Presenter of 1 Presentation
MULTI-OMIC PROFILING OF LXR ACTIVATION IDENTIFIES SLPG AS A STEROL-INDUCIBLE LYSOPLASMALOGENASE IN MACROPHAGES
Abstract
Background and Aims
Next to their direct role in cholesterol metabolism, liver X receptors (LXRs) also govern remodeling of membrane composition, which in turn has profound consequences on e.g. cholesterol synthesis and transport. We aim to investigate the involvement of LXRs in the remodeling of lipid species using a multi-omics approach.
Methods
We isolated bone-marrow-derived macrophages (BMDM) from C57BL/6 mice and determined the transcriptomic and lipidomic landscape in response to the potent LXR ligand GW3965. Subsequently, gain- and loss-of-function studies in BMDM were used to clarify the localization and function of identified novel genes.
Results
An unbiased lipidomic analysis identified a reduction in lysoplasmalogen levels following LXR stimulation of BMDM. To identify the molecular mechanism underlying this effect we used RNAseq to map the transcriptional response to LXR activation. Next to the canonical LXR targets, we observed that an uncharacterized gene, named SLPG (sterol inducible lysoplasmalogenase), was increased 2.5-fold by LXR activation. SLPG is induced by distinct LXR ligands in macrophages in an LXR-dependent, but LXR isoform-independent manner. These findings were further supported by ATAC-seq and ChiP-seq experiments that identified an LXR-responsive enhancer region in the Slpg locus. We experimentally confirm that SLPG shows lysoplasmalogenase activity. Gain and loss-of-function studies show that SLPG is responsible for the LXR regulated reduction of lysoplasmalogens.
Conclusions
We have identified LXR-dependent remodeling of lysoplasmalogens and further investigated SLPG, the gene that underlies this activity. Our study expands the roles of LXR in the remodeling of cellular membranes and demonstrates that multi-omics has the potential to address this complex cellular process.
