Project P8
Structure-composition-function relation in LD physiology & disease
Triglycerides (TGs) and cholesterol esters (CEs) stored in lipid droplets LDs are assumed to exist in an amorphous liquid state. However, using state-of-the-art in-cell cryo-electron microscopy, we recently uncovered that LDs can exhibit liquid-crystalline structures: starvation or increased demand for membrane biosynthesis stimulate the consumption of TGs from LDs, resulting in enrichment of CE and its subsequent structural phase transition into liquid crystals, in agreement with known CE phase behavior in vitro. We hypothesize that structural transitions are a consequence of differential lipid compositions resulting from dynamic cellular metabolic needs and interactions of LDs with cellular organelles, ultimately giving rise to diverse LD populations inside the cell. We expect the core structural phase transitions to impact the surface phospholipid monolayer organization and packing, and to consequently affect the composition of metabolic enzymes or lipid-transfer proteins on the LD surface and in membrane contact sites.
Together with partners of this RU, we will bring together cross-disciplinary expertise in LD in-cell structural biology, cell biology, proteomics, lipidomics, chemical biology and mouse models to address: how the LD surface lipidome and proteome respond to core lipid structural transitions? How does this mechanistically influence the versatile LD cellular functions? And the prevalence and relevance of liquid-crystalline LDs in healthy and diseased tissues in animal models. Our project will unravel how cell-state-related LD internal structure could play a role in modulating LD functions as central hubs of cellular lipid fluxes.
Principle Investigator
