Fatty acid transduction of nitric oxide signaling - Multiple nitrated unsaturated fatty acid derivatives exist in human blood and urine and serve as endogenous peroxisome proliferator-activated receptor ligands
Fatty acid transduction of nitric oxide signaling - Multiple nitrated unsaturated fatty acid derivatives exist in human blood and urine and serve as endogenous peroxisome proliferator-activated receptor ligands
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DOI：
10.1074/jbc.m504212200
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发表时间：
2005-12-23
影响因子：
4.8
通讯作者：
Freeman, BA
中科院分区：
文献类型：
--
作者：
Baker, PRS;Lin, YM;Freeman, BA
人血浆和尿液的质谱分析显示，所有主要不饱和脂肪酸的硝化衍生物丰富。硝化棕榈油酸，油酸，亚油酸，亚麻酸，花生四烯酸和二十碳五烯酸检测与他们的硝基羟基衍生物。合成了最常见的脂肪酸油酸的两种硝基烯烃衍生物（9-和10-硝基-9顺式-十八碳烯酸; OA-NO2），其结构表征并确定与健康人血浆、红细胞和尿液中发现的OA-NO2相同。这些区域异构体的OA-NO2的临床样品中使用C-13同位素稀释定量。血浆游离和酯化OA-NO2浓度分别为619 +/- 52和302 +/- 369 nM，浓缩红细胞游离和酯化OA-NO2浓度分别为59 +/- 11和155 +/- 65 nM。血液中的OA-NO2浓度比硝化亚油酸的浓度高50%，这两种脂肪酸衍生物的游离和酯化血液水平的总和超过1 μ M。OA-NO2在生理浓度下是过氧化物酶体增殖物激活受体的有效配体。在过氧化物酶体增殖物激活受体（PPAR）反应元件调控下，与PPAR γ、PPAR α或PPAR δ表达质粒共转染荧光素酶基因的CV-1细胞显示出OA-NO2对所有PPARs的剂量依赖性激活。PPARgamma显示出最大的反应，在100 nM时具有显著的活化，而PPARalpha和PPARdelta在类似于300 nM OA-NO2时被活化。OA-NO2还诱导3 T3-L1前脂肪细胞中的PPAR γ依赖性脂肪生成和脱氧葡萄糖摄取，其效力超过硝基亚油酸并与合成噻唑烷二酮相媲美。这些数据表明，硝化脂肪酸包括一类一氧化氮衍生的，受体依赖性的，细胞信号传导介质，在生理浓度范围内发挥作用。
Mass spectrometric analysis of human plasma and urine revealed abundant nitrated derivatives of all principal unsaturated fatty acids. Nitrated palmitoleic, oleic, linoleic, linolenic, arachidonic and eicosapentaenoic acids were detected in concert with their nitrohydroxy derivatives. Two nitroalkene derivatives of the most prevalent fatty acid, oleic acid, were synthesized (9- and 10-nitro-9cis-octadecenoic acid; OA-NO2), structurally characterized and determined to be identical to OA-NO2 found in plasma, red cells, and urine of healthy humans. These regioisomers of OA-NO2 were quantified in clinical samples using C-13 isotope dilution. Plasma free and esterified OA-NO2 concentrations were 619 +/- 52 and 302 +/- 369 nM, respectively, and packed red blood cell free and esterified OA-NO2 was 59 +/- 11 and 155 +/- 65 nM. The OA-NO2 concentration of blood is similar to 50% greater than that of nitrated linoleic acid, with the combined free and esterified blood levels of these two fatty acid derivatives exceeding 1 mu M. OA-NO2 is a potent ligand for peroxisome proliferator activated receptors at physiological concentrations. CV-1 cells co-transfected with the luciferase gene under peroxisome proliferator-activated receptor (PPAR) response element regulation, in concert with PPAR gamma, PPAR alpha, or PPAR delta expression plasmids, showed dose-dependent activation of all PPARs by OA-NO2. PPAR gamma showed the greatest response, with significant activation at 100 nM, while PPAR alpha and PPAR delta were activated at similar to 300 nM OA-NO2. OA-NO2 also induced PPAR gamma-dependent adipogenesis and deoxyglucose uptake in 3T3-L1 preadipocytes at a potency exceeding nitrolinoleic acid and rivaling synthetic thiazolidinediones. These data reveal that nitrated fatty acids comprise a class of nitric oxide-derived, receptor-dependent, cell signaling mediators that act within physiological concentration ranges.