Rao Zhigang, Lackner Katharina, Dorigatti Ilaria, Brigo Natascha, Kummer Denise, Hoang Minh Bui, Pfeifhofer-Obermair Christa, Weiss Günter, Werner Ernst R, Koeberle Andreas, Watschinger Katrin
Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria.
Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Cell Biosci. 2025 Jun 5;15(1):80. doi: 10.1186/s13578-025-01419-5.
Ether lipids are important constituents of biological membranes and harbor fatty alcohols attached via ether linkages to the sn-1 position of the glycerol backbone. Depending on the nature of the ether bond, they are subdivided into 1-O-alkyl (plasmanyl) and 1-O-alk-1'-enyl (plasmenyl) subclasses. They often contain polyunsaturated fatty acids at the sn-2 position, implicating them in cellular signaling and inflammatory processes including lipid mediator biosynthesis. Lipid mediators are produced by immune and non-immune cells, have diverse homeostatic and immunoregulatory functions and, together with other factors, orchestrate the initiation and resolution of inflammation. To date, alkylglycerol monooxygenase is the only known enzyme capable of cleaving alkylglycerols, one of two ether lipid subclasses. However, the exact role of alkylglycerol monooxygenase and that of its substrates in lipid mediator biosynthesis remains unclear.
Using a knockout mouse model, we demonstrate a sex- and cell type-dependent role of alkylglycerol monooxygenase in limiting prostanoid formation without affecting polyunsaturated fatty acid release, as revealed by metabololipidomics profiling of lipid mediators using ultra-performance liquid chromatography‒tandem mass spectrometry. This female-specific effect is driven by the suppression of prostaglandin G/H synthase 2 transcription, as deficiency in alkylglycerol monooxygenase significantly elevated prostaglandin G/H synthase 2 gene expression in female bone marrow-derived macrophages of the M1 phenotype. Furthermore, this regulatory role of alkylglycerol monooxygenase extends to visceral white adipose tissue, where elevated prostaglandin G/H synthase 2 expression and enhanced prostaglandin E production were observed in female samples following alkylglycerol monooxygenase knockout.
Our results expand the immunomodulatory functions of ether lipid metabolism and highlight the sex- and cell type-dependent role of alkylglycerol monooxygenase in controlling lipid mediator production and maintaining tissue homeostasis.
醚脂是生物膜的重要组成部分，其甘油主链的sn-1位通过醚键连接着脂肪醇。根据醚键的性质，它们可细分为1-O-烷基（缩醛磷脂酰）和1-O-烯基-1'-烯基（缩醛磷脂）亚类。它们在sn-2位通常含有多不饱和脂肪酸，这使其参与细胞信号传导和炎症过程，包括脂质介质的生物合成。脂质介质由免疫细胞和非免疫细胞产生，具有多种稳态和免疫调节功能，并与其他因素共同协调炎症的起始和消退。迄今为止，烷基甘油单加氧酶是唯一已知的能够裂解烷基甘油（两种醚脂亚类之一）的酶。然而，烷基甘油单加氧酶及其底物在脂质介质生物合成中的确切作用仍不清楚。
使用基因敲除小鼠模型，我们证明了烷基甘油单加氧酶在限制前列腺素形成中具有性别和细胞类型依赖性作用，而不影响多不饱和脂肪酸的释放，这是通过使用超高效液相色谱-串联质谱对脂质介质进行代谢脂质组学分析揭示的。这种雌性特异性效应是由前列腺素G/H合酶2转录的抑制驱动的，因为烷基甘油单加氧酶的缺乏显著提高了M1表型雌性骨髓来源巨噬细胞中前列腺素G/H合酶2基因的表达。此外，烷基甘油单加氧酶的这种调节作用扩展到内脏白色脂肪组织，在烷基甘油单加氧酶基因敲除后的雌性样本中观察到前列腺素G/H合酶2表达升高和前列腺素E产生增强。
我们的结果扩展了醚脂代谢的免疫调节功能，并突出了烷基甘油单加氧酶在控制脂质介质产生和维持组织稳态中的性别和细胞类型依赖性作用。
