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

PROVIDER: PRJNA767547 | ENA |

REPOSITORIES: ENA

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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

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

Project description:Fatty acid metabolites generated by the sequential actions of cytochrome P450 enzymes and the soluble epoxide hydrolase (sEH) regulate inflammation. Here we report that the TGF--induced polarization of macrophages to a pro-resolving phenotype requires the activation of Alk5 and Smad2 to increase sEH expression and activity. Macrophages lacking sEH failed to fully repolarize, were less efficient at phagocytosis, and retained a pro-inflammatory gene expression profile. 11,12-Epoxyeicosatrienoic acid (EET) was one of the fatty acid metabolites altered in sEH-/- macrophages and was able to reproduce the effect of sEH deletion on gene expression. Importantly, 11,12-EET also attenuated the expression of Alk5 to inhibit the TGF--induced phosphorylation of Smad2 by eliciting the cytosolic translocation of the E3 ligase Smurf2. These results indicate that the expression of sEH is not only controlled by TGF- but that the activity of the enzyme, which keeps 11,12-EET levels low, actually promotes TGF- signaling by preventing the proteolytic degradation of Alk5. Thus, an autocrine loop between the sEH/11,12-EET and TGF-1 determines macrophage function.

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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.

Project description: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's microvasculature. The objective of our study was to determine the molecular effects of an HGD on hippocampal microvessels and cognitive function and determine if a soluble epoxide hydrolase (sEH) inhibitor (sEHI), known to be vasculoprotective and anti-inflammatory, modulates these effects. Wild type male mice were fed a low glycemic diet (LGD, 12% sucrose/weight) or an HGD (34% sucrose/weight) with/without the sEHI, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), for 12 weeks. Brain hippocampal microvascular gene expression was assessed by microarray and data analyzed using a multi-omic approach for differential expression of protein and non-protein-coding genes, gene networks, functional pathways, and transcription factors. 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. Ours is the first study to demonstrate that high dietary glycemia contributes to brain hippocampal microvascular inflammation through sEH.

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