Comparison of free serum oxylipin concentrations in hyper- vs. normolipidemic men

Abstract

Oxylipins, the oxidation products of unsaturated fatty acids (FA), are potent endogenous mediators being involved in the regulation of various biological processes such as inflammation, pain and blood coagulation. Compared to oxylipins derived from arachidonic acid (AA) by cyclooxygenase action, i.e. prostanoides, only limited information is available about the endogenous levels of hydroxy-, epoxy- and dihydroxy-FA of linoleic acid (LA), AA, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in humans. Particularly, it is unknown how metabolic disorders affect endogenous oxylipin levels in humans. Therefore, in the present study we compared the serum concentrations of 44 oxylipins in 20 normolipidemic with 20 hyperlipidemic (total cholesterol >200 mg/dl; LDL-C>130 mg/dl; TG>150 mg/dl) men (age 29-51 y). The serum concentration varied strongly among subjects. For most hydroxy-, epoxy- and dihydroxy-FA the concentrations were comparable to those in plasma reported in earlier studies. Despite the significant change in blood lipid levels the hyperlipidemic group showed only minor differences in oxylipin levels. The hyperlipidemic subjects had a slightly higher serum concentration of 8,9-DiHETrE, 5-HEPE, 10,11-DiHDPE, and a lower concentration of 12,13-DiHOME, 12-HETE, 9,10-DiHODE, and 12,13-DiHODE compared to normolipidemic subjects. Overall the hydroxy-, epoxy- and dihydroxy-FA levels were not changed suggesting that mild combined hyperlipidemia has no apparent effect on the concentration of circulating oxylipins. By contrast, serum levels of several hydroxy-, epoxy-, and dihydroxy-FA are dependent on the individual status of the parent FA. Particularly, a strong correlation between the EPA content in the erythrocyte membrane and the serum concentration of EPA derived oxylipins was observed. Given that the synthesis of EPA from other n-3 FA in humans is low; this suggests that oxylipin levels can be directly influenced by the diet.

Figure 1

Top: Simplified scheme of the formation of hydroxy-, epoxy- and dihydroxy-fatty acids from their PUFA precursors. Bottom: The structure of several oxylipins are exemplary shown exemplary for the generation of 12-HETE via the lipoxygenase (LOX) pathway and 14(15)-EpETrE and 14,15-DiHETrE by Cytochrom-P450 monooxygenases (CYP) and the soluble epoxide hydrolase (sEH).

Figure 2

Flow chart of recruitment of the human subjects.

Figure 3

Dependence of serum oxylipin levels on parent fatty acid status. Oxylipin levels derived from A) linoleic acid (LA, 18:2 n-6), B) arachidonic acid (AA, 20:4 n-6), C) alpha-linolenic acid (ALA, 18:3 n-3), D) eicosapentaenoic acid (EPA, 20:5 n-3) and E) docosahexaenoic acid (DHA, 22:6 n-3) were compared in tertiles of the whole study population with low and high PUFA percentage in erythrocyte membranes. All results are shown as the mean ± SE. Significant differences were determined by independent sample t-test for normal distributed variables. ¹ Mann-Whitney U test was used for skewed distributed variables.

Figure 4

Serum hydroxy fatty acid ratios depending on parent fatty acid status. Ratios between 5-lipoxygenase (5-LOX) products (A: 5-HETE:5-HEPE), 12-LOX products (B: 12-HETE:12-HEPE), and 15-LOX products (C: 15-HETE:15-HEPE; 15-HETE:13-HODE; 15-HETE:13-HOTrE) were compared between tertiles of the total study population with low and high PUFA status. All results are shown as the mean ± SE of group measurement. Significant differences in group means were determined by independent sample t-test.