Bulging and budding of lipid droplets from symmetric and asymmetric membranes: Competition between membrane elastic energy and interfacial energy

Soft Matter ◽  
2021 ◽  
Author(s):  
Meng Wang ◽  
Xin Yi
Keyword(s):  
Interfacial Energy ◽  
Elastic Energy ◽  
Protein Trafficking ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Cellular Metabolism ◽  
Asymmetric Membranes ◽  
Intracellular Organelles ◽  
Hydrolysis Of

Lipid droplets are ubiquitous intracellular organelles regulating the storage and hydrolysis of neutral lipids, and play key roles in cellular metabolism and other functions such as protein trafficking and coordinating...

scholarly journals Interactions of Lipid Droplets with the Intracellular Transport Machinery

2021 ◽  
Vol 22 (5) ◽  
pp. 2776
Author(s):  
Selma Yilmaz Dejgaard ◽  
John F. Presley
Keyword(s):  
Membrane Trafficking ◽  
Lipid Droplets ◽  
Intracellular Transport ◽  
Neutral Lipids ◽  
Small Gtpases ◽  
Lipid Phase ◽  
Intracellular Organelles ◽  
And Function ◽  
Lipid Phase Separation ◽  
Endocytic Pathways

Historically, studies of intracellular membrane trafficking have focused on the secretory and endocytic pathways and their major organelles. However, these pathways are also directly implicated in the biogenesis and function of other important intracellular organelles, the best studied of which are peroxisomes and lipid droplets. There is a large recent body of work on these organelles, which have resulted in the introduction of new paradigms regarding the roles of membrane trafficking organelles. In this review, we discuss the roles of membrane trafficking in the life cycle of lipid droplets. This includes the complementary roles of lipid phase separation and proteins in the biogenesis of lipid droplets from endoplasmic reticulum (ER) membranes, and the attachment of mature lipid droplets to membranes by lipidic bridges and by more conventional protein tethers. We also discuss the catabolism of neutral lipids, which in part results from the interaction of lipid droplets with cytosolic molecules, but with important roles for both macroautophagy and microautophagy. Finally, we address their eventual demise, which involves interactions with the autophagocytotic machinery. We pay particular attention to the roles of small GTPases, particularly Rab18, in these processes.

scholarly journals Seipin accumulates and traps diacylglycerols and triglycerides in its ring-like structure

2020 ◽  
Author(s):  
Valeria Zoni ◽  
Wataru Shinoda ◽  
Stefano Vanni
Keyword(s):  
Molecular Dynamics ◽  
Endoplasmic Reticulum ◽  
Molecular Dynamics Simulations ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Health Concern ◽  
Intracellular Organelles ◽  
Dynamics Simulations ◽  
Precise Role

AbstractLipid droplets (LD) are intracellular organelles responsible for lipid storage, and they emerge from the endoplasmic reticulum (ER) upon the accumulation of neutral lipids, mostly triglycerides (TG), between the two leaflets of the ER membrane. LD biogenesis takes place at ER sites that are marked by the protein seipin, which subsequently recruits additional proteins to catalyse LD formation. Deletion of seipin, however, does not abolish LD biogenesis, and its precise role in controlling LD assembly remains unclear. Here we use molecular dynamics simulations to investigate the molecular mechanism through which seipin promotes LD formation. We find that seipin clusters TG molecules inside its unconventional ring-like oligomeric structure, and that both its luminal and transmembrane regions contribute to this process. Diacylglycerol, the precursor of TG, also clusters inside the seipin oligomer, in turn promoting TG accumulation. Our results suggest that seipin remodels the membrane of specific ER sites to prime them for LD biogenesis.Significance statementMetabolic disorders related to aberrant fat accumulation, including lipodystrophy and obesity, are a particularly serious health concern. In cells, fat accumulates in intracellular organelles, named lipid droplets (LDs). LDs form in the endoplasmic reticulum, where triglycerides, the most abundant form of fat, is produced. The Bernardinelli-Seip congenital lipodystrophy type 2 protein, seipin, has been identified as a key regulator of LD formation, but its mechanism of action remains debated and its molecular details mostly obscure. Here, we use molecular dynamics simulations to investigate the mechanism of seipin. We find that seipin can cluster and trap both triglycerides and its precursor, diacylglycerol. Our results suggest that seipin organizes the lipid composition of specific ER sites to prime them for LD biogenesis.

scholarly journals Seipin accumulates and traps diacylglycerols and triglycerides in its ring-like structure

