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The Role of Cytochrome P450 Epoxygenases, Soluble Epoxide Hydrolase, and Epoxyeicosatrienoic Acids in Metabolic Diseases.

ABSTRACT: Metabolic diseases are associated with an increased risk of developing cardiovascular disease. The features comprising metabolic diseases include obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hypertension. Recent evidence has emerged showcasing a role for cytochrome P450 epoxygenases, soluble epoxide hydrolase, and epoxyeicosatrienoic acids (EETs) in the development and progression of metabolic diseases. This review discusses the current knowledge related to the modulation of cytochrome P450 epoxygenases and soluble epoxide hydrolase to alter concentrations of biologically active EETs, resulting in effects on insulin resistance, lipid metabolism, obesity, and diabetes. Future areas of research to address current deficiencies in the understanding of these enzymes and their eicosanoid metabolites in various aspects of metabolic diseases are also discussed.

SUBMITTER: Xu X

PROVIDER: S-EPMC5105036 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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The Role of Cytochrome P450 Epoxygenases, Soluble Epoxide Hydrolase, and Epoxyeicosatrienoic Acids in Metabolic Diseases.

Xu Xizhen X Li Rui R Chen Guangzhi G Hoopes Samantha L SL Zeldin Darryl C DC Wang Dao Wen DW

Advances in nutrition (Bethesda, Md.) 20161115 6

Metabolic diseases are associated with an increased risk of developing cardiovascular disease. The features comprising metabolic diseases include obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hypertension. Recent evidence has emerged showcasing a role for cytochrome P450 epoxygenases, soluble epoxide hydrolase, and epoxyeicosatrienoic acids (EETs) in the development and progression of metabolic diseases. This review discusses the current knowledge related to the modulation of c ...[more]

PMID: 28140329

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Project description:BackgroundAlzheimer's disease, cardiovascular disease, and other cardiometabolic disorders may share inflammatory origins. Lipid mediators, including oxylipins, endocannabinoids, bile acids, and steroids, regulate inflammation, energy metabolism, and cell proliferation with well-established involvement in cardiometabolic diseases. However, their role in Alzheimer's disease is poorly understood. Here, we describe the analysis of plasma and cerebrospinal fluid lipid mediators in a case-control comparison of ~150 individuals with Alzheimer's disease and ~135 healthy controls, to investigate this knowledge gap.MethodsLipid mediators were measured using targeted quantitative mass spectrometry. Data were analyzed using the analysis of covariates, adjusting for sex, age, and ethnicity. Partial least square discriminant analysis identified plasma and cerebrospinal fluid lipid mediator discriminates of Alzheimer's disease. Alzheimer's disease predictive models were constructed using machine learning combined with stepwise logistic regression.ResultsIn both plasma and cerebrospinal fluid, individuals with Alzheimer's disease had elevated cytochrome P450/soluble epoxide hydrolase pathway components and decreased fatty acid ethanolamides compared to healthy controls. Circulating metabolites of soluble epoxide hydrolase and ethanolamides provide Alzheimer's disease predictors with areas under receiver operator characteristic curves ranging from 0.82 to 0.92 for cerebrospinal fluid and plasma metabolites, respectively.ConclusionsPrevious studies report Alzheimer's disease-associated soluble epoxide hydrolase upregulation in the brain and that endocannabinoid metabolism provides an adaptive response to neuroinflammation. This study supports the involvement of P450-dependent and endocannabinoid metabolism in Alzheimer's disease. The results further suggest that combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimer's disease.

Project description:AIMS/HYPOTHESIS:Insulin resistance is frequently associated with hypertension and type 2 diabetes. The cytochrome P450 (CYP) arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure and may also improve glucose homeostasis. However, the direct contribution of endogenous EET production on insulin sensitivity has not been previously investigated. In this study, we tested the hypothesis that endogenous CYP2C-derived EETs alter insulin sensitivity by analysing mice lacking CYP2C44, a major EET producing enzyme, and by testing the association of plasma EETs with insulin sensitivity in humans. METHODS:We assessed insulin sensitivity in wild-type (WT) and Cyp2c44 -/- mice using hyperinsulinaemic-euglycaemic clamps and isolated skeletal muscle. Insulin secretory function was assessed using hyperglycaemic clamps and isolated islets. Vascular function was tested in isolated perfused mesenteric vessels. Insulin sensitivity and secretion were assessed in humans using frequently sampled intravenous glucose tolerance tests and plasma EETs were measured by mass spectrometry. RESULTS:Cyp2c44 -/- mice showed decreased glucose tolerance (639 ± 39.5 vs 808 ± 37.7 mmol/l × min for glucose tolerance tests, p = 0.004) and insulin sensitivity compared with WT controls (hyperinsulinaemic clamp glucose infusion rate average during terminal 30 min 0.22 ± 0.02 vs 0.33 ± 0.01 mmol kg-1 min-1 in WT and Cyp2c44 -/- mice respectively, p = 0.003). Although glucose uptake was diminished in Cyp2c44 -/- mice in vivo (gastrocnemius Rg 16.4 ± 2.0 vs 6.2 ± 1.7 ?mol 100 g-1 min-1, p < 0.01) insulin-stimulated glucose uptake was unchanged ex vivo in isolated skeletal muscle. Capillary density was similar but vascular KATP-induced relaxation was impaired in isolated Cyp2c44 -/- vessels (maximal response 39.3 ± 6.5% of control, p < 0.001), suggesting that impaired vascular reactivity produces impaired insulin sensitivity in vivo. Similarly, plasma EETs positively correlated with insulin sensitivity in human participants. CONCLUSIONS/INTERPRETATION:CYP2C-derived EETs contribute to insulin sensitivity in mice and in humans. Interventions to increase circulating EETs in humans could provide a novel approach to improve insulin sensitivity and treat hypertension.

Dataset Information

The Role of Cytochrome P450 Epoxygenases, Soluble Epoxide Hydrolase, and Epoxyeicosatrienoic Acids in Metabolic Diseases.

Publications

The Role of Cytochrome P450 Epoxygenases, Soluble Epoxide Hydrolase, and Epoxyeicosatrienoic Acids in Metabolic Diseases.

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