Paul Sudip, Morgan Pooranee, Pernes Gerard, Schooneveldt Yvette, Duong Thy, Mellett Natalie A, Huynh Kevin, Murphy Andrew J, Lancaster Graeme I, Meikle Peter J
Metabolomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia; Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Bundoora, Victoria, Australia.
Haematopoesis and Leukocyte Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
J Lipid Res. 2025 May;66(5):100808. doi: 10.1016/j.jlr.2025.100808. Epub 2025 Apr 17.
Plasmalogens are a distinct subclass of glycerophospholipids that exhibit unique structural features, notably possessing a vinyl ether linkage at the sn1 position of the glycerol backbone. These specialized lipids play crucial roles in various biological functions. Although the biosynthetic pathway of plasmalogens has been well-characterized, their catabolism remains less studied. In this study, we investigated the impact of global and tissue-specific loss-of-function of a plasmalogen catabolizing enzyme, lysoplasmalogenase (TMEM86B), on circulatory and tissue lipidomes. We generated both global and hepatocyte-specific Tmem86b knockout mice using cre-loxP technology. Mice with homozygous global inactivation of Tmem86b (Tmem86b KO mice) were viable and did not display any marked phenotypic abnormalities. Tmem86b KO mice demonstrated significantly elevated levels of the plasmalogens, alkenylphosphatidylethanolamine (PE(P)), and alkenylphosphatidylcholine (PC(P)), as well as lysoplasmalogens, in the plasma, liver, and natural killer cells compared to their wild-type counterparts. The endogenous alkenyl chain composition of plasmalogens remained unaltered in Tmem86b KO mice. Consistent with the global knockout findings, hepatocyte-specific Tmem86b knockout mice also exhibited increased plasmalogen levels in the plasma and liver compared to their floxed control counterparts. Overall, our findings shed light on the role of Tmem86b in plasmalogen catabolism, demonstrating how its ablation leads to elevated plasmalogen levels in select tissues and cells. This study enhances our understanding of the regulatory mechanisms governing plasmalogen metabolism and highlights the potential of targeting Tmem86b to therapeutically raise plasmalogen levels.
缩醛磷脂是甘油磷脂的一个独特亚类，具有独特的结构特征，特别是在甘油主链的sn1位置具有乙烯基醚键。这些特殊的脂质在各种生物学功能中发挥着关键作用。尽管缩醛磷脂的生物合成途径已得到充分表征，但其分解代谢的研究仍较少。在本研究中，我们研究了缩醛磷脂分解酶溶血缩醛磷脂酶（TMEM86B）的全身和组织特异性功能丧失对循环和组织脂质组的影响。我们使用cre-loxP技术生成了全身和肝细胞特异性Tmem86b基因敲除小鼠。Tmem86b基因纯合全身失活的小鼠（Tmem86b基因敲除小鼠）是活的，没有表现出任何明显的表型异常。与野生型对照相比，Tmem86b基因敲除小鼠的血浆、肝脏和自然杀伤细胞中的缩醛磷脂、烯基磷脂酰乙醇胺（PE(P)）、烯基磷脂酰胆碱（PC(P)）以及溶血缩醛磷脂的水平显著升高。Tmem86b基因敲除小鼠中缩醛磷脂的内源性烯基链组成保持不变。与全身敲除的结果一致，肝细胞特异性Tmem86b基因敲除小鼠与对照小鼠相比，血浆和肝脏中的缩醛磷脂水平也有所增加。总体而言，我们的研究结果揭示了Tmem86b在缩醛磷脂分解代谢中的作用，表明其缺失如何导致特定组织和细胞中缩醛磷脂水平升高。这项研究增进了我们对缩醛磷脂代谢调控机制的理解，并突出了靶向Tmem86b以治疗性提高缩醛磷脂水平的潜力。
