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

多不饱和脂肪酸（PUFA）在人体代谢中以复杂的转化、逆转化和氧化网络进行代谢。ω-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促延伸和去饱和过程中转化为生理上更有活性的长链（LC）PUFA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）。反过来，AA、EPA和DHA通过酶催化和自动氧化转化为氧化代谢物（氧脂）。AA、EPA和DHA的许多生理作用是由它们的氧化脂质介导的，氧化脂质作为有效的脂质介质参与许多生物过程。虽然在过去的几十年中，环氧化酶（考克斯）介导的AA代谢物（例如1-和2-系列的野牡丹素）的类别已被深入研究，但对羟基-，环氧-和二羟基-FA的新家族知之甚少。除了自动氧化外，这些氧脂素还在由i.a.介导的部分多阶段转化过程中形成。本课题的目的是系统研究健康男性体内LCn-3和n-6多不饱和脂肪酸（PUFA）向羟基、环氧和二羟基脂肪酸（dihydroxy-FA）的短期和长期代谢。将进行三项概念验证研究，以研究在规定的时间内摄入ALA、EPA和DHA以及不同的ALA/LA比例对血浆和尿液中游离氧化脂质（羟基-FA、环氧-FA、二羟基-FA以及几种示例性前列腺素）水平的影响。另一个重点将是LC PUFA谱，这将在不同的血液成分中进行测量a）在摄入ALA、EPA、DHA和不同比例的n-3/n-6前体脂肪酸后，血液和尿液中的氧脂素谱以及血液中的LC PUFA谱的短期和长期变化，B）LC PUFA在不同血液级分之间的摄取、生物利用度和分布，c）LC PUFA的转化和逆转化，d）血液中氧脂素水平的可能的昼夜节律波动，和e）离体免疫刺激后血液中的氧脂素谱。

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.