2021 ◽  
Vol 118 (10) ◽  
pp. e2017205118
Author(s):  
Valeria Zoni ◽  
Rasha Khaddaj ◽  
Ivan Lukmantara ◽  
Wataru Shinoda ◽  
Hongyuan Yang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Endoplasmic Reticulum ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Oligomeric Structure ◽  
Hydrophobic Residues ◽  
Intracellular Organelles ◽  
Transmembrane Regions ◽  
Dynamics Simulations ◽  
Precise Role

Lipid droplets (LDs) are intracellular organelles responsible for lipid storage, and they emerge from the endoplasmic reticulum (ER) upon the accumulation of neutral lipids, mostly triglycerides (TG), between the two leaflets of the ER membrane. LD biogenesis takes place at ER sites that are marked by the protein seipin, which subsequently recruits additional proteins to catalyze LD formation. Deletion of seipin, however, does not abolish LD biogenesis, and its precise role in controlling LD assembly remains unclear. Here, we use molecular dynamics simulations to investigate the molecular mechanism through which seipin promotes LD formation. We find that seipin clusters TG, as well as its precursor diacylglycerol, inside its unconventional ring-like oligomeric structure and that both its luminal and transmembrane regions contribute to this process. This mechanism is abolished upon mutations of polar residues involved in protein–TG interactions into hydrophobic residues. Our results suggest that seipin remodels the membrane of specific ER sites to prime them for LD biogenesis.

scholarly journals The ARF-Like GTPase ARFRP1 Is Essential for Lipid Droplet Growth and Is Involved in the Regulation of Lipolysis

2009 ◽  
Vol 30 (5) ◽  
pp. 1231-1242 ◽  
Author(s):  
Angela Hommel ◽  
Deike Hesse ◽  
Wolfgang Völker ◽  
Alexander Jaschke ◽  
Markus Moser ◽  
...  
Keyword(s):  
Lipid Droplet ◽  
Protein Trafficking ◽  
Lipid Droplets ◽  
Hormone Sensitive Lipase ◽  
Droplet Growth ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Hormone Sensitive ◽  
Intracellular Organelles ◽  
Adp Ribosylation Factor

ABSTRACT ADP-ribosylation factor (ARF)-related protein 1 (ARFRP1) is a GTPase regulating protein trafficking between intracellular organelles. Here we show that mice lacking Arfrp1 in adipocytes (Arfrp1 ad−/−) are lipodystrophic due to a defective lipid droplet formation in adipose cells. Ratios of mono-, di-, and triacylglycerol, as well as the fatty acid composition of triglycerides, were unaltered. Lipid droplets of brown adipocytes of Arfrp1 ad−/− mice were considerably smaller and exhibited ultrastructural alterations, such as a disturbed interaction of small lipid-loaded particles with the larger droplets, suggesting that ARFRP1 mediates the transfer of newly formed small lipid particles to the large storage droplets. SNAP23 (synaptosomal-associated protein of 23 kDa) associated with small lipid droplets of control adipocytes but was located predominantly in the cytosol of Arfrp1 ad−/− adipocytes, suggesting that lipid droplet growth is defective in Arfrp1 ad−/− mice. In addition, levels of phosphorylated hormone-sensitive lipase (HSL) were elevated, and association of adipocyte triglyceride lipase (ATGL) with lipid droplets was enhanced in brown adipose tissue from Arfrp1 ad−/− mice. Accordingly, basal lipolysis was increased after knockdown of Arfrp1 in 3T3-L1 adipocytes. The data indicate that disruption of ARFRP1 prevents the normal enlargement of lipid droplets and produces an activation of lipolysis.

scholarly journals Lipid Droplet-Associated Factors, PNPLA3, TM6SF2, and HSD17B Proteins in Hepatopancreatobiliary Cancer

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4391
Author(s):  
Yoshiaki Sunami ◽  
Artur Rebelo ◽  
Jörg Kleeff
Keyword(s):  
Liver Cancer ◽  
Lipid Droplet ◽  
Associated Factors ◽  
Lipid Droplets ◽  
Cancer Metabolism ◽  
Neutral Lipids ◽  
Cancer Type ◽  
Hepatic Diseases ◽  
Cell Type Specific ◽  
Intracellular Organelles

