Triglyceride lipolysis triggers liquid crystalline phases in lipid droplets and alters the LD proteome

S Rogers and L Gui and A Kovalenko and V Zoni and M Carpentier and K Ramji and K Ben Mbarek and A Bacle and P Fuchs and P Campomanes and E Reetz and NO Speer and E Reynolds and AR Thiam and S Vanni and D Nicastro and WM Henne, JOURNAL OF CELL BIOLOGY, 221, e202205053 (2022).

DOI: 10.1083/jcb.202205053

Lipid droplets (LDs) can exhibit liquid crystalline sterol-esters in vivo, but the mechanisms governing this are unclear. Rogers et al. describe how yeast glucose restriction drives triglyceride lipolysis that promotes liquid crystalline phase transitions within LDs. They also investigate how these phase transitions alter the LD proteome. Lipid droplets (LDs) are reservoirs for triglycerides (TGs) and sterol-esters (SEs), but how these lipids are organized within LDs and influence their proteome remain unclear. Using in situ cryo-electron tomography, we show that glucose restriction triggers lipid phase transitions within LDs generating liquid crystalline lattices inside them. Mechanistically this requires TG lipolysis, which decreases the LD's TG:SE ratio, promoting SE transition to a liquid crystalline phase. Molecular dynamics simulations reveal TG depletion promotes spontaneous TG and SE demixing in LDs, additionally altering the lipid packing of the PL monolayer surface. Fluorescence imaging and proteomics further reveal that liquid crystalline phases are associated with selective remodeling of the LD proteome. Some canonical LD proteins, including Erg6, relocalize to the ER network, whereas others remain LD-associated. Model peptide LiveDrop also redistributes from LDs to the ER, suggesting liquid crystalline phases influence ER-LD interorganelle transport. Our data suggests glucose restriction drives TG mobilization, which alters the phase properties of LD lipids and selectively remodels the LD proteome.

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