9.B.446.  The Sterol-regulated Lysoplasmalogenase (TMEM68) Family 

Lysoplasmalogens, acyl transferases, are a class of vinyl ether bioactive lipids that have a central role in plasmalogen metabolism and membrane fluidity. The liver X receptor transcription factors (LXRs) are important determinants of cellular lipid homeostasis owing to their ability to regulate cholesterol and fatty acid metabolism. van Wouw et al. 2022 mapped the lipidome of bone marrow-derived macrophages (BMDM) following LXR activation. A reduction in the levels of lysoplasmalogen species was observed in the absence of changes in the levels of plasmalogens. Transcriptional profiling of LXR-activated macrophages identified the gene encoding TMEM86a, an integral endoplasmic reticulum protein, as a sterol-regulated gene. TMEM86a is a direct transcriptional target of LXR in macrophages and microglia, and it is highly expressed in TREM2(+)/lipid-associated macrophages in human atherosclerotic plaques, where its expression positively correlates with other LXR-regulated genes. Both murine and human TMEM86a display active lysoplasmalogenase activity that can be abrogated by inactivating mutations in the predicted catalytic site. Consequently, overexpression of Tmem86a in BMDM markedly reduces lysoplasmalogen abundance and membrane fluidity, while reciprocally, silencing of Tmem86a increases basal lysoplasmalogen levels and abrogates the LXR-dependent reduction of this lipid species. Thus, TMEM86a is a sterol-regulated lysoplasmalogenase in macrophages that contributes to sterol-dependent membrane remodeling (van Wouw et al. 2022). TMEM68 functions as an acyltransferase and affects lipogenic gene expression, glycerolipid metabolism and TG storage in mammalian cells (Wang et al. 2023).