scholarly journals Lipid Droplets, Phospholipase A2, Arachidonic Acid, and Atherosclerosis

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1891
Author(s):  
Miguel A. Bermúdez ◽  
María A. Balboa ◽  
Jesús Balsinde
Keyword(s):  
Arachidonic Acid ◽  
Phospholipase A2 ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Lipid Synthesis ◽  
Lipid Mediator ◽  
Droplet Dynamics ◽  
Potent Inducer ◽  
Inflammatory State ◽  
Dynamic Structures

Lipid droplets, classically regarded as static storage organelles, are currently considered as dynamic structures involved in key processes of lipid metabolism, cellular homeostasis and signaling. Studies on the inflammatory state of atherosclerotic plaques suggest that circulating monocytes interact with products released by endothelial cells and may acquire a foamy phenotype before crossing the endothelial barrier and differentiating into macrophages. One such compound released in significant amounts into the bloodstream is arachidonic acid, the common precursor of eicosanoids, and a potent inducer of neutral lipid synthesis and lipid droplet formation in circulating monocytes. Members of the family of phospholipase A2, which hydrolyze the fatty acid present at the sn-2 position of phospholipids, have recently emerged as key controllers of lipid droplet homeostasis, regulating their formation and the availability of fatty acids for lipid mediator production. In this paper we discuss recent findings related to lipid droplet dynamics in immune cells and the ways these organelles are involved in regulating arachidonic acid availability and metabolism in the context of atherosclerosis.

scholarly journals The localization of phospholipase A2 in the secretory granule

1994 ◽  
Vol 300 (3) ◽  
pp. 619-622 ◽  
Author(s):  
S P Chock ◽  
E A Schmauder-Chock ◽  
E Cordella-Miele ◽  
L Miele ◽  
A B Mukherjee
Keyword(s):  
Arachidonic Acid ◽  
Phospholipase A2 ◽  
Secretory Granule ◽  
Secretory Granules ◽  
Lipid Mediator ◽  
Arachidonic Acid Cascade ◽  
Surface Receptors ◽  
The Matrix ◽  
Immunocytochemical Techniques ◽  
Granule Matrix

A heat-resistant phospholipase A2 has been detected in the secretory granules of the mast cell [Chock, Rhee, Tang and Schmauder-Chock (1991) Eur. J. Biochem. 195, 707-713]. By using ultrastructural immunocytochemical techniques, we have now localized this enzyme to the matrix of the secretory granule. Like the cyclo-oxygenase [Schmauder-Chock and Chock (1989) J. Histochem. Cytochem. 37, 1319-1328], this enzyme also adheres tightly to the ribbon-like granule matrix components. The results from Western-blot analysis suggest that it has a molecular mass of about 14 kDa. The localization of the phospholipase A2, the presence of a phospholipid store with millimolar concentrations of calcium and the localization of the enzymes of the arachidonic acid cascade make the secretory granule a natural site for lipid-mediator synthesis. The packaging of phospholipase A2, together with its substrate and the components of the arachidonic acid cascade, in the secretory granule represents a physical arrangement by which the initiation of the cascade and the release of mediators can be directly linked to the stimulation of cell-surface receptors.

scholarly journals A lipid droplet-peroxisome network drives longevity by monounsaturated fatty acids via modulating ether lipid synthesis and ferroptosis

2021 ◽  
Author(s):  
Anne Brunet ◽  
Katharina Papsdorf ◽  
Amir Hosseini ◽  
Jason Miklas ◽  
Matias Cabruja ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Unsaturated Fatty Acids ◽  
Lipid Synthesis ◽  
Ether Lipid ◽  
Monounsaturated Fatty Acids ◽  
Human Longevity ◽  
Ether Lipids ◽  
C Elegans

Abstract Dietary mono-unsaturated fatty acids (MUFAs) are linked to human longevity and extend lifespan in several species1-12. But the mechanisms by which MUFAs promote longevity remain unclear. Here we show that an organelle hub involving lipid droplets and peroxisomes is critical for lifespan extension by MUFAs in C. elegans. MUFA accumulation increases lipid droplet number in fat storage tissues, and lipid droplet synthesis is necessary for MUFA-mediated longevity. Interestingly, the number of lipid droplets in young individuals can predict their remaining lifespan. MUFA accumulation also increases the number of peroxisomes, and peroxisome activity is required for MUFA-mediated longevity. By performing a targeted screen, we uncover a functional network between lipid droplets and peroxisomes in longevity. Interestingly, our screen also identifies ether lipids as critical components of the lipid droplet-peroxisome network. Using lipidomics, we find that the ratio of MUFAs to polyunsaturated fatty acids (PUFAs) in ether lipids is increased by MUFA accumulation. Ether lipids are involved in ferroptosis, a non-apoptotic form of cell death13-17, and MUFAs promote longevity in part via suppression of ferroptosis. Our results identify a mechanism of action for MUFAs to extend lifespan and uncover an organelle network involved in the homeostasis of MUFA-rich ether lipids. Our work also opens new avenues for lipid-based interventions to delay aging.

