epoxy Fatty Acids and Inhibition of the Soluble Epoxide Hydrolase Selectively Modulate GABA Mediated Neurotransmission to Delay Onset of Seizures

PLoS ONE ◽

10.1371/journal.pone.0080922 ◽

2013 ◽

Vol 8 (12) ◽

pp. e80922 ◽

Cited By ~ 39

Author(s):

Bora Inceoglu ◽

Dorota Zolkowska ◽

Hyun Ju Yoo ◽

Karen M. Wagner ◽

Jun Yang ◽

...

Keyword(s):

Fatty Acids ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Epoxy Fatty Acids

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Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues

International Journal of Molecular Sciences ◽

10.3390/ijms22094993 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4993

Author(s):

Christophe Morisseau ◽

Sean D. Kodani ◽

Shizuo G. Kamita ◽

Jun Yang ◽

Kin Sing Stephen Lee ◽

...

Keyword(s):

Fatty Acids ◽

Epoxide Hydrolase ◽

Protein Quantification ◽

The Body ◽

Biologically Active ◽

Relative Importance ◽

Epoxide Hydrolases ◽

Epoxy Fatty Acids ◽

Hydrolysis Of

Epoxy-fatty acids (EpFAs) are endogenous lipid mediators that have a large breadth of biological activities, including the regulation of blood pressure, inflammation, angiogenesis, and pain perception. For the past 20 years, soluble epoxide hydrolase (sEH) has been recognized as the primary enzyme for degrading EpFAs in vivo. The sEH converts EpFAs to the generally less biologically active 1,2-diols, which are quickly eliminated from the body. Thus, inhibitors of sEH are being developed as potential drug therapeutics for various diseases including neuropathic pain. Recent findings suggest that other epoxide hydrolases (EHs) such as microsomal epoxide hydrolase (mEH) and epoxide hydrolase-3 (EH3) can contribute significantly to the in vivo metabolism of EpFAs. In this study, we used two complementary approaches to probe the relative importance of sEH, mEH, and EH3 in 15 human tissue extracts: hydrolysis of 14,15-EET and 13,14-EDP using selective inhibitors and protein quantification. The sEH hydrolyzed the majority of EpFAs in all of the tissues investigated, mEH hydrolyzed a significant portion of EpFAs in several tissues, whereas no significant role in EpFAs metabolism was observed for EH3. Our findings indicate that residual mEH activity could limit the therapeutic efficacy of sEH inhibition in certain organs.

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Epoxy fatty acid dysregulation and neuroinflammation in Alzheimer’s disease is resolved by a soluble epoxide hydrolase inhibitor

10.1101/2020.06.30.180984 ◽

2020 ◽

Cited By ~ 1

Author(s):

Anamitra Ghosh ◽

Michele E. Comerota ◽

Debin Wan ◽

Fading Chen ◽

Nicholas E. Propson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Fatty Acids ◽

Cognitive Function ◽

Mouse Models ◽

Small Molecule ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Epoxy Fatty Acids ◽

5Xfad Mouse ◽

Β Amyloid

AbstractNeuroinflammation has been increasingly recognized to play critical roles in Alzheimer’s disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by the soluble epoxide hydrolase (sEH). We found that sEH is predominantly expressed in astrocytes where its levels are significantly elevated in postmortem human AD brains and in β-amyloid mouse models, and the latter is correlated with drastic reductions of brain EpFA levels. Using a highly potent and specific small molecule sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report here that TPPU treatment potently protected against LPS-induced inflammation in vitro and in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation, and this is associated with reduced β–amyloid pathology and improved synaptic integrity and cognitive function. Importantly, TPPU treatment reinstated and positively correlated EpFA levels in the 5xFAD mouse brain, demonstrating its brain penetration and target engagement. These findings support TPPU as a novel therapeutic target for the treatment of AD and related disorders.One Sentence SummaryWe show that soluble epoxide hydrolase is upregulated in AD patients and mouse models, and that inhibition of this lipid metabolic pathway using an orally bioavailable small molecule inhibitor is effective in restoring brain epoxy fatty acids, ameliorating AD neuropathology and improving synaptic and cognitive function.

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Soluble Epoxide Hydrolase Inhibition in Liver Diseases: A Review of Current Research and Knowledge Gaps

Biology ◽

10.3390/biology9060124 ◽

2020 ◽

Vol 9 (6) ◽

pp. 124 ◽

Cited By ~ 1

Author(s):

Jeffrey Warner ◽

Josiah Hardesty ◽

Kara Zirnheld ◽

Craig McClain ◽

Dennis Warner ◽

...

Keyword(s):

Fatty Acids ◽

Liver Diseases ◽

Epoxide Hydrolase ◽

Molecular Mechanisms ◽

Soluble Epoxide Hydrolase ◽

Biologically Active ◽

Future Research ◽

Omega 3 ◽

Alcoholic Fatty Liver ◽

Epoxy Fatty Acids

Emerging evidence suggests that soluble epoxide hydrolase (sEH) inhibition is a valuable therapeutic strategy for the treatment of numerous diseases, including those of the liver. sEH rapidly degrades cytochrome P450-produced epoxygenated lipids (epoxy-fatty acids), which are synthesized from omega-3 and omega-6 polyunsaturated fatty acids, that generally exert beneficial effects on several cellular processes. sEH hydrolysis of epoxy-fatty acids produces dihydroxy-fatty acids which are typically less biologically active than their parent epoxide. Efforts to develop sEH inhibitors have made available numerous compounds that show therapeutic efficacy and a wide margin of safety in a variety of different diseases, including non-alcoholic fatty liver disease, liver fibrosis, portal hypertension, and others. This review summarizes research efforts which characterize the applications, underlying effects, and molecular mechanisms of sEH inhibitors in these liver diseases and identifies gaps in knowledge for future research.

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