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Inhibition of Soluble Epoxide Hydrolase is Protective Against the Multiomic Effects of a High Glycemic Diet on Brain Microvascular Inflammation and Cognitive Dysfunction

ABSTRACT: Diet is a modifiable risk factor for cardiovascular disease (CVD) and dementia, yet relatively little is known about the effect of a high glycemic diet (HGD) on the brain microvasculature. The objective of our study was to determine the molecular effects of a HGD on hippocampal microvessels and cognitive function, and to determine if a soluble epoxide hydrolase (sEH) inhibitor (sEHI), known to be vasculoprotective and anti-inflammatory, modulates these effects. Global hippocampal microvascular gene expression was fundamentally different for mice fed the HGD vs the LGD. The HGD response was characterized by differential expression of 608 genes involved in cell signaling, neurodegeneration, metabolism, and cell adhesion/inflammation/oxidation effects reversible by t-AUCB and hence sEH inhibitor correlated with protection against Alzheimer’s dementia.

ORGANISM(S): Mus musculus

PROVIDER: GSE185057 | GEO | 2021/12/07

REPOSITORIES: GEO

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Differential Multigenomic Effect of Soluble Epoxide Hydrolase Inhibition on the Hippocampal Brain Microvasculature of FeFemale Mice on Low and High Glycemic Diets.

Project description:Microvascular dysfunction is central to the development of dementia. The effect of high glycemic diet (HGD), independent from dietary fat, on brain microvasculature is crucial, yet an understudied research topic, especially in feFemales. Our study aimed to determine the transcriptomic changes in feFemale brain hippocampal microvasculature induced by a HGD and characterize the response to soluble epoxide hydrolase inhibitor (sEHI). We demonstrated for the first time in feFemales that the HGD had an opposite gene expression profile compared to the LGD and differentially expressed 506 genes, primarily downregulated, with functions related to cell signaling, cell adhesion, cellular metabolism, and neurodegenerative diseases. Surprisingly, the sEHI modified the transcriptome of feFemale mice consuming the LGD more than the HGD, by modulating genes involved in metabolic pathways that synthesize neuroprotective epoxyeicosatrienoic acids (EETs) and associated with a higher EETs/ dihydroxyeicosatrienoic acids (DHETs) ratio.

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A regulatory loop involving the cytochrome P450-soluble epoxide hydrolase axis and TGF-b signaling

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Project description:Soluble epoxide hydrolase (sEH) plays a key role in the metabolic conversion of the protective eicosanoid 14,15-epoxyeicosatrienoic acid to 14,15-dihydroxyeicosatrienoic acid. Accordingly, inhibition of sEH hydrolase activity has been shown to be beneficial in multiple models of cardiovascular diseases, thus identifying sEH as a valuable therapeutic target. Recently, a common human polymorphism (R287Q) was identified that reduces sEH hydrolase activity and is localized to the dimerization interface of the protein, suggesting a relationship between sEH dimerization and activity. To directly test the hypothesis that dimerization is essential for the proper function of sEH, we generated mutations within the sEH protein that would either disrupt or stabilize dimerization. We quantified the dimerization state of each mutant using a split firefly luciferase protein fragment-assisted complementation system. The hydrolase activity of each mutant was determined using a fluorescence-based substrate conversion assay. We found that mutations that disrupted dimerization also eliminated hydrolase enzymatic activity. In contrast, a mutation that stabilized dimerization restored hydrolase activity. Finally, we investigated the kinetics of sEH dimerization and found that the human R287Q polymorphism was metastable and capable of swapping dimer partners faster than the WT enzyme. These results indicate that dimerization is required for sEH hydrolase activity. Disrupting sEH dimerization may therefore serve as a novel therapeutic strategy for reducing sEH hydrolase activity.

| S-EPMC3597810 | biostudies-literature

Inhibition of Soluble Epoxide Hydrolase is Protective Against the Multiomic Effects of a High Glycemic Diet on Brain Microvascular Inflammation and Cognitive Dysfunction

Project description:Inhibition of Soluble Epoxide Hydrolase is Protective Against the Multiomic Effects of a High Glycemic Diet on Brain Microvascular Inflammation and Cognitive Dysfunction

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Transcription profiling of rats in a long-term Clofibric acid study

Project description:F344 rats were divided into 4 groups: vehicle control, DEN, DEN+CLO and CLO. After one week of basal diet, rats belonging to the groups DEN and DEN+CLO underwent intraperitoneal injection of DEN (30mg/kg body weight) dissolved in NaCl 9â°. The two other groups were injected with NaCl 9â° alone. At 30mg/kg, DEN is non-necrogenic thus only exhibiting initiating properties. Twelve days after injection, diet from rats belonging to the groups CLO and DEN+CLO was changed for diet containing 5000ppm CLO for up to 608 days. Series of 5 rats from each group were necropsied at days 18, 46, 102, 264, 377, 447 (reverse phase from day 377: no more CLO in the diet for rats belonging to the DEN+CLO group), and for the CLO and Control group 524, and 608 days after the injection of DEN or saline. From day 524, half of the CLO-treated rats were kept on basal diet (reverse phase) until day 608.

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Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase.

Project description:Hepoxilins are lipid signaling molecules derived from arachidonic acid through the 12-lipoxygenase pathway. These trans-epoxy hydroxy eicosanoids play a role in a variety of physiological processes, including inflammation, neurotransmission, and formation of skin barrier function. Mammalian hepoxilin hydrolase, partly purified from rat liver, has earlier been reported to degrade hepoxilins to trioxilins. Here, we report that hepoxilin hydrolysis in liver is mainly catalyzed by soluble epoxide hydrolase (sEH): i) purified mammalian sEH hydrolyses hepoxilin A? and B? with a V(max) of 0.4-2.5 ?mol/mg/min; ii) the highly selective sEH inhibitors N-adamantyl-N'-cyclohexyl urea and 12-(3-adamantan-1-yl-ureido) dodecanoic acid greatly reduced hepoxilin hydrolysis in mouse liver preparations; iii) hepoxilin hydrolase activity was abolished in liver preparations from sEH(-/-) mice; and iv) liver homogenates of sEH(-/-) mice show elevated basal levels of hepoxilins but lowered levels of trioxilins compared with wild-type animals. We conclude that sEH is identical to previously reported hepoxilin hydrolase. This is of particular physiological relevance because sEH is emerging as a novel drug target due to its major role in the hydrolysis of important lipid signaling molecules such as epoxyeicosatrienoic acids. sEH inhibitors might have undesired side effects on hepoxilin signaling.

| S-EPMC3284163 | biostudies-literature

Long-term Clofibric acid study

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