scholarly journals Lipid droplets are required for lipid mediator production and cancer cell proliferation

2021 ◽  
Author(s):  
Toni Petan ◽  
Thomas O. Eichmann ◽  
Robert Zimmermann ◽  
Anja Pucer Janež ◽  
Jana Gerstmeier ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cell Proliferation ◽  
Fatty Acid ◽  
Cancer Cell ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Lipid Mediators ◽  
Lipid Mediator ◽  
Cancer Cell Proliferation ◽  
Membrane Phospholipids

Lipid droplets are dynamic organelles with a central role in fatty acid metabolism. They protect cells from lipotoxicity by sequestering excess fatty acids but also provide fatty acids for metabolic reactions and signalling events. Here we show that lipid droplet turnover in cancer cells is required for production of ω-3 and ω-6 polyunsaturated fatty acid (PUFA)-derived inflammatory lipid mediators, including eicosanoids and specialised pro-resolving mediators. We show that incorporation of PUFAs into triglycerides mediated by diacylglycerol acyltransferase 1 (DGAT1), and their release by adipose triglyceride lipase (ATGL), are required for cyclooxygenase- and lipoxygenase-dependent lipid mediator production and cancer cell proliferation. The human group X secreted phospholipase A2 (hGX sPLA2) drives the delivery of membrane-derived PUFAs into lipid droplets, while ATGL promotes the incorporation of lipid droplet-derived PUFAs into phospholipids. The group IVA cytosolic PLA2 (cPLA2α) acts on membrane phospholipids and complements ATGL in the regulation of PUFA trafficking between phospholipids and triglycerides. This study identifies lipid droplets as essential cellular hubs that control PUFA availability for production of lipid mediators involved in inflammation and tumorigenesis.

scholarly journals An in vivo reporter for tracking lipid droplet dynamics in transparent zebrafish

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Dianne Lumaquin ◽  
Eleanor Johns ◽  
Emily Montal ◽  
Joshua M Weiss ◽  
David Ola ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Large Scale ◽  
Fluorescent Dyes ◽  
Cell Types ◽  
Structural Protein ◽  
Droplet Dynamics

Lipid droplets are lipid storage organelles found in nearly all cell types from adipocytes to cancer cells. Although increasingly implicated in disease, current methods to study lipid droplets in vertebrate models rely on static imaging or the use of fluorescent dyes, limiting investigation of their rapid in vivo dynamics. To address this, we created a lipid droplet transgenic reporter in whole animals and cell culture by fusing tdTOMATO to Perilipin-2 (PLIN2), a lipid droplet structural protein. Expression of this transgene in transparent casper zebrafish enabled in vivo imaging of adipose depots responsive to nutrient deprivation and high-fat diet. Simultaneously, we performed a large-scale in vitro chemical screen of 1280 compounds and identified several novel regulators of lipolysis in adipocytes. Using our Tg(-3.5ubb:plin2-tdTomato) zebrafish line, we validated several of these novel regulators and revealed an unexpected role for nitric oxide in modulating adipocyte lipid droplets. Similarly, we expressed the PLIN2-tdTOMATO transgene in melanoma cells and found that the nitric oxide pathway also regulated lipid droplets in cancer. This model offers a tractable imaging platform to study lipid droplets across cell types and disease contexts using chemical, dietary, or genetic perturbations.

scholarly journals Mast cells: from lipid droplets to lipid mediators

2013 ◽  
Vol 125 (3) ◽  
pp. 121-130 ◽  
Author(s):  
Andrea Dichlberger ◽  
Petri T. Kovanen ◽  
Wolfgang J. Schneider
Keyword(s):  
Arachidonic Acid ◽  
Mast Cells ◽  
Lipid Droplets ◽  
Current Knowledge ◽  
Physiological State ◽  
Inflammatory Cells ◽  
The Body ◽  
Lipid Mediator ◽  
Main Function ◽  
Human Mast Cells

LDs (lipid droplets) are metabolically highly active intracellular organelles. The lipid and protein profiles of LDs are cell-type-specific, and they undergo dynamic variation upon changes in the physiological state of a cell. It is well known that the main function of the LDs in adipocytes is to ensure energy supply and to maintain lipid homoeostasis in the body. In contrast, LDs in inflammatory cells have been implicated in eicosanoid biosynthesis, particularly under inflammatory conditions, thereby enabling them to regulate immune responses. Human mast cells are potent effector cells of the innate immune system, and the triacylglycerol (triglyceride) stores of their cytoplasmic LDs have been shown to contain large amounts of arachidonic acid, the main precursor of pro-inflammatory eicosanoids. In the present review, we discuss the current knowledge about the formation and function of LDs in inflammatory cells with specific emphasis on arachidonic acid and eicosanoid metabolism. On the basis of findings reported previously and our new observations, we propose a model in which lipolysis of LD-triacylglycerols provides arachidonic acid for lipid mediator generation in human mast cells.

