Effects of omega-3 fatty acids on the levels of oxylipins in blood and urine

多不饱和脂肪酸(PUFA)在人体新陈代谢中以一个复杂的转化、逆转和氧化网络进行代谢。Omega-6(n-6)系列亚油酸(LA，C18：2)和n-3系列α-亚麻酸(Ala，C18：3)的前体脂肪酸在低效的酶延长和脱饱和过程中转化为更具生理活性的长链(LC)多不饱和脂肪酸花生四烯酸(AA，C20：4)或二十碳五烯酸(EPA，C20：5)和二十二碳六烯酸(DHA，C22：6)。然后，AA、EPA和DHA在酶催化和自氧化作用下转化为氧化代谢产物(氧化脂质)。AA、EPA和DHA的许多生理作用都是由它们的氧脂介导的，它们作为强效的脂质介质参与了许多生物学过程。虽然环氧合酶(COX)介导的AA代谢物(如1系列和2系列前列腺素)在过去的几十年里得到了广泛的研究，但对于羟基、环氧基和二羟基-FA这一新家族的研究却很少。除了自氧化作用外，这些氧化脂质是在I.A.介导的部分多阶段转化过程中形成的。脂氧合酶(LOX)、细胞色素P450单加氧酶(CYP)和可溶性环氧化物水解酶(SEH)。本项目的目的是系统地研究LC n-3和n-6多不饱和脂肪酸在健康男性受试者体内对羟基、环氧基和二羟基-FA的短期和长期代谢。将进行三项概念验证研究，以研究ALA、EPA和DHA的摄入量以及在规定的时间内不同的ALA/LA比率对血浆和尿中游离氧脂(羟基-FA、环氧脂-FA、二羟基-FA以及几种示例性前列腺素)水平的影响。这些研究提供了以下方面的知识：a)在摄入ALA、EPA、DHA和n-3/n-6前体脂肪酸的不同比例后，血液和尿液中氧脂分布的短期和长期变化以及血液中LC PUFA分布；b)不同血液组分之间LC PUFA的摄取、生物利用度和分配；c)LC PUFA的转化和反向转化；d)血液中氧脂水平的可能昼夜波动，和e)体外免疫刺激后血液中的氧合脂谱。

Polyunsaturated fatty acids (PUFA) are metabolized in the human metabolism in a complex network of conversion, retroconversion and oxidation. The precursor fatty acids of the omega-6 (n-6) series linoleic acid (LA, C18:2) and the n-3 series alpha-linolenic acid (ALA, C18:3) are transformed in an inefficient enzymatic elongation and desaturation process into the physiologically more active long chain (LC) PUFAs arachidonic acid (AA, C20:4) or eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6). In turn, AA, EPA and DHA are converted to oxidized metabolites (oxylipins) by enzymatic catalysis and autoxidation. Many physiologic actions of AA, EPA and DHA are mediated by their oxylipins, which are involved in numerous biological processes as potent lipid mediators. While the class of cyclooxygenase (COX)-mediated AA-metabolites (e.g. 1- and 2-series prostaglandins) have been intensively studies during the last decades, little is known about the novel family of hydroxy-, epoxy- und dihydroxy-FA. Besides autoxidation, these oxylipins are formed in partly multistage conversion processes mediated by i.a. lipoxygenase (LOX), cytochrom P450 monooxygenase (CYP) as well as soluble epoxid hydrolase (sEH).The aim of the project is to systematically investigate the short and long term metabolism of LC n-3 and n-6 PUFA to hydroxy-, epoxy- und dihydroxy-FA in healthy male subjects. Three proof-of-concept studies will be carried out to study the effects of the intake of ALA, EPA and DHA as well as different ALA/LA ratios over a defined period on the levels of free oxylipins (hydroxy-FA, epoxy-FA, dihydroxy-FA as well as several exemplary prostanoids) in plasma and urine. An additional focus will be directed on LC PUFA profiles, which will be measured in different blood fractions (plasma, erythrocyte membranes, free fatty acids, phospholipids).These studies provide knowledge on a) short and long term changes in oxylipin profiles in blood and urine as well as LC PUFA profiles in blood after intake of ALA, EPA, DHA and varying ratios of the n-3/n-6 precursor fatty acids, b) the uptake, bioavailability and distribution of LC PUFA between different blood fractions, c) the conversion and retroconversion of LC PUFA, d) possible circadian fluctuations of oxylipin levels in the blood, and e) oxylipin profiles in blood after ex vivo immune stimulation.