Abstract
Cells store energy in the form of neutral lipids packaged into micrometer-sized organelles named lipid droplets (LDs). These structures emerge from the endoplasmic reticulum (ER), but their biogenesis remains poorly understood. Using molecular simulations, we found that LD formation proceeds via a liquid-liquid phase separation process that is modulated by the physical properties and lipid composition of the ER membrane. LD formation is promoted at ER sites characterized by high membrane curvature and by the presence of the ER-associated protein seipin, that cause accumulation of triglycerides by slowing down their diffusion in the membrane. Our data indicate how a combination of membrane physical properties and protein scaffolding is used by the cell to regulate a broad and energetically-efficient biophysical process such as liquid/liquid phase separation to achieve LD biogenesis.