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

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e80922 ◽  
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

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

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.

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

2020 ◽  
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.

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

Biology ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 124 ◽  
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.

Toxicity of Epoxy Fatty Acids and Related Compounds to Cells Expressing Human Soluble Epoxide Hydrolase

2000 ◽  
Vol 13 (4) ◽  
pp. 217-226 ◽  
Author(s):  
Jessica F. Greene ◽  
John W. Newman ◽  
Kristin C. Williamson ◽  
Bruce D. Hammock
Keyword(s):  
Fatty Acids ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Epoxy Fatty Acids ◽  
Related Compounds

scholarly journals Pharmacological Inhibition of Soluble Epoxide Hydrolase by t-TUCB Improves Brown Adipose Tissue Activities in Diet-Induced Obesity

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1703-1703
Author(s):  
Yang Yang ◽  
Xinyun Xu ◽  
Katie Graham ◽  
Ahmed Bettaieb ◽  
Christophe Morisseau ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Food Intake ◽  
Brown Adipose Tissue ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Obese Mice ◽  
Treatment And Prevention ◽  
Insulin Tolerance ◽  
Brown Adipose

Abstract Objectives Brown adipose tissue (BAT), responsible for energy expenditure through nonshivering thermogenesis, has emerged as a novel target for obesity treatment and prevention. Soluble epoxide hydrolase (sEH), encoded by Ephx2 gene, is a cytosolic enzyme that converts epoxy fatty acids (EpFAs) that are produced by cytochrome P-450 enzymes from polyunsaturated fatty acids into less active diols. Pharmacological inhibitors of sEH, such as trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido] cyclohexyloxy} benzoic acid (t-TUCB), have been shown to be beneficial for chronic diseases by inhibiting the degradation of EpFAs. We have previously shown that t-TUCB dose-dependently promotes brown adipogenesis in vitro. This study investigated the therapeutic effects of t-TUCB on BAT activation in diet-induced obese mice. Methods Male C57BL6/J mice were fed a high-fat diet (60% kcal from fat) for 8 weeks followed by random assignment into either the control or t-TUCB group (n = 10 per group) to receive either the vehicle control or t-TUCB (3 mg/kg/day) via osmotic minipump delivery at the subcutaneous area near the interscapular BAT for 6 weeks. Bodyweight and food intake, glucose and insulin tolerance tests, cold tolerance tests, and indirect calorimetry were measured before the mice were euthanized for further biochemical analysis. Results sEH inhibition by t-TUCB in the obese mice did not change body weight, fat pad weight, food intake, fasting blood glucose, glucose and insulin tolerance, or cold tolerance, but significantly decreased blood triglyceride levels and increased heat production during both day and night. Moreover, t-TUCB significantly increased protein expression of brown marker gene PGC-1alpha and lipid droplet-associated protein perilipin (PLIN), but not uncoupling protein 1 (UCP1), in the interscapular BAT of diet-induced obese mice. Conclusions Our results suggest that sEH pharmacological inhibition may be beneficial for BAT activation by increasing mitochondrial biogenesis and lipolysis in the BAT. Further studies using the sEH inhibitors and/or EpFA generating diets for obesity treatment and prevention are warranted. Funding Sources The work was supported by NIH 1R15DK114790–01A1 (to L.Z.), K99DK100736 and R00DK100736 (to A.B.), R15AT008733 (to S.W.), R35 ES030443 and P42ES004699 (to B.D.H).

scholarly journals Epoxide hydrolase activities and epoxy fatty acids in the mosquito Culex quinquefasciatus

2015 ◽  
Vol 59 ◽  
pp. 41-49 ◽  
Author(s):  
Jiawen Xu ◽  
Christophe Morisseau ◽  
Jun Yang ◽  
Dadala M. Mamatha ◽  
Bruce D. Hammock
Keyword(s):  
Fatty Acids ◽  
Culex Quinquefasciatus ◽  
Epoxide Hydrolase ◽  
Epoxy Fatty Acids

scholarly journals Inhibition of soluble epoxide hydrolase ameliorates hyperhomocysteinemia-induced hepatic steatosis by enhancing β-oxidation of fatty acid in mice

2019 ◽  
Vol 316 (4) ◽  
pp. G527-G538 ◽  
Author(s):  
Liu Yao ◽  
Boyang Cao ◽  
Qian Cheng ◽  
Wenbin Cai ◽  
Chenji Ye ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver

Hepatic steatosis is the beginning phase of nonalcoholic fatty liver disease, and hyperhomocysteinemia (HHcy) is a significant risk factor. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids, attenuating their cardiovascular protective effects. However, the involvement of sEH in HHcy-induced hepatic steatosis is unknown. The current study aimed to explore the role of sEH in HHcy-induced lipid disorder. We fed 6-wk-old male mice a chow diet or 2% (wt/wt) high-metnionine diet for 8 wk to establish the HHcy model. A high level of homocysteine induced lipid accumulation in vivo and in vitro, which was concomitant with the increased activity and expression of sEH. Treatment with a highly selective specific sEH inhibitor (0.8 mg·kg−1·day−1 for the animal model and 1 μM for cells) prevented HHcy-induced lipid accumulation in vivo and in vitro. Inhibition of sEH activated the peroxisome proliferator-activated receptor-α (PPAR-α), as evidenced by elevated β-oxidation of fatty acids and the expression of PPAR-α target genes in HHcy-induced hepatic steatosis. In primary cultured hepatocytes, the effect of sEH inhibition on PPAR-α activation was further confirmed by a marked increase in PPAR-response element luciferase activity, which was reversed by knock down of PPAR-α. Of note, 11,12-EET ligand dependently activated PPAR-α. Thus increased sEH activity is a key determinant in the pathogenesis of HHcy-induced hepatic steatosis, and sEH inhibition could be an effective treatment for HHcy-induced hepatic steatosis. NEW & NOTEWORTHY In the current study, we demonstrated that upregulation of soluble epoxide hydrolase (sEH) is involved in the hyperhomocysteinemia (HHcy)-caused hepatic steatosis in an HHcy mouse model and in murine primary hepatocytes. Improving hepatic steatosis in HHcy mice by pharmacological inhibition of sEH to activate peroxisome proliferator-activated receptor-α was ligand dependent, and sEH could be a potential therapeutic target for the treatment of nonalcoholic fatty liver disease.

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