Gerhard Liebisch, Eoin Fahy, Junken Aoki, Edward A. Dennis, Thierry Durand, Christer S. Ejsing, Maria Fedorova, Ivo Feussner, William J. Griffiths, Harald Köfeler, Alfred H. Merrill Jr., Robert C. Murphy, Valerie B. O’Donnell, Olga Oskolkova, Shankar Subramaniam, Michael J. O. Wakelam, Friedrich Spener

There is a need for a standardized, practical annotation for structures of lipid species derived from mass spectrometric approaches; i.e., for high-throughput data obtained from instruments operating in either high- or low-resolution modes. This proposal is based on common, officially accepted terms and builds upon the LIPID MAPS terminology. It aims to add defined levels of information below the LIPID MAPS nomenclature, as detailed chemical structures, including stereochemistry, are usually not automatically provided by mass spectrometric analysis. To this end, rules for lipid species annotation were developed that reflect the structural information derived from the analysis. For example, commonly used head group-specific analysis of glycerophospholipids (GP) by low-resolution instruments is neither capable of differentiating the fatty acids linked to the glycerol backbone nor able to define their bond type (ester, alkyl-, or alk-1-enyl-ether). This and other missing structural information is covered by the proposed shorthand notation presented here. Beyond GPs, we provide shorthand notation for fatty acids/acyls (FA), glycerolipids (GL), sphingolipids (SP), and sterols (ST). In summary, this defined shorthand nomenclature provides a standard methodology for reporting lipid species from mass spectrometric analysis and for constructing databases.

The retinoid X receptor (RXR) is a nuclear receptor that functions as a ligand-activated transcription factor. Little is known about the ligands that activate RXR in vivo. Here, we identified a factor in brain tissue from adult mice that activates RXR in cell-based assays. Purification and analysis of the factor by mass spectrometry revealed that it is docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid that is highly enriched in the adult mammalian brain. Previous work has shown that DHA is essential for brain maturation, and deficiency of DHA in both rodents and humans leads to impaired spatial learning and other abnormalities. These data suggest that DHA may influence neural function through activation of an RXR signaling pathway.

Recent studies suggest that the sterol metabolic network participates in the interferon (IFN) antiviral response. However, the molecular mechanisms linking IFN with the sterol network and the identity of sterol mediators remain unknown. Here we report a cellular antiviral role for macrophage production of 25-hydroxycholesterol (cholest-5-en-3β,25-diol, 25HC) as a component of the sterol metabolic network linked to the IFN response via Stat1. By utilizing quantitative metabolome profiling of all naturally occurring oxysterols upon infection or IFN-stimulation, we reveal 25HC as the only macrophage-synthesized and -secreted oxysterol. We show that 25HC can act at multiple levels as a potent paracrine inhibitor of viral infection for a broad range of viruses. We also demonstrate, using transcriptional regulatory-network analyses, genetic interventions and chromatin immunoprecipitation experiments that Stat1 directly coupled Ch25h regulation to IFN in macrophages. Our studies describe a physiological role for 25HC as a sterol-lipid effector of an innate immune pathway.

LIPID MAPS (LIPID Metabolites and Pathways Strategy), www.lipidmaps.org, provides a systematic and standardized approach to organizing lipid structural and biochemical data. Founded 20 years ago, the LIPID MAPS nomenclature and classification has become the accepted community standard. LIPID MAPS provides databases for cataloging and identifying lipids at varying levels of characterization in addition to numerous software tools and educational resources, and became an ELIXIR-UK data resource in 2020. This paper describes the expansion of existing databases in LIPID MAPS, including richer metadata with literature provenance, taxonomic data and improved interoperability to facilitate FAIR compliance. A joint project funded by ELIXIR-UK, in collaboration with WikiPathways, curates and hosts pathway data, and annotates lipids in the context of their biochemical pathways. Updated features of the search infrastructure are described along with implementation of programmatic access via API and SPARQL. New lipid-specific databases have been developed and provision of lipidomics tools to the community has been updated. Training and engagement have been expanded with webinars, podcasts and an online training school.