The lipid droplet–associated protein Fsp27 mediates lipid droplet growth by promoting directional lipid transfer from smaller to larger lipid droplets.

Lipid incorporation from the ER to lipid droplets (LDs) influences LD growth and intracellular lipid homeostasis. Xu et al. identify Rab18 as an important regulator of LD dynamics: activated Rab18 binds to ER-associated proteins such as the NRZ complex and SNAREs. The Rab18-NRZ-SNARE complex tethers LDs to the ER, facilitating lipid incorporation and LD growth.

Mature white adipocytes contain a characteristic unilocular lipid droplet. However, the molecular mechanisms underlying unilocular lipid droplet formation are poorly understood. We previously showed that Fsp27, an adipocyte-specific lipid droplet-associated protein, promotes lipid droplet growth by initiating lipid exchange and transfer. Here, we identify Perilipin1 (Plin1), another adipocyte-specific lipid droplet-associated protein, as an Fsp27 activator. Plin1 interacts with the CIDE-N domain of Fsp27 and markedly increases Fsp27-mediated lipid exchange, lipid transfer and lipid droplet growth. Functional cooperation between Plin1 and Fsp27 is required for efficient lipid droplet growth in adipocytes, as depletion of either protein impairs lipid droplet growth. The CIDE-N domain of Fsp27 forms homodimers and disruption of CIDE-N homodimerization abolishes Fsp27-mediated lipid exchange and transfer. Interestingly, Plin1 can restore the activity of CIDE-N homodimerization-defective mutants of Fsp27. We thus uncover a novel mechanism underlying lipid droplet growth and unilocular lipid droplet formation that involves the cooperative action of Fsp27 and Plin1 in adipocytes.