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 High fat diet enriched with saturated, but not monounsaturated fatty acids adversely affects femur, and both diets increase calcium absorption in older female mice

2016 ◽  
Vol 36 (7) ◽  
pp. 742-750 ◽  
Author(s):  
Yang Wang ◽  
Peter Dellatore ◽  
Veronique Douard ◽  
Ling Qin ◽  
Malcolm Watford ◽  
...  
Keyword(s):  
Fatty Acids ◽  
High Fat Diet ◽  
Calcium Absorption ◽  
Monounsaturated Fatty Acids ◽  
High Fat ◽  
Female Mice

scholarly journals Differential Effects of Combined Soluble Epoxide Hydrolase Inhibitor t-TUCB and n-3 Epoxides in Diet-Induced Obesity

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1260-1260
Author(s):  
Yang Yang ◽  
Xinyun Xu ◽  
Christophe Morisseau ◽  
Bruce Hammock ◽  
Ahmed Bettaieb ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Protein Expression ◽  
Cold Tolerance ◽  
High Fat Diet ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Brown Adipose

Abstract Objectives Brown adipose tissue (BAT) is a promising target for obesity prevention. N-3 epoxides are fatty acid epoxides produced from n-3 polyunsaturated fatty acids and shown to be beneficial for health. However, these epoxides are unstable and quickly metabolized by the cytosolic soluble epoxide hydrolase (sEH). Here, we investigated the effects of sEH inhibitor (t-TUCB) alone or combined with two different n-3 epoxides on BAT activation in the development of diet-induced obesity and associated metabolic disorders. Methods Male C57BL6/J mice were fed a high-fat diet and received either of the following treatment: the vehicle control, t-TUCB alone (T), or t-TUCB combined with 19,20-EDP (T + EDP) or 17,18-EEQ (T + EEQ) via osmotic minipump delivery near the interscapular BAT for 6 weeks. Mice were examined for changes in body weight, food intake, glucose, insulin, and cold tolerance tests, and indirect calorimetry. Blood and tissue biochemical analyses were also performed to assess changes in metabolic homeostasis. Results Although no differences in food intake were observed, there were small but significant increases in body weight in both T and T + EDP groups. Mice in the T + EDP and T + EEQ groups showed significant decreases in fasting glucose and serum TG levels, higher core body temperature, and better cold tolerance compared to the controls. However, heat production was significantly increased only in the T + EEQ group. Thermogenic UCP1 protein expression showed a moderate, but not significant, increase in the T + EEQ group. On the other hand, PGC1 α protein expression was significantly increased in the T, T + EDP, and T + EEQ groups compared to the controls. Perilipin protein expression and phosphorylation were also significantly increased in the three treated groups. In contrast, protein expression of FABP4 and HSL was only increased in the T and T + EDP groups, and CD36 protein expression was only increased in the T + EEQ group. Conclusions Our results suggest that sEH pharmacological inhibition by t-TUCB combined with n-3 epoxides may prevent high-fat diet-induced glucose and lipid disorders, in part through increased thermogenesis and upregulating of protein expression of thermogenic and lipid metabolic genes. Funding Sources The work was supported by NIH grants to L.Z., A.B., and B.D.H.

Elevated n-3 fatty acids in a high-fat diet attenuate the increase in PDH kinase activity but not PDH activity in human skeletal muscle

2005 ◽  
Vol 98 (1) ◽  
pp. 350-355 ◽  
Author(s):  
Erin A. Turvey ◽  
George J. F. Heigenhauser ◽  
Michelle Parolin ◽  
Sandra J. Peters
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Pyruvate Dehydrogenase ◽  
High Fat Diet ◽  
Human Skeletal Muscle ◽  
Fat Content ◽  
Pyruvate Dehydrogenase Kinase ◽  
High Fat ◽  
High Fat Diets ◽  
Fat Diets

