A Conserved Role for Atlastin GTPases in Regulating Lipid Droplet Size

Klemm, Robin W.; Norton, Justin P.; Cole, Ronald A.; Li, Chen S.; Park, Seong H.; Crane, Matthew M.; Li, Liying; Jin, Diana; Boye-Doe, Alexandra; Liu, Tina Y.; Shibata, Yoko; Lu, Hang; Rapoport, Tom A.; Farese, Robert V.; Blackstone, Craig; Guo, Yi; Mak, Ho Yi

doi:10.1016/j.celrep.2013.04.015

Cited by 141 publications

(138 citation statements)

References 35 publications

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“…This indicates that ER-LD connections are crucial for LD growth. Consistent with this, factors maintaining ER structure, such as atlastin, a GTPase that mediates membrane fusion to connect ER tubules, play a critical role in regulating LD size [61]. …”

mentioning

confidence: 79%

Lipid Droplet Biogenesis

Walther

Chung

Farese

2017

Annu. Rev. Cell Dev. Biol.

613

581

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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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mentioning

confidence: 79%

Lipid Droplet Biogenesis

Walther

Chung

Farese

2017

Annu. Rev. Cell Dev. Biol.

613

581

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“…Our results support that LDs can simply form at different sizes as a result of differences in the ER phospholipid composition and/or tension ( Figures 5G and 6A). For example, the deletion of proteins such as Rab, Atlastin, Reticulon, or Torsin, which do not necessarily affect ER phospholipids but morphology or shape, modulate LD size probably through modulating ER surface tension (Grillet et al, 2016;Klemm et al, 2013;Zerial and McBride, 2001). Indeed, mechanical pulling on the ER membrane increases tension, works against budding, and increases LD formation size.…”

Section: Discussionmentioning

confidence: 99%

ER Membrane Phospholipids and Surface Tension Control Cellular Lipid Droplet Formation

et al. 2017

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SUMMARYCells convert excess energy into neutral lipids that are made in the endoplasmic reticulum (ER) bilayer. The lipids are then packaged into spherical or budded lipid droplets (LDs) covered by a phospholipid monolayer containing proteins. LDs play a key role in cellular energy metabolism and homeostasis. A key unanswered question in the life of LDs is how they bud off from the ER. Here, we tackle this question by studying the budding of artificial LDs from model membranes. We find that the bilayer phospholipid composition and surface tension are key parameters of LD budding. Phospholipids have differential LD budding aptitudes, and those inducing budding decrease the bilayer tension. We observe that decreasing tension favors the egress of neutral lipids from the bilayer and LD budding. In cells, budding conditions favor the formation of small LDs. Our discovery reveals the importance of altering ER physical chemistry for controlled cellular LD formation.

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“…Since C. elegans tissues are refractory to large-scale dissection, biochemical analyses of lipid content is conducted on extracts derived from whole organism populations, which makes it impossible to know whether the measured triglycerides are derived from yolk or storage depots. As one remedy, certain protein markers are being used as indicators of yolk or lipid droplets [8,70–73]. However, the specificities of these markers or the fraction of yolk or lipid droplets that are captured by each are unknown.…”

Section: Figurementioning

confidence: 99%

Investigating Connections between Metabolism, Longevity, and Behavior in Caenorhabditis elegans

Lemieux

Ashrafi

2016

Trends in Endocrinology & Metabolism

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An overview of C. elegans as an experimental organism for studying energy balance is presented. Some of the unresolved questions that complicate the interpretation of lipid measurements from C. elegans are highlighted. We review studies that show both lipid synthesis and breakdown pathways are activated and needed for the longevity of hermaphrodites that lack their germ lines. These findings illustrate the heterogeneity of triglyceride rich lipid particles in C. elegans and reveal specific lipid signals that promote longevity. Finally, we provide a brief overview of feeding behavioral responses of C. elegans to varying nutritional conditions and highlight an unanticipated metabolic pathway that allows for the incorporation of experience in feeding behavior.

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A Conserved Role for Atlastin GTPases in Regulating Lipid Droplet Size

Cited by 141 publications

References 35 publications

Lipid Droplet Biogenesis

Lipid Droplet Biogenesis

ER Membrane Phospholipids and Surface Tension Control Cellular Lipid Droplet Formation

Investigating Connections between Metabolism, Longevity, and Behavior in Caenorhabditis elegans

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