scholarly journals An in vivo reporter for tracking lipid droplet dynamics in transparent zebrafish

2020 ◽  
Author(s):  
Dianne Lumaquin ◽  
Eleanor Johns ◽  
Joshua Weiss ◽  
Emily Montal ◽  
Olayinka Ooladipupo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Droplet ◽  
High Fat Diet ◽  
Lipid Droplets ◽  
Cell Types ◽  
Structural Protein ◽  
High Fat ◽  
Droplet Dynamics ◽  
Perilipin 2

AbstractLipid droplets are lipid storage organelles found in nearly all cell types from adipocytes to cancer cells. Although increasingly implicated in disease, current methods to study lipid droplets require fixation or static imaging which limits investigation of their rapid in vivo dynamics. To address this, we created a lipid droplet transgenic reporter in whole animals and cell culture by fusing tdTOMATO to Perilipin-2 (PLIN2), a lipid droplet structural protein. Expression of this transgene in transparent casper zebrafish enabled in vivo imaging of adipose depots responsive to nutrient deprivation and high-fat diet. Using this system, we tested novel regulators of lipolysis, revealing an unexpected role for nitric oxide in modulating adipocyte lipid droplets. Similarly, we expressed the PLIN2-tdTOMATO transgene in melanoma cells and found that the nitric oxide pathway also regulated lipid droplets in cancer. This model offers a tractable imaging platform to study lipid droplets across cell types and disease contexts.

scholarly journals Imaging cytoplasmic lipid droplets in vivo with fluorescent perilipin 2 and perilipin 3 knock-in zebrafish

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Meredith H Wilson ◽  
Stephen C Ekker ◽  
Steven Arthur Farber
Keyword(s):  
Lipid Droplet ◽  
Lipid Droplets ◽  
Cultured Cells ◽  
Droplet Dynamics ◽  
Associated Proteins ◽  
Perilipin 2 ◽  
Cytoplasmic Lipid Droplets ◽  
Endogenous Loci

Cytoplasmic lipid droplets are highly dynamic storage organelles that are critical for cellular lipid homeostasis. While the molecular details of lipid droplet dynamics are a very active area of investigation, this work has been primarily performed in cultured cells. Taking advantage of the powerful transgenic and in vivo imaging opportunities available in zebrafish, we built a suite of tools to study lipid droplets in real-time from the subcellular to the whole organism level. Fluorescently tagging the lipid-droplet-associated proteins, perilipin 2 and perilipin 3, in the endogenous loci permits visualization of lipid droplets in the intestine, liver, and adipose tissue. Using these tools, we found that perilipin 3 is rapidly loaded on intestinal lipid droplets following a high-fat meal and later replaced by perilipin 2. These powerful new tools will facilitate studies on the role of lipid droplets in different tissues, under different genetic and physiological manipulations, and in a variety of human disease models.

scholarly journals A Lipidomic Perspective of the Action of Group IIA Secreted Phospholipase A2 on Human Monocytes: Lipid Droplet Biogenesis and Activation of Cytosolic Phospholipase A2α

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 891 ◽  
Author(s):  
Juan P. Rodríguez ◽  
Elbio Leiguez ◽  
Carlos Guijas ◽  
Bruno Lomonte ◽  
José M. Gutiérrez ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Phospholipase A2 ◽  
Lipid Droplet ◽  
Human Peripheral Blood ◽  
Fatty Acid Content ◽  
Blood Monocytes ◽  
Membrane Phospholipids ◽  
Cytosolic Phospholipase ◽  
Secreted Phospholipase A2 ◽  
Cytosolic Phospholipase A2α

Phospholipase A2s constitute a wide group of lipid-modifying enzymes which display a variety of functions in innate immune responses. In this work, we utilized mass spectrometry-based lipidomic approaches to investigate the action of Asp-49 Ca2+-dependent secreted phospholipase A2 (sPLA2) (MT-III) and Lys-49 sPLA2 (MT-II), two group IIA phospholipase A2s isolated from the venom of the snake Bothrops asper, on human peripheral blood monocytes. MT-III is catalytically active, whereas MT-II lacks enzyme activity. A large decrease in the fatty acid content of membrane phospholipids was detected in MT III-treated monocytes. The significant diminution of the cellular content of phospholipid-bound arachidonic acid seemed to be mediated, in part, by the activation of the endogenous group IVA cytosolic phospholipase A2α. MT-III triggered the formation of triacylglycerol and cholesterol enriched in palmitic, stearic, and oleic acids, but not arachidonic acid, along with an increase in lipid droplet synthesis. Additionally, it was shown that the increased availability of arachidonic acid arising from phospholipid hydrolysis promoted abundant eicosanoid synthesis. The inactive form, MT-II, failed to produce any of the effects described above. These studies provide a complete lipidomic characterization of the monocyte response to snake venom group IIA phospholipase A2, and reveal significant connections among lipid droplet biogenesis, cell signaling and biochemical pathways that contribute to initiating the inflammatory response.

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