Lipidomics profile of a NAPE-PLD KO mouse provides evidence of a broader role of this enzyme in lipid metabolism in the brain.
Lipidomics profile of a NAPE-PLD KO mouse provides evidence of a broader role of this enzyme in lipid metabolism in the brain.
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DOI：
10.1016/j.bbalip.2016.03.003
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Bradshaw HB
中科院分区：
文献类型：
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作者：
Leishman E;Mackie K;Luquet S;Bradshaw HB
N-酰基乙醇胺（NAE）生物合成（包括内源性大麻素anandamide（AEA））的一个主要假设是，它依赖于N-酰基磷脂酰乙醇胺（NAPE）特异性磷脂酶D（NAPE-PLD）对NAPE的水解。因此，NAPE-PLD的缺失应减弱NAE水平。先前对两种不同的NAPE-PLD敲除（KO）菌株的分析在NAPE-PLD对AEA生物合成的重要性方面产生了相互矛盾的数据。在这里，我们研究了这一假设与一个品系的NAPE-PLD基因敲除小鼠的脂质体是uncharacterized。使用HPLC/MS/MS，在KO和野生型（WT）小鼠的8个脑区中分析了超过70种脂质，包括AEA代谢产物N-花生四烯酸甘氨酸（NAGly）、内源性大麻素2-花生四烯酸甘油（2-AG）和洋地黄素（PGE 2和PGF 2 α），以及超过60种脂胺。该第三种NAPE-PLD KO菌株的脂质组学分析显示了受脂质种类和脑区域差异影响的广泛脂质。重要的是，测量的所有6种NAE均显著降低，尽管效果的大小因脂肪酸饱和长度和大脑区域而异。2-AG水平仅在脑干中受到影响，在KO小鼠中水平显著增加。相应地，花生四烯酸水平显着下降，仅在脑干。在KO小鼠中，NAGly水平在4个脑区域中显著增加，并且PGE 2水平在8个脑区域中的6个中增加。这些数据表明，NAPE-PLD的缺失对脂质组的影响比以前认识到的要广泛得多。因此，抑制NAPE-PLD活性的行为特征可能是由于对脂质的无数影响，而不仅仅是由于AEA生物合成减少。
A leading hypothesis of N-acyl ethanolamine (NAE) biosynthesis, including the endogenous cannabinoid anandamide (AEA), is that it depends on hydrolysis of N-acyl-phosphatidylethanolamines (NAPE) by a NAPE-specific phospholipase D (NAPE-PLD). Thus, deletion of NAPE-PLD should attenuate NAE levels. Previous analyses of two different NAPE-PLD knockout (KO) strains produced contradictory data on the importance of NAPE-PLD to AEA biosynthesis. Here, we examine this hypothesis with a strain of NAPE-PLD KO mice whose lipidome is uncharacterized. Using HPLC/MS/MS, over 70 lipids, including the AEA metabolite, N-arachidonoyl glycine (NAGly), the endocannabinoid 2-arachidonyl glycerol (2-AG) and prostaglandins (PGE2 and PGF2α), and over 60 lipoamines were analyzed in 8 brain regions of KO and wild-type (WT) mice. Lipidomics analysis of this third NAPE-PLD KO strain shows a broad range of lipids that were differentially affected by lipid species and brain region. Importantly, all 6 NAEs measured were significantly reduced, though the magnitude of the effect varied by fatty acid saturation length and brain region. 2-AG levels were only impacted in the brainstem, where levels were significantly increased in KO mice. Correspondingly, levels of arachidonic acid were significantly decreased exclusively in brainstem. NAGly levels were significantly increased in 4 brain regions and levels of PGE2 increased in 6 of 8 brain regions in KO mice. These data indicate that deletion of NAPE-PLD has far broader effects on the lipidome than previously recognized. Therefore, behavioral characteristics of suppressing NAPE-PLD activity may be due to a myriad of effects on lipids and not simply due to reduced AEA biosynthesis.