The birth of a lipid droplet: a molecular interpretation

Lipid droplets (LD) are important storage organelles in all organisms. However, LD biogenesis is everything but clear. Here we present a theoretical investigation of LD synthesis based on a biophysical model. In accordance with the prevailing model, we assume that neutral lipids oil-out between the membrane leaflets of the endoplasmic reticulum (ER), resulting in LD that bud-off when a critical size is reached. We model LD as spherical protuberances in an otherwise planar ER membrane, estimate the local phospholipid composition, and calculate the change in elastic free energy of the membrane caused by nascent LD. Our model allows for an easy molecular interpretation. Based on this model, we find gradual demixing of lipids in the membrane leaflet that goes along with an increase in surface curvature at the site of LD formation. During demixing, the phospholipid monolayer is able to gain energy during LD growth, which suggests that the formation of curved interfaces is supported by or even driven by lipid demixing. In addition, we show that demixing is thermodynamically necessary, as LD cannot bud-off otherwise. We illustrate LD biosynthesis using the yeast accharomyces cerevisiae as an example, for which we predict an LD bud-off diameter of about 12 nm. This diameter is below the experimentally determined size of typical yeast LD. Thus, we conclude that if the standard model of LD formation is valid, LD biogenesis is a two-step process. Small LD are produced from the ER, which subsequently ripen within the cytosol through a series of fusions.