Perilipin membrane-integration 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.

Molecular mechanisms of perilipin protein function in lipid droplet metabolism

“…In agreement, a recent preprint shows that PLIN1 can interact with the ER and LDs using hydrophobic segments in its degenerate C‐ter region (Fig. 1), suggesting that PLIN1 targets LDs via the ERTOLD pathway [65].…”

“…The mode of interaction of this region of PLIN1 with LDs has been recently explored by Klemm and coworkers. They show that the first hydrophobic segment mediates high lipid‐binding affinity of PLIN1, possibly acting as a hairpin loop to anchor PLIN1 to the LD surface or the ER bilayer, with an additional contribution of a downstream hydrophobic region [65].…”

Controlling lipid droplet dynamics via tether condensates

“…We investigated the spatial organization of confined LDs with ER and mitochondria to verify this hypothesis. We first examined Plin1 which relocates from the ER to LDs 24,27,31 , and found that LDs labeled by emGFP-Plin1 were juxtaposed to ER structures labeled with mCherry-Sec61 (Fig. 6A).…”

CIDE proteins and their regulatory mechanisms in lipid droplet fusion and growth

“…However, when the Cidec-GFP-or GFP-Plin1-positive signals surrounding a LD were completely bleached, the recovery rate of GFP-positive signals was very low, and there was no fluorescence signal recovery even after 5 min, indicating a slow replenishing of Cidec or Plin1 from the ER to the LD surface [41,98]. Some studies have shown that CIDEs and Plin1 are a class of ER-bound proteins, which move from the ER to LDs [43,99,100]. On the contrary, ADRP and Plin5 can rapidly shuttle between LDs and the cytoplasm, rather than just moving on the LD surface [41,98].…”