Relationship between a Common Variant in the Fatty Acid Desaturase (FADS) Cluster and Eicosanoid Generation in Humans
Relationship between a Common Variant in the Fatty Acid Desaturase (FADS) Cluster and Eicosanoid Generation in Humans
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DOI：
10.1074/jbc.m114.579557
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发表时间：
2014-08-08
影响因子：
4.8
通讯作者：
Chilton, Floyd H.
中科院分区：
文献类型：
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作者：
Hester, Austin G.;Murphy, Robert C.;Chilton, Floyd H.
西方饮食的巨大变化导致n-6多不饱和脂肪酸（PUFA）和亚油酸（LA）的饮食摄入量显着增加。膳食LA然后可以利用三个酶促步骤转化为花生四烯酸（ARA）。其中两个步骤由脂肪酸去饱和酶（FADS）簇（染色体11，11q12.2-q13）编码，簇内的某些遗传变异与ARA水平高度相关。然而，迄今为止还没有研究检查这些变体是否进一步影响促炎性、环氧合酶和脂氧合酶类花生酸产物。本研究检测了一个高度影响力的FADS SNP rs 174537对刺激全血中白三烯、HETE、前列腺素和血栓素生物合成的影响。对30名受试者在rs 174537处进行基因分型（GG，n = 11; GT，n = 13; TT，n = 6），分析来自全血清的一组脂肪酸，并计算作为组织（特别是肝脏）合成长链PUFA的能力的标志物的底物与产物PUFA比率。通过LC-MS/MS测量由刺激的人血液产生的类花生酸。我们观察到rs 174537与ARA/LA、白三烯B-4和5-HETE的比率之间的关联，但对环氧合酶产物的水平没有影响。我们的研究结果表明，rs 174537的变异不仅影响ARA的合成，而且影响全血合成5-脂氧合酶产物的总体能力;这些基因型相关的类花生酸水平变化可能对各种炎症性疾病具有重要意义。
Dramatic shifts in the Western diet have led to a marked increase in the dietary intake of the n-6 polyunsaturated fatty acid (PUFA), linoleic acid (LA). Dietary LA can then be converted to arachidonic acid (ARA) utilizing three enzymatic steps. Two of these steps are encoded for by the fatty acid desaturase (FADS) cluster (chromosome 11, 11q12.2-q13) and certain genetic variants within the cluster are highly associated with ARA levels. However, no study to date has examined whether these variants further influence pro-inflammatory, cyclooxygenase and lipoxygenase eicosanoid products. This study examined the impact of a highly influential FADS SNP, rs174537 on leukotriene, HETE, prostaglandin, and thromboxane biosynthesis in stimulated whole blood. Thirty subjects were genotyped at rs174537 (GG, n = 11; GT, n = 13; TT, n = 6), a panel of fatty acids from whole serum was analyzed, and precursor-to-product PUFA ratios were calculated as a marker of the capacity of tissues (particularly the liver) to synthesize long chain PUFAs. Eicosanoids produced by stimulated human blood were measured by LC-MS/MS. We observed an association between rs174537 and the ratio of ARA/LA, leukotriene B-4, and 5-HETE but no effect on levels of cyclooxygenase products. Our results suggest that variation at rs174537 not only impacts the synthesis of ARA but the overall capacity of whole blood to synthesize 5-lipoxygenase products; these genotype-related changes in eicosanoid levels could have important implications in a variety of inflammatory diseases.