Alterations in ether lipid metabolism and the consequences for the mouse lipidome
Alterations in ether lipid metabolism and the consequences for the mouse lipidome
复制标题
醚类脂质代谢的改变及其对小鼠脂质组的影响
DOI：
10.1016/j.bbalip.2023.159285
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Watschinger Katrin
中科院分区：
文献类型：
--
作者：
Lackner Katharina;Sailer Sabrina;van Klinken Jan-Bert;Wever Eric;Pras-Raves Mia L.;Dane Adrie D.;Honsho Masanori;Abe Yuichi;Keller Markus A.;Golderer Georg;Werner-Felmayer Gabriele;Fujiki Yukio;Vaz Fr?d?ric M.;Werner Ernst R.;Watschinger Katrin
烷基甘油单加氧酶（AGMO）和血浆乙醇胺去饱和酶（PEDS 1）是参与醚脂代谢的酶。AGMO通过醚键的氧化裂解降解血浆酰脂质，而PEDS 1通过将乙烯基醚双键引入血浆乙醇胺磷脂中，专门合成醚脂质的特定亚类，即缩醛磷脂。醚脂的特征在于甘油主链的n-1位上的醚键，它们存在于不同细胞类型的膜中。血浆酶原水平的降低与神经系统疾病如阿尔茨海默氏病有关。Agmo缺陷小鼠在未受攻击的条件下不呈现明显的表型。相反，Peds 1基因敲除小鼠显示生长表型。为了研究Agmo和Peds 1缺陷对小鼠脂质体的分子影响，从每个小鼠模型中分离五个组织，并进行高分辨率质谱分析，从而可以表征来自42个脂质亚类的多达2013种脂质种类。Agmo敲除小鼠适度积累了血浆酰和血浆酰脂质种类。缺陷型小鼠表现出显著的变化，其特征在于胞浆酰脂质的强烈减少和伴随的胞浆酰脂质的大量积累，导致所分析的组织中除这类磷脂酰乙醇胺的总水平在Peds 1基因敲除小鼠中也保持显著恒定。醚脂代谢中的限速酶FAR 1在Peds 1缺陷小鼠中没有上调，表明缩醛磷脂的选择性丢失不足以激活在总醚脂缺乏中观察到的反馈机制。
Alkylglycerol monooxygenase (AGMO) and plasmanylethanolamine desaturase (PEDS1) are enzymes involved in ether lipid metabolism. While AGMO degrades plasmanyl lipids by oxidative cleavage of the ether bond, PEDS1 exclusively synthesizes a specific subclass of ether lipids, the plasmalogens, by introducing a vinyl ether double bond into plasmanylethanolamine phospholipids. Ether lipids are characterized by an ether linkage at thesn-1 position of the glycerol backbone and they are found in membranes of different cell types. Decreased plasmalogen levels have been associated with neurological diseases like Alzheimer's disease.Agmo-deficient mice do not present an obvious phenotype under unchallenged conditions. In contrast,Peds1knockout mice display a growth phenotype. To investigate the molecular consequences ofAgmoandPeds1deficiency on the mouse lipidome, five tissues from each mouse model were isolated and subjected to high resolution mass spectrometry allowing the characterization of up to 2013 lipid species from 42 lipid subclasses.Agmoknockout mice moderately accumulated plasmanyl and plasmenyl lipid species.Peds1-deficient mice manifested striking changes characterized by a strong reduction of plasmenyl lipids and a concomitant massive accumulation of plasmanyl lipids resulting in increased total ether lipid levels in the analyzed tissues except for the class of phosphatidylethanolamines where total levels remained remarkably constant also inPeds1knockout mice. The rate-limiting enzyme in ether lipid metabolism, FAR1, was not upregulated inPeds1-deficient mice, indicating that the selective loss of plasmalogens is not sufficient to activate the feedback mechanism observed in total ether lipid deficiency.