PR001488 (Project)

Description:Cellular metabolism regulates almost all critical cellular activities including cell growth, proliferation, energy homeostasis and signaling transduction. SCAP controls SREBP signaling, an important pathway regulating cellular lipid biosynthesis. SCAP KO B cells have multiple defects and cannot form germinal centers. To test whether these defects of SCAP KO B cells are associated with an altered global metabolic state. We stimulated B cells isolated from SCAPfl/fl CD19Cre/+ mice (KO) and SCAP+/+ CD19Cre/+ mice (WT) with ?-CD40 or LPS for 24 and 48 hours, followed by targeted metabolomics analysis to evaluate global metabolic changes. We found that the metabolic profiles of unstimulated SCAP KO and WT B cells were largely overlapping, corroborating our findings that SCAP deficiency did not affect B cell development or their metabolic profile at steady state. In contrast, after stimulation with either LPS or ?-CD40, SCAP KO and WT B cells were clearly separated at 24 hours, with an even more pronounced separation at 48 hours. SREBP signaling can regulated the metabolism of many ceramides and sphingolipids. For example, lactosyl-N-palmitoyl-sphingosine (d18:1/16:0), one of the lactosylceramides (LacCer), is highly accumulated in SCAP KO B cells activated by either ?-CD40 or LPS. Strikingly, besides lipid metabolism, SCAP deficiency also alters many other metabolites that belong to different metabolic pathways such as energy, amino acids, peptide, cofactors and vitamins, nucleotide, carbohydrate, and xenobiotics. Taken together, the metabolomics analysis revealed previously unrecognized roles of SREBP signaling in regulating multiple cellular activities in activated B cells.