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.

Not Just Fat: The Structure and Function of the Lipid Droplet

“…Several studies show that down-regulation of the ARF1-COPI pathway induces LD enlargement (Beller et al 2008;Guo et al 2008;Soni et al 2009). It was conjectured that the ARF1-COPI pathway might increase lipolysis at LDs by modulating PAT protein composition in LDs and/or targeting ATGL to LDs.…”

Dropping in on the lipid droplet- tumor protein D52 (TPD52) as a new regulator and resident protein

“…5,6,[14][15][16][17][18]43 Although TPD52 did not emerge as a strong candidate from these collective studies, the direct expression of TPD52 in cultured cells resulted in significantly increased LD numbers. 7 This finding suggests that there may be other important regulators of LDs identified through RNAi screening and proteomics approaches that are yet to be prioritised for further study.…”

“…The mouse Tpd52 ortholog was reported to be upregulated 5-fold in obese versus lean mouse adipose tissue, 13 and knock-down of the ancestral C. elegans TPD52 ortholog F13E6.1 was subsequently associated with reduced lipid storage. 14 However, this latter result was not supported by several whole genome RNAi screening studies in D. melanogaster, [15][16][17] although a proteomics study reported a moderate association between the ancestral D. melanogaster TPD52 ortholog CG5174 and LDs. 18 In both these C. elegans and D. melanogaster studies, 14,18 TPD52 orthologues were identified as anonymous proteins, and the The green bar includes a 14-3-3 binding motif, whereas the purple bar represents an alternatively-spliced region termed insert 2 (Ins 2), which is present in some TPD52L2 isoforms, but not other TPD52-like proteins.…”

“…7 Whereas the formation of LDs within the endoplasmic reticulum has been the subject of intense research and discussion, 4 the role of the Golgi in LD biology has been studied to a lesser extent. However, a number of Golgi-associated proteins have been shown through RNAi screening approaches to regulate LD biology, 15,16 and other LD regulators can be detected at both the Golgi and LDs. 46,47 Further studies will be required to determine whether TPD52 functions at the Golgi are related to its LD functions.…”

COPI Budding within the Golgi Stack

“…By mediating the delivery of enzymes to this compartment, the COPI system might help control the homeostasis of lipids in the cell (Beller et al 2008;Soni et al 2009), although carriers with cargo indicative of this pathway have not yet been described.…”