Pancreatic and liver cancer are leading causes of cancer deaths, and by 2030, they are projected to become the second and the third deadliest cancer respectively. Cancer metabolism, especially lipid metabolism, plays an important role in progression and metastasis of many types of cancer, including pancreatic and liver cancer. Lipid droplets are intracellular organelles that store neutral lipids, but also act as molecular messengers, and signaling factors. It is becoming increasingly evident that alterations in the regulation of lipid droplets and their associated factors influence the risk of developing not only metabolic disease but also fibrosis and cancer. In the current review article, we summarized recent findings concerning the roles of lipid droplet-associated factors, patatin-like phospholipase domain-containing 3, Transmembrane 6 superfamily member 2, and 17β-hydroxysteroid dehydrogenase 11 and 13 as well as genetic variants in pancreatic and hepatic diseases. A better understanding of cancer type- and cell type-specific roles of lipid droplet-associated factors is important for establishing new therapeutic options in the future.

scholarly journals Regulation of lipid droplets by metabolically controlled Ldo isoforms

2017 ◽  
Vol 217 (1) ◽  
pp. 127-138 ◽  
Author(s):  
Vitor Teixeira ◽  
Lisa Johnsen ◽  
Fernando Martínez-Montañés ◽  
Alexandra Grippa ◽  
Laura Buxó ◽  
...  
Keyword(s):  
Lipid Droplets ◽  
Growth Stage ◽  
Energy Homeostasis ◽  
Neutral Lipids ◽  
Protein Localization ◽  
Cellular Metabolism ◽  
Coupling Energy ◽  
Tightly Coupled ◽  
Triglyceride Content ◽  
Splicing Isoforms

Storage and consumption of neutral lipids in lipid droplets (LDs) are essential for energy homeostasis and tightly coupled to cellular metabolism. However, how metabolic cues are integrated in the life cycle of LDs is unclear. In this study, we characterize the function of Ldo16 and Ldo45, two splicing isoforms of the same protein in budding yeast. We show that Ldo proteins interact with the seipin complex, which regulates contacts between LDs and the endoplasmic reticulum (ER). Moreover, we show that the levels of Ldo16 and Ldo45 depend on the growth stage of cells and that deregulation of their relative abundance alters LD morphology, protein localization, and triglyceride content. Finally, we show that absence of Ldo proteins results in defects in LD morphology and consumption by lipophagy. Our findings support a model in which Ldo proteins modulate the activity of the seipin complex, thereby affecting LD properties. Moreover, we identify ER–LD contacts as regulatory targets coupling energy storage to cellular metabolism.

scholarly journals The architecture of Cidec-mediated interfaces between lipid droplets

2021 ◽  
Author(s):  
Iva Ganeva ◽  
Koini Lim ◽  
Jerome Boulanger ◽  
Patrick C. Hoffmann ◽  
David B. Savage ◽  
...  
Keyword(s):  
Fluorescence Microscopy ◽  
Neutral Lipid ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Lipid Transfer ◽  
Surplus Energy ◽  
White Adipocytes ◽  
Architectural Features ◽  
Intracellular Organelles ◽  
Kinetics Of

Lipid droplets (LDs) are intracellular organelles responsible for storing surplus energy as neutral lipids. Their size and number vary enormously. In white adipocytes, they reach up to 100 μm in size, occupying >90% of the cell. Cidec, which is strictly required for the formation of such large LDs, is concentrated at interfaces between adjacent LDs and facilitates the directional flux of neutral lipids from the smaller to the larger LD. However, the mechanism of lipid transfer is unclear, in part because the architecture of interfaces between LDs has remained elusive. Here we visualised interfaces between LDs by electron cryo-tomography and analysed the kinetics of lipid transfer by quantitative live fluorescence microscopy. We show that transfer occurs through closely apposed intact monolayers, is slowed down by increasing the distance between the monolayers and follows exponential kinetics suggesting a pressure-driven mechanism. We thus propose that unique architectural features of LD-LD interfaces are mechanistic determinants of neutral lipid transfer.

A Molecular Logic Gate Enables Super-Resolved Imaging of Intracellular Lipid Droplets

2019 ◽  
Author(s):  
Adam Eördögh ◽  
Carolina Paganini ◽  
Dorothea Pinotsi ◽  
Paolo Arosio ◽  
Pablo Rivera-Fuentes
Keyword(s):  
Single Molecule ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Logic Gate ◽  
Living Cells ◽  
Three Dimensions ◽  
Single Molecule Imaging ◽  
Molecular Logic Gate ◽  
Molecular Logic ◽  
Cellular Compartments

