Abstract
Lipid droplets (LDs) are important cellular organelles that govern the storage and turnover of lipids. Little is known about how the size of LDs is controlled, although LDs of diverse sizes have been observed in different tissues and under different (patho)physiological conditions. Recent studies have indicated that the size of LDs may influence adipogenesis, the rate of lipolysis and the oxidation of fatty acids. Here, a genome-wide screen identifies ten yeast mutants producing “supersized” LDs that are up to 50 times the volume of those in wild-type cells. The mutated genes include: FLD1, which encodes a homologue of mammalian seipin; five genes (CDS1, INO2, INO4, CHO2, and OPI3) that are known to regulate phospholipid metabolism; two genes (CKB1 and CKB2) encoding subunits of the casein kinase 2; and two genes (MRPS35 and RTC2) of unknown function. Biochemical and genetic analyses reveal that a common feature of these mutants is an increase in the level of cellular phosphatidic acid (PA). Results from in vivo and in vitro analyses indicate that PA may facilitate the coalescence of contacting LDs, resulting in the formation of “supersized” LDs. In summary, our results provide important insights into how the size of LDs is determined and identify novel gene products that regulate phospholipid metabolism.
Highlights
Lipid droplets (LDs) are dynamic organelles that govern the storage and turnover of lipids [1]
Lipid droplets (LD) are primary lipid storage structures that function in membrane and lipid trafficking, protein turnover, and the reproduction of deadly viruses
Increased LD accumulation in liver, skeletal muscle, and adipose tissue is a hallmark of the metabolic syndrome
Summary
Lipid droplets (LDs) are dynamic organelles that govern the storage and turnover of lipids [1]. They play important roles in membrane and lipid trafficking, protein storage, protein degradation and the replication of hepatitis C and dengue viruses [1,2,3,4,5]. LDs of various sizes have been observed in different tissues or within the same cell type under different (patho)physiological conditions [7,8]. Deletion of FSP27 (fat-specific protein of 27 kDa) resulted in many smaller LDs in white adipocytes, enhanced lipolysis and protection from diet-induced obesity and insulin resistance [8,10]. Screens of the viable yeast deletion library found extensive clustering of LDs and formation of ‘‘Supersized’’ LDs (SLDs) that are up to 50 times the normal volume in cells deleted for FLD1 [12], which encodes a functional homologue of a human lipodystrophic protein: seipin [13,14]
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