Therefore, squalene seems to have a higher nucleation concentration than TG. Squalene alone fails to form LDs in yeast and accumulates in the ER and in vitro membranes 16, 26, 27. Thereupon, seipin ensures that only a few TG LDs are nucleated and mature properly 1, 12.Ĭells can make other neutral lipids such as squalene, an intermediate in the cholesterol biosynthesis pathway. In seipin deletion, more TG LDs are nucleated 11, 24, 25 but they fail to grow normally 12. Seipin decreases the TG nucleation concentration to ~1.25% 10, 13, 14 to induce nascent LD formation and growth 21, 22, 23. Seipin is an integral ER protein, forming an oligomeric donut shape 10, 18, 19, 20 and displaying favorable interactions with TG. In cells, this concentration is altered by several lipid and protein factors, including seipin 5, 8. Triacylglycerols (TGs) are the major neutral lipids in mammalian cells and, in silico, they can condense and nucleate a droplet in a bilayer if their ratio to phospholipids exceeds 3–4% 15, 16, 17. Despite many advances in understanding LD biogenesis 8, 9, 10, 11, 12, 13, 14, the molecular mechanisms underlying the different steps of LD formation are not fully resolved. There, neutral lipids condense and nucleate a nascent LD which grows by acquiring more neutral lipids and buds off as a spherical LD out of the ER bilayer 7. As neutral lipids are often apolar and hydrophobic, they are released in the hydrophobic core of the ER bilayer 1. LD formation is initiated when sufficient amounts of neutral lipids accumulate in the endoplasmic reticulum (ER) 5, 6. LDs control cellular energy and lipid homeostasis but also possess several other functions 2 attuned to the LD formation triggering cue 2, 3, 4. Our data point to a unique model whereby TG pre-clusters, favorable at seipins, catalyze the nucleation of CE LDs.įrom plant to human, dozens of neutral lipids can be made by cells and deposited into lipid droplets (LDs) 1. However, when TG synthesis is inhibited, similar numbers of LDs are generated in the presence and absence of seipin, suggesting that seipin controls CE LD formation via its TG clustering capacity. Finally, CE LDs emerged at seipins, which cluster and nucleate TG LDs in the ER. Accordingly, blocking TG synthesis in cells is sufficient to strongly dampen CE LD nucleation. This concentration is reduced by TG pre-clusters in the membrane that thereby facilitate CE nucleation. In model bilayers, CEs condense and nucleate droplets when the CE/phospholipid ratio reaches over 10-15%. Here, we show that CE forms supercooled droplets when the CE concentration in LDs is above 20% to TG and, in particular, liquid-crystalline phases when the fraction of CEs is above 90% at 37 ☌. However, while TG melts at ~4 ☌, CE melts at ~44 ☌, raising the question of how CE-rich LDs form in cells. With triacylglycerols (TGs), CEs represent the main neutral lipids in LDs. Cellular cholesterol can be metabolized to its fatty acid esters, cholesteryl esters (CEs), to be stored in lipid droplets (LDs).
0 kommentar(er)
