COPI Complex Is a Regulator of Lipid Homeostasis

Abstract

Lipid droplets are ubiquitous triglyceride and sterol ester storage organelles required for energy storage homeostasis and biosynthesis. Although little is known about lipid droplet formation and regulation, it is clear that members of the PAT (perilipin, adipocyte differentiation related protein, tail interacting protein of 47 kDa) protein family coat the droplet surface and mediate interactions with lipases that remobilize the stored lipids. We identified key Drosophila candidate genes for lipid droplet regulation by RNA interference (RNAi) screening with an image segmentation-based optical read-out system, and show that these regulatory functions are conserved in the mouse. Those include the vesicle-mediated Coat Protein Complex I (COPI) transport complex, which is required for limiting lipid storage. We found that COPI components regulate the PAT protein composition at the lipid droplet surface, and promote the association of adipocyte triglyceride lipase (ATGL) with the lipid droplet surface to mediate lipolysis. Two compounds known to inhibit COPI function, Exo1 and Brefeldin A, phenocopy COPI knockdowns. Furthermore, RNAi inhibition of ATGL and simultaneous drug treatment indicate that COPI and ATGL function in the same pathway. These data indicate that the COPI complex is an evolutionarily conserved regulator of lipid homeostasis, and highlight an interaction between vesicle transport systems and lipid droplets. Fat cells, and cells in general, convert fatty acids into triglycerides that are stored in droplets for future use. Despite the enormous importance of lipid droplets in obesity and other disease processes, we know very little about how lipid reserves in droplets are formed and how those reserves are drawn down. We have used the model fruit fly Drosophila to identify candidate regulators of lipid storage and utilization, and have shown that many of these candidates have functions that are conserved in mammals. We focused our attention on a vesicle-trafficking pathway that we show is required for the modulation of the types of regulatory and enzymatic proteins found on the lipid droplet surface. Interfering with the function of this trafficking system with either RNA interference or small-molecule compounds alters lipid storage. The understanding of this new pathway, as well as the specific reagents we used, may ultimately lead to new therapeutics.