Phospholipid demixing and the birth of a lipid droplet

TL;DR

This study presents a biophysical model explaining lipid droplet formation in yeast, highlighting the role of phospholipid demixing and membrane curvature in LD biogenesis, suggesting a two-step process involving initial budding and subsequent growth.

Contribution

The paper introduces a thermodynamic model linking phospholipid demixing to lipid droplet formation, proposing a two-step biogenesis process in yeast.

Findings

Lipid demixing supports membrane curvature during LD formation

LD bud-off diameter predicted at about 13 nm, smaller than observed

LD formation involves a two-step process: initial budding and subsequent growth

Abstract

The biogenesis of lipid droplets (LD) in the yeast Saccharomyces cerevisiae was theoretically investigated on basis of a biophysical model. In accordance with the prevailing model of LD formation, we assumed 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. Mathematically, LD were modeled as spherical protuberances in an otherwise planar ER membrane. We estimated the local phospholipid composition, and calculated the change in elastic free energy of the membrane caused by nascent LD. Based on this model calculation, we found a 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 was able to gain energy during LD growth, which suggested that the formation of curved interfaces was supported by or even driven by lipid demixing. In addition, we show that demixing is thermodynamically necessary as LD cannot bud-off otherwise. In the case of Saccharomyces cerevisiae our model predicts a LD bud-off diameter of about 13 nm. This diameter is far below the experimentally determined size of typical yeast LD. Thus, we concluded 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 ripe within the cytosol through a series of fusions.