Lipid Droplet Biogenesis

Abstract

Lipid droplets (LDs) are found in most cells, where they play central roles in energy and membrane lipid metabolism. The de novo biogenesis of LDs is a fascinating, yet poorly understood process involving the formation of a monolayer bound organelle from a bilayer membrane. Additionally, large LDs can form either by growth of existing LDs or by the combination of smaller LDs through several distinct mechanisms. Here, we review recent insights into the molecular process governing LD biogenesis and highlight areas of incomplete knowledge.Lipid droplets (LDs) are ubiquitous, dynamic cellular organelles that serve as important reservoirs of lipids. These lipids provide energy and serve as substrates for membrane synthesis, making LDs crucial metabolic hubs. Indeed, many of the enzymes that synthesize phospholipids (PLs), triacylglycerols (TGs), and their intermediates, as well as lipases and lipolytic regulators, localize to LD surfaces. In addition to their known role in lipid metabolism, increasing evidence suggests that LDs also participate in protein degradation [1,2], response to ER stress [3], protein glycosylation [4], and pathogen infection [5]. Further details about the general aspects of LD cell biology and physiology are discussed in numerous recent reviews [6][7][8][9][10]. However, despite recent focus and the application of new technologies to study LDs, a number of basic questions remain unanswered. Chief among these are the molecular processes governing how LDs form and grow. Here, we review recent advances in this area. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access LD FormationLDs could either form de novo or could be derived from existing LDs by fission. Most evidence favors the former process as a major source, however, fission of LDs has been observed [24]. De novo formation of LDs in eukaryotes occurs from the ER [25,26], where neutral lipids are synthesized [27]. Precisely how LDs form, however, remains mostly unanswered. Here we present a model for LD formation in three stages ( Figure 1): (1) neutral lipid synthesis, (2) lens formation (intra-membrane lipid accumulation), and (3) drop formation. We highlight recent advances in the understanding of each of these stages.Step 1 Step 3: Droplet FormationAbove a certain size, depending on the oil and phospholipid composition, lipid lenses in the ER are predicted to be unstable and bud, by a mechanism similar to de-wetting, due to thermal fluctuations [6] (Figure 1). The smallest mature cytosolic LDs have diameters in the range of 250-500 nm [21,54], which establishes an upper li...

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