We tested the hypothesis that a high-fat diet (75% fat; 5% carbohydrates; 20% protein), for which 15% of the fat content was substituted with n-3 fatty acids, would not exhibit the diet-induced increase in pyruvate dehydrogenase kinase (PDK) activity, which is normally observed in human skeletal muscle. The fat content was the same in both the regular high-fat diet (HF) and in the n-3-substituted diet (N3). PDK activity increased after both high-fat diets, but the increase was attenuated after the N3 diet (0.051 ± 0.007 and 0.218 ± 0.047 min−1 for pre- and post-HF, respectively; vs. 0.073 ± 0.016 and 0.133 ± 0.032 min−1 for pre- and post-N3, respectively). However, the active form of pyruvate dehydrogenase (PDHa) activity decreased to a similar extent in both conditions (0.93 ± 0.17 and 0.43 ± 0.09 mmol/kg wet wt pre- and post-HF; vs. 0.87 ± 0.19 and 0.39 ± 0.05 mmol/kg wet wt pre- and post-N3, respectively). This suggested that the difference in PDK activity did not affect PDHa activation in the basal state, and it was regulated by intramitochondrial effectors, primarily muscle pyruvate concentration. Muscle glycogen content was consistent throughout the study, before and after both diet conditions, whereas muscle glucose-6-phosphate, glycerol-3-phosphate, lactate, and pyruvate were decreased after the high-fat diets. Plasma triglycerides decreased after both high-fat diets but decreased to a greater extent after the N3, whereas plasma free fatty acids increased after both diets, but to a lesser extent after the N3. In summary, PDK activity is decreased after a high-fat diet that is rich in n-3 fatty acids, although PDHa activity was unaltered. In addition, our data demonstrated that the hypolipidemic effect of n-3 fatty acids occurs earlier (3 days) than previously reported and is evident even when the diet has 75% of its total energy derived from fat.

scholarly journals Inhibition of soluble epoxide hydrolase attenuates a high-fat diet-mediated renal injury by activating PAX2 and AMPK

2019 ◽  
Vol 116 (11) ◽  
pp. 5154-5159 ◽  
Author(s):  
Ying Luo ◽  
Ming-Yu Wu ◽  
Bing-Qing Deng ◽  
Jian Huang ◽  
Sung Hee Hwang ◽  
...  
Keyword(s):  
Renal Injury ◽  
High Fat Diet ◽  
Epoxide Hydrolase ◽  
Mesangial Cells ◽  
Soluble Epoxide Hydrolase ◽  
Epoxyeicosatrienoic Acids ◽  
High Fat ◽  
Plasmid Construction ◽  
Protein Levels ◽  
Chaperone Mediated Autophagy

A high-fat diet (HFD) causes obesity-associated morbidities involved in macroautophagy and chaperone-mediated autophagy (CMA). AMPK, the mediator of macroautophage, has been reported to be inactivated in HFD-caused renal injury. However, PAX2, the mediator for CMA, has not been reported in HFD-caused renal injury. Here we report that HFD-caused renal injury involved the inactivation of Pax2 and Ampk, and the activation of soluble epoxide hydrolase (sEH), in a murine model. Specifically, mice fed on an HFD for 2, 4, and 8 wk showed time-dependent renal injury, the significant decrease in renal Pax2 and Ampk at both mRNA and protein levels, and a significant increase in renal sEH at mRNA, protein, and molecular levels. Also, administration of an sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea, significantly attenuated the HFD-caused renal injury, decreased renal sEH consistently at mRNA and protein levels, modified the renal levels of sEH-mediated epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) as expected, and increased renal Pax2 and Ampk at mRNA and/or protein levels. Furthermore, palmitic acid (PA) treatment caused significant increase in Mcp-1, and decrease in both Pax2 and Ampk in murine renal mesangial cells (mRMCs) time- and dose-dependently. Also, 14(15)-EET (a major substrate of sEH), but not its sEH-mediated metabolite 14,15-DHET, significantly reversed PA-induced increase in Mcp-1, and PA-induced decrease in Pax2 and Ampk. In addition, plasmid construction revealed that Pax2 may positively regulate Ampk transcriptionally in mRMCs. This study provides insights into and therapeutic target for the HFD-mediated renal injury.

