Peptide mimotopes of malondialdehyde epitopes for clinical applications in cardiovascular disease
Peptide mimotopes of malondialdehyde epitopes for clinical applications in cardiovascular disease
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DOI：
10.1194/jlr.m025445
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发表时间：
2012-07-01
影响因子：
6.5
通讯作者：
Binder, Christoph J.
中科院分区：
文献类型：
--
作者：
Amir, Shahzada;Hartvigsen, Karsten;Binder, Christoph J.
FA2 -羟化酶（FA2H）是一种NAD(P) h依赖性酶，可启动FA α氧化，也负责哺乳动物细胞中2-羟基FA (2-OH FA)-鞘脂的生物合成。2-OH - FA是手性的，因为不对称碳带有羟基。本研究进行了立体化学研究，发现FA2H对(R)-对映体具有立体特异性。脂肪细胞中FA2H的下调增加了筏相关脂质的扩散流动性，导致GLUT4蛋白水平降低、葡萄糖摄取和脂肪生成。外源性(R)-2-羟基棕榈酸可逆转FA2H敲低引起的影响，但(S)-对映体不能逆转。对鞘脂的进一步分析表明，(R)-对映体在己糖神经酰胺中富集，而(S)-对映体则优先与神经酰胺结合，这表明所观察到的差异效应部分是由于鞘脂合成中含有不同的2-OH FA对映体。这些结果可能有助于阐明最近发现的与人类FA2H突变相关的疾病的机制，并可能导致潜在的药物和饮食治疗。该研究还为研究2-OH FA对映体在FA α氧化和其他可能的鞘脂非依赖性途径中的功能提供了关键信息。-郭丽丽，张晓东，周东东，奥库纳德，苏旭。脂肪酸2-羟基化酶的立体特异性及2-羟基脂肪酸对映体的差异功能。[j] .油脂杂志。2012。53: 1327 - 1335。
FA 2-hydroxylase (FA2H) is an NAD(P) H-dependent enzyme that initiates FA alpha oxidation and is also responsible for the biosynthesis of 2-hydroxy FA (2-OH FA)-containing sphingolipids in mammalian cells. The 2-OH FA is chiral due to the asymmetric carbon bearing the hydroxyl group. Our current study performed stereochemistry investigation and showed that FA2H is stereospecific for the production of (R)-enantiomers. FA2H knockdown in adipocytes increases diffusional mobility of raft-associated lipids, leading to reduced GLUT4 protein level, glucose uptake, and lipogenesis. The effects caused by FA2H knockdown were reversed by treatment with exogenous (R)-2-hydroxy palmitic acid, but not with the (S)-enantiomer. Further analysis of sphingolipids demonstrated that the (R)-enantiomer is enriched in hexosylceramide whereas the (S)-enantiomer is preferentially incorporated into ceramide, suggesting that the observed differential effects are in part due to synthesis of sphingolipids containing different 2-OH FA enantiomers.(Jlr) These results may help clarify the mechanisms underlying the recently identified diseases associated with FA2H mutations in humans and may lead to potential pharmaceutical and dietary treatments. This study also provides critical information to help study functions of 2-OH FA enantiomers in FA alpha oxidation and possibly other sphingolipid-independent pathways.-Guo, L., X. Zhang, D. Zhou, A. L. Okunade, and X. Su. Stereospecificity of fatty acid 2-hydroxylase and differential functions of 2-hydroxy fatty acid enantiomers. J. Lipid Res. 2012. 53: 1327-1335.