Accumulation of squalene is associated with the clustering of lipid droplets

Abstract

The isoprenoid squalene is an important precursor for the biosynthesis of sterols. The cellular storage of squalene and its impact on membrane properties have been the subject of recent investigations. In a screen for abnormal lipid droplet morphology and distribution in the yeast Saccharomyces cerevisiae, we found significant lipid droplet clustering (arbitrarily defined as an aggregation of six or more lipid droplets) in a number of mutants (e.g. erg1) that are defective in sterol biosynthesis. Interestingly, these mutants are also characterized by accumulation of large amounts of squalene. Reducing the level of squalene in these mutants restored normal lipid droplet distribution. Moreover, inhibition of squalene monooxygenase in two mammalian cell lines (CHO-K1 and 3T3-L1) by terbinafine also resulted in lipid droplet clustering. These results indicate that the level of squalene may affect the growth and distribution of lipid droplets. IntroductionLipid droplets (LDs) are energy storage organelles that comprise a neutral lipid core of triacylglycerols (TAG) and sterol esters (SE), surrounded by a monolayer of phospholipids with proteins embedded [1][2][3][4][5]. Formation of LDs is thought to occur in the endoplasmic reticulum (ER) [6,7]. The most favored model of LD biosynthesis [6][7][8][9] proposes that newly synthesized neutral lipids accumulate between two leaflets of the endoplasmic reticulum (ER) membrane before budding into the cytosol [10,11]. Varying in size and composition, LDs are found in nearly all eukaryotic cells [12][13][14][15], and provide a store of energy and of bioactive lipids, such as fatty acids and sterols [16]. For instance, although mature adipocytes usually contain one or a few huge TAG-rich LDs (25-300 lm in diameter) [16], other mammalian cell types contain smaller neutral LDs with different TAG : SE ratios. Plant seeds usually store abundant TAG-rich LDs, and some seed tissues may contain as much as 76% lipid w/w [17]. Depending on the growth phase, cells of the budding yeast Saccharomyces cerevisiae contain up to a dozen lipid particles/droplets (~0.4 lm in diameter) per cell [1,18], which are made up of equal amounts of TAG and SE [1,19,20].LDs may grow in size in response to increased lipid synthesis and/or uptake [7]. Giant or supersized LDs represent the most efficient form of lipid storage in terms of surface to volume ratio. Small LDs, on the other hand, provide more surface area for LD-associated proteins, such as lipases. Giant LDs may also affect the cell structure and cytoskeleton in a negative way, given their sheer volume. Therefore, the growth and final size of LDs have important implications in cell biology and function. Recent studies have suggested that LDs may grow through fusion, and the clustering of LDs may be a prerequisite for LD growth and fusion [21]. Despite rapid progress in LD research, the fundamental mechanisms that govern the formation, size and distribution of cellular LDs are still unclear. Little is Abbreviations ER, endoplasmic reticulum; LD, ...

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