Abstract W P363: Mechanism of Protection by Soluble Epoxide Hydrolase Inhibition in Type 2 Diabetic Stroke

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Kristen L Zuloaga ◽  
Stephanie M Krasnow ◽  
Wenri Zhang ◽  
Robert E Shangraw ◽  
Daniel L Marks ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Artery Occlusion ◽  
High Fat ◽  
Gene Encoding ◽  
Glucose Levels ◽  
Normal Chow ◽  
And Control

Hyperglycemia worsens stroke, yet rigorous glycemic control does not improve neurologic outcome. An alternative is to target downstream molecular mediators triggered by hyperglycemia. Soluble epoxide hydrolase (sEH) is a potential mediator of ischemic injury via its metabolism of neuroprotective epoxyeicosatrienoic acids (EETs). We previously demonstrated that sEH mRNA is overexpressed in type 1 diabetic (T1D) mice, and specific sEH blockade protects the brain from the deleterious effect of T1D on stroke. We tested the hypothesis that type 2 diabetes (T2D) exacerbates injury following middle cerebral artery occlusion (MCAO) in part by up-regulating expression of EPHX2 (gene encoding for sEH) and decreasing brain concentrations of neuroprotective EETs. T2D was produced by combined high-fat diet, nicotinamide and streptozotocin in male C57BL/6J mice. T2D and control mice were treated with vehicle or the sEH inhibitor trans-4-[4-(3-Adamantan-1-yl-ureido) -cyclohexyloxy]-benzoic acid (t-AUCB; 1mg/kg, i.p., 7 days), then subjected to 60-min MCAO. Compared to normal chow-fed mice, high fat diet-fed mice exhibited a 1.7 fold upregulation of EPHX2 mRNA in brain (p<0.05, n=7). T2D mice had increased blood glucose levels compared to control mice before, during and after MCAO (p<0.001, n=4-5). Relative laser-Doppler perfusion of the MCA territory after reperfusion was decreased in T2D mice compared to controls (p<0.05, n= 4-5). Vehicle-treated T2D mice sustained larger cortical infarcts than vehicle-treated control mice (p<0.05, n=5-7). t-AUCB decreased fasting glucose levels at baseline and throughout ischemia (p<0.001, n=4-5) and improved cortical perfusion after MCAO (p<0.001, n=4-5) in T2D mice. In line with these improvements, t-AUCB significantly reduced infarct size in T2D mice (p<0.05 vs. T2D vehicle, n= 5-7). We conclude that increasing EETs bioavailability via sEH inhibition improves stroke outcome in T2D in part by improving glycemic status and improving post-ischemic reperfusion in the ischemic territory.

scholarly journals Soluble Epoxide Hydrolase Deficiency or Inhibition Attenuates Diet-induced Endoplasmic Reticulum Stress in Liver and Adipose Tissue

2013 ◽  
Vol 288 (20) ◽  
pp. 14189-14199 ◽  
Author(s):  
Ahmed Bettaieb ◽  
Naoto Nagata ◽  
Daniel AbouBechara ◽  
Samah Chahed ◽  
Christophe Morisseau ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Er Stress ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Hepg2 Cells ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
High Fat ◽  
Pharmacological Inhibition

Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose inhibition has beneficial effects in cardiovascular, inflammatory, and metabolic diseases in murine models. Mice with targeted deletion or pharmacological inhibition of sEH exhibit improved insulin signaling in liver and adipose tissue. Herein, we assessed the role of sEH in regulating endoplasmic reticulum (ER) stress in liver and adipose tissue. We report that sEH expression was increased in the livers and adipose tissue of mice fed a high fat diet, the adipose tissue of overweight humans, and palmitate-treated cells. Importantly, sEH deficiency or inhibition in mice attenuated chronic high fat diet-induced ER stress in liver and adipose tissue. Similarly, pharmacological inhibition of sEH in HepG2 cells and 3T3-L1 adipocytes mitigated chemical-induced ER stress and activation of JNK, p38, and cell death. In addition, insulin signaling was enhanced in HepG2 cells treated with sEH substrates and attenuated in cells treated with sEH products. In summary, these findings demonstrate that sEH is a physiological modulator of ER stress and a potential target for mitigating complications associated with obesity.

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 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.

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