Perilipin membrane-association determines lipid droplet heterogeneity in differentiating adipocytes

Abstract

SummaryThe storage of fat within lipid droplets (LDs) of adipocytes is critical for whole-body health. Acute fatty acid uptake by adipocytes leads to the formation of at least two LD-classes marked by distinct members of the perilipin (PLIN) protein-family. How LD-heterogeneity arises is an important yet unresolved cell biological problem. Here, we show that an unconventional integral membrane-segment targets the adipocyte specific LD-surface factor PLIN1 to the endoplasmic reticulum (ER) and binds with high affinity to the first LD-class. The other PLINs do not insert into the ER and remain cytoplasmic until fatty acid influx recruits them to a newly forming LD-population. Preventing ER-localization turns PLIN1 into a cytoplasmic LD-protein, reduces its LD-affinity and switches its LD-class specificity. Our results explain how differences in organelle targeting and disparities in lipid-affinity of LD-surface factors establish LD-heterogeneity. These findings have direct implications for mechanism-based interference with fatty-liver disease, type-2 diabetes and obesity.