Functional Lipidomics: From Lipid Timelines To Regulation Of Metabolic Networks

Lipids play essential roles in membrane structure and dynamics, energy homeostasis, and signal transduction. The lipidome of eukaryotic cells comprises several hundred molecular lipid species produced by a metabolic network that interconnects and coordinates the metabolism of fatty acids, glycerophospholipids, glycerolipids, sphingolipids and sterol lipids. One of the grand challenges in cell physiology is to understand how cells regulate the activities of all lipid metabolic pathways simultaneously not only to maintain lipid homeostasis but also to remodel cellular processes and architecture. To delineate the regulatory landscape of lipid metabolism, we deploy systems biology approaches to reproducibly, comprehensively and quantitatively monitor both lipid molecules and the proteins that operate the lipid metabolic network. These approaches include high throughput lipidomics workflows capitalizing on nanoelectrospray ionization and high‐resolution Orbitrap mass spectrometry combined with quantitative shotgun proteomics for time‐resolved quantitative analysis of lipidome and proteome dynamics. The power of this platform is exemplified by our recent discoveries that: (i) activation of cardiolipin synthesis and remodeling supports mitochondrial biogenesis, (ii) down‐regulation of de novo sterol synthesis machinery prompts differential turnover of lipid droplet‐associated triacylglycerols and sterol esters, and (iii) sphingolipid metabolism is regulated in a previously unrecognized growth stage‐specific manner. The application of this proteolipidomics technology serves as a new experimental paradigm for understanding, at unprecedented temporal resolution, how lipid metabolism is regulated and coordinated with the remodeling of cellular architecture and processes.