11-hydroxy-5-8-12-14-eicosatetraenoic-acid and Inflammation

Oxylipids are oxygenated polyunsaturated fatty acid (PUFA) metabolites that are responsible for the onset and resolution of the inflammatory response. Enzymatic oxygenation through the lipoxygenase (LOX) or cytochrome P450 (CYP) pathways can form oxylipids that have either proinflammatory or proresolving functions depending on the type of PUFA substrate and degree of metabolism. The objective of this study was to determine how PUFA substrates and their corresponding oxylipids are associated with obesity.. Plasma non-esterified FA and oxylipids were isolated from 123 Caucasian males using solid phase extraction and quantified using high performance liquid chromatography-tandem mass spectrometry. Statistical analyses included linear regressions and polytomous logistic regressions, and the responses were body mass index (BMI) and waist circumference (WC), and serum leptin, total adiponectin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-peptide. Models were adjusted for age and smoking, and p-values were corrected for false discovery per Benjamini-Hochberg and Bonferroni.. We report that BMI, WC, and several serum cytokines were highly associated arachidonic acid (ARA)-derived hydroxyeicosatetraenoic acids (HETEs), and vicinal diols (i.e., alcohols on adjacent carbon atoms) derived from several PUFAs. There was a significant linear relationship between BMI, WC, and serum leptin, and ARA-derived 5-, 11-, and 15-HETE. Specifically, BMI and WC were positively associated with proinflammatory 5- and 11-hydroxyeicosatetraenoic acid (HETE), even after normalization to ARA concentrations and false discovery p-value correction. Individuals with 5-HETE concentrations >5.01nmol/L or 11-HETE concentrations and >0.89nmol/L were over 5 times more likely to be obese compared to those with ≤1.86nmol/L and ≤0.39nmol/L, respectively. Vicinal diols from linoleic, eicosapentaenoic, and docosahexaenoic acid were inversely associated with obesity. Across all statistical tests, vicinal diols were inversely associated with obesity whether normalized to parent PUFA concentrations or normalized to precursor epoxides. Interestingly, the proinflammatory cytokines IL-6 and TNF-α were not associated with any oxylipids. Since 5-HETE is a 5LOX product, 11-HETE is marker of lipid peroxidation, and vicinal diols are formed through soluble epoxide hydrolase (sEH) metabolism of CYP epoxygenated PUFAs, therefore, these results indicate that obesity is likely associated with altered metabolism with distinct oxygenating pathways. Taken together, our results indicate that obesity is associated with specific oxylipids indicative of altered PUFA metabolism through several pathways (i.e., LOX, reactive oxygen species, and sEH and CYP epoxygenase), rather than attributed solely to altered dietary PUFA intake.

Topics: Aged; Arachidonic Acid; Biomarkers; Cross-Sectional Studies; Cytochrome P-450 Enzyme System; Fatty Acids, Unsaturated; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Lipoxygenase; Male; Metabolic Networks and Pathways; Middle Aged; Obesity; White People

An inherited deficiency of the mitochondrial protein frataxin causes Friedreich's ataxia (FRDA); the mechanism by which this deficiency triggers neuro- and cardio-degeneration is unclear. Microarrays of neural tissue of animal models of the disease showed decreases in antioxidant genes, and increases in inflammatory genes. Cyclooxygenase (COX)-derived oxylipins are important mediators of inflammation. We measured oxylipin levels using tandem mass spectrometry and ELISAs in multiple cell and animal models of FRDA. Mass spectrometry revealed increases in concentrations of prostaglandins, thromboxane B2, 15-HETE and 11-HETE in cerebellar samples of knockin knockout mice. One possible explanation for the elevated oxylipins is that frataxin deficiency results in increased COX activity. While constitutive COX1 was unchanged, inducible COX2 expression was elevated over 1.35-fold (P < 0.05) in two Friedreich's mouse models and Friedreich's lymphocytes. Consistent with higher COX2 expression, its activity was also increased by 58% over controls. COX2 expression is driven by multiple transcription factors, including activator protein 1 and cAMP response element-binding protein, both of which were elevated over 1.52-fold in cerebella. Taken together, the results support the hypothesis that reduced expression of frataxin leads to elevation of COX2-mediated oxylipin synthesis stimulated by increases in transcription factors that respond to increased reactive oxygen species. These findings support a neuroinflammatory mechanism in FRDA, which has both pathomechanistic and therapeutic implications.

Topics: Animals; B-Lymphocytes; Cell Line; Cerebellum; Cyclic AMP Response Element-Binding Protein; Cyclooxygenase 1; Cyclooxygenase 2; Frataxin; Friedreich Ataxia; Gene Expression Regulation; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Iron-Binding Proteins; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oxylipins; Prostaglandins; Reactive Oxygen Species; Signal Transduction; Thromboxane B2; Transcription Factor AP-1