Married at Birth: Regulation of Cellular Fat Metabolism by ER–Lipid Droplet Crosstalk

The endoplasmic reticulum (ER) is a hub that coordinates neutral lipid synthesis, storage, and export. To fulfill this role, the ER maintains close contact with lipid droplets (LDs), which are evolutionarily conserved organelles for the storage of neutral lipids. Decades of biochemical evidence points to fatty acid modification and neutral lipid synthesis in the ER. Conceptually, lipid export into extracellular space or lipid retention intracellularly require the subsequent remodeling of an ER membrane leaflet that faces the lumen or cytoplasm, respectively. This is because LDs and very-low-density lipoprotein particles are all structures surrounded by a phospholipid monolayer. While the export of neutral lipids via very-low-density lipoprotein production is well characterized, there has been increasing interest in the mechanisms that underlie neutral lipid retention in LDs. Structural determination, in vitro reconstitution, and localization of key proteins by advanced microscopy techniques collectively enrich models of ER-LD engagement. In this review, we consider current concepts on how LDs emerge from the ER in a directional manner and how sustained ER-LD contacts support LD expansion.