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Enzymatic Synthesis of Epoxidized Metabolites of Docosahexaenoic, Eicosapentaenoic, and Arachidonic Acids
Published on: June 28, 2019
Eicosanoid imbalance in the NOD mouse is related to a dysregulation in soluble epoxide hydrolase and 15-PGDH
Michelle Rodriguez1, Michael Clare-Salzler
1Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, 1600 SW Archer Road No. D11-41, Gainesville, FL 32610, USA. rodrigm@pathology.ufl.edu
Abstract:
Eicosanoids promote or resolve inflammation depending on the class produced. Macrophage from nonobese diabetic (NOD) mouse produce increased proinflammatory lipid mediators and low levels of antiinflammatory lipoxin A4 (LXA4). The enhanced proinflammatory eicosanoids is secondary to increased cyclooxygenase-2 (Cox-2) expression and low levels of prostaglandin/leukotriene catabolic enzyme, 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Deficient LXA4 production is not due to deficient lipoxygenase (LO) activity, but is related to increased soluble epoxide hydrolase (sEH), involved in metabolism of anti-inflammatory epoxyeicosatrienoic acids (EET). These aberrations in eicosanoid biology suggest that inflammation in the NOD mouse is likely to be prolonged and robust and may contribute to type 1 diabetes (T1D) pathogenesis.
Insights
Nonobese diabetic mice exhibit heightened inflammation due to skewed eicosanoid production, with increased pro-inflammatory mediators and reduced anti-inflammatory compounds, potentially driving type 1 diabetes.
Area of Science:
- Immunology
- Endocrinology
- Metabolism
Background:
- Eicosanoids play a dual role in inflammation, either promoting or resolving it.
- Macrophages from nonobese diabetic (NOD) mice show an imbalance in eicosanoid production.
Purpose of the Study:
- To investigate the underlying mechanisms of altered eicosanoid metabolism in NOD mice.
- To understand the contribution of these metabolic aberrations to type 1 diabetes (T1D) pathogenesis.
Main Methods:
- Analysis of macrophage eicosanoid production in NOD mice.
- Assessment of key enzyme expression and activity involved in eicosanoid synthesis and degradation (e.g., cyclooxygenase-2, 15-hydroxyprostaglandin dehydrogenase, soluble epoxide hydrolase).
Main Results:
- NOD mouse macrophages produce elevated pro-inflammatory eicosanoids and reduced anti-inflammatory lipoxin A4 (LXA4).
- Increased cyclooxygenase-2 (Cox-2) expression contributes to higher pro-inflammatory mediators.
- Deficient LXA4 is linked to increased soluble epoxide hydrolase (sEH) activity, impacting anti-inflammatory epoxyeicosatrienoic acids (EETs).
Conclusions:
- Aberrant eicosanoid metabolism in NOD mice leads to prolonged and robust inflammation.
- These immune and metabolic dysregulations are implicated as contributing factors in type 1 diabetes development.