<div>Photoactivatable dyes enable single-molecule imaging in biology. Despite progress in the development of new fluorophores and labeling strategies, many cellular compartments remain difficult to image beyond the limit of diffraction in living cells. For example, lipid droplets, which are organelles that contain mostly neutral lipids, have eluded single-molecule imaging. To visualize these challenging subcellular targets, it is necessary to develop new fluorescent molecular devices beyond simple on/off switches. Here, we report a fluorogenic molecular logic gate that can be used to image single molecules associated with lipid droplets with excellent specificity. This probe requires the subsequent action of light, a lipophilic environment and a competent nucleophile to produce a fluorescent product. The combination of these requirements results in a probe that can be used to image the boundary of lipid droplets in three dimensions with resolutions beyond the limit of diffraction. Moreover, this probe enables single-molecule tracking of lipids within and between droplets in living cells.</div>

scholarly journals Intracellular Lipid Droplets: From Structure to Function

2017 ◽  
Vol 10 ◽  
pp. 117863531774551 ◽  
Author(s):  
Stefano Vanni
Keyword(s):  
Lipid Droplets ◽  
Neutral Lipids ◽  
Interfacial Structure ◽  
Aqueous Environment ◽  
Sterol Esters ◽  
Computational Approaches ◽  
Main Site ◽  
Natural Surfactant ◽  
Oil Emulsions ◽  
Function Relationship

Lipid droplets (LDs) are unique intracellular organelles that are mainly constituted by neutral lipids (triglycerides, sterol esters). As such they serve as the main site of energy storage in the cell and they are akin to oil emulsions in water. To prevent the direct exposure of the hydrophobic neutral lipids to the aqueous environment of the cytosol, LDs are surrounded by a monolayer of phospholipids that thus behave as a natural surfactant. This interfacial structure is rather unique inside the cell, but a molecular understanding of how the LD structure modulates its functions is still lacking, mainly due to technical challenges in both experimental and computational approaches to investigate oil-in-water emulsions. Recently, we have investigated the structure of LDs using a combination of existing and newly developed computational approaches that are optimized to study oil-water interfaces.1 Our simulations provide a comprehensive molecular characterization of the unique surface properties of LDs, suggesting structure-function relationship in several LD-related metabolic processes.

scholarly journals AMPK-Mediated Regulation of Alpha-Arrestins and Protein Trafficking

2019 ◽  
Vol 20 (3) ◽  
pp. 515 ◽  
Author(s):  
Allyson F. O’Donnell ◽  
Martin C. Schmidt
Keyword(s):  
Glucose Uptake ◽  
Protein Trafficking ◽  
Transmembrane Domain ◽  
Carbon Sources ◽  
Cellular Metabolism ◽  
Glucose Transporters ◽  
Adenosine Monophosphate ◽  
Kinetic Properties ◽  
Glucose Limitation ◽  
Additional Layer

Abstract: The adenosine monophosphate-activated protein kinase (AMPK) plays a central role in the regulation of cellular metabolism. Recent studies reveal a novel role for AMPK in the regulation of glucose and other carbohydrates flux by controlling the endocytosis of transporters. The first step in glucose metabolism is glucose uptake, a process mediated by members of the GLUT/SLC2A (glucose transporters) or HXT (hexose transporters) family of twelve-transmembrane domain glucose transporters in mammals and yeast, respectively. These proteins are conserved from yeast to humans, and multiple transporters—each with distinct kinetic properties—compete for plasma membrane occupancy in order to enhance or limit the rate of glucose uptake. During growth in the presence of alternative carbon sources, glucose transporters are removed and replaced with the appropriate transporter to help support growth in response to this environment. New insights into the regulated protein trafficking of these transporters reveal the requirement for specific α-arrestins, a little-studied class of protein trafficking adaptor. A defining feature of the α-arrestins is that each contains PY-motifs, which can bind to the ubiquitin ligases from the NEDD4/Rsp5 (Neural precursor cell Expressed, Developmentally Down-regulated 4 and Reverses Spt- Phenotype 5, respectively) family. Specific association of α-arrestins with glucose and carbohydrate transporters is thought to bring the ubiquitin ligase in close proximity to its membrane substrate, and thereby allows the membrane cargo to become ubiquitinated. This ubiquitination in turn serves as a mark to stimulate endocytosis. Recent results show that AMPK phosphorylation of the α-arrestins impacts their abundance and/or ability to stimulate carbohydrate transporter endocytosis. Indeed, AMPK or glucose limitation also controls α-arrestin gene expression, adding an additional layer of complexity to this regulation. Here, we review the recent studies that have expanded the role of AMPK in cellular metabolism to include regulation of α-arrestin-mediated trafficking of transporters and show that this mechanism of regulation is conserved over the ~150 million years of evolution that separate yeast from man.

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