Alkylglycerol monooxygenase represses prostanoid biosynthesis in a sex-dependent manner.

Abstract

Background: 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.

Results: 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 E₂ production were observed in female samples following alkylglycerol monooxygenase knockout.

Conclusion: 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.