Lipid droplet

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Lipid droplets, also referred to as lipid bodies, oil bodies or adiposomes, [1] are lipid-rich cellular organelles that regulate the storage and hydrolysis of neutral lipids and are found largely in the adipose tissue. [2] They also serve as a reservoir for cholesterol and acyl-glycerols for membrane formation and maintenance. Lipid droplets are found in all eukaryotic organisms and store a large portion of lipids in mammalian adipocytes. Initially, these lipid droplets were considered to merely serve as fat depots, but since the discovery in the 1990s of proteins in the lipid droplet coat that regulate lipid droplet dynamics and lipid metabolism, lipid droplets are seen as highly dynamic organelles that play a very important role in the regulation of intracellular lipid storage and lipid metabolism. The role of lipid droplets outside of lipid and cholesterol storage has recently begun to be elucidated and includes a close association to inflammatory responses through the synthesis and metabolism of eicosanoids and to metabolic disorders such as obesity, cancer, [3] [4] and atherosclerosis. [5] In non-adipocytes, lipid droplets are known to play a role in protection from lipotoxicity by storage of fatty acids in the form of neutral triacylglycerol, which consists of three fatty acids bound to glycerol. Alternatively, fatty acids can be converted to lipid intermediates like diacylglycerol (DAG), ceramides and fatty acyl-CoAs. These lipid intermediates can impair insulin signaling, which is referred to as lipid-induced insulin resistance and lipotoxicity. [6] Lipid droplets also serve as platforms for protein binding and degradation. Finally, lipid droplets are known to be exploited by pathogens such as the hepatitis C virus, the dengue virus and Chlamydia trachomatis among others. [7] [8]

Contents

Structure

Lipid droplets are composed of a neutral lipid core consisting mainly of triacylglycerols (TAGs) and cholesteryl esters surrounded by a phospholipid monolayer. [2] The surface of lipid droplets is decorated by a number of proteins which are involved in the regulation of lipid metabolism. [2] The first and best-characterized family of lipid droplet coat proteins is the perilipin protein family, consisting of five proteins. These include perilipin 1 (PLIN1), perilipin 2 (PLIN2/ ADRP), [9] perilipin 3 (PLIN3/ TIP47), perilipin 4 (PLIN4/ S3-12) and perilipin 5 (PLIN5/ OXPAT/ LSDP5/ MLDP). [10] [11] [12] Proteomics studies have elucidated the association of many other families of proteins to the lipid surface including proteins involved in membrane trafficking, vesicle docking, endocytosis and exocytosis. [13] Analysis of the lipid composition of lipid droplets has revealed the presence of a diverse set of phospholipid species; [14] phosphatidylcholine and phosphatidylethanolamine are the most abundant, followed by phosphatidylinositol.

Lipid droplets vary greatly in size, ranging from 20 to 40 nm to 100 um. [15] In adipocytes, lipid bodies tend to be larger and they may compose the majority of the cell, while in other cells they may only be induced under certain conditions and are considerably smaller in size.

Formation

Lipid droplets bud off the membrane of the endoplasmic reticulum. Initially, a lens is formed by accumulation of TAGs between the two layers of its phospholipid membrane. Nascent lipid droplets may grow by diffusion of fatty acids, endocytosis of sterols, or fusion of smaller lipid droplets through the aid of SNARE proteins. [15] The budding of lipid droplets is promoted by an asymmetric accumulation of phospholipids that decrease surface tension towards the cytosol. [16] Lipid droplets have also been observed to be created by the fission of existing lipid droplets, though this is thought to be less common than de novo formation. [17]

Lipid droplets visualized with label-free live-cell imaging Lipid droplets.gif
Lipid droplets visualized with label-free live-cell imaging

The formation of lipid droplets from the endoplasmic reticulum begins with the synthesis of the neutral lipids to be transported. The manufacture of TAGs from diacylglycerol (by the addition of a fatty acyl chain) is catalyzed by the DGAT proteins, though the extent to which these and other proteins are required depends on cell type. [18] Neither DGAT1 nor DGAT2 is singularly essential for TAG synthesis or droplet formation, though mammalian cells lacking both cannot form lipid droplets and have severely stunted TAG synthesis. DGAT1, which seems to prefer exogenous fatty acid substrates, is not essential for life; DGAT2, which seems to prefer endogenously synthesized fatty acids, is. [17]

In non-adipocytes, lipid storage, lipid droplet synthesis and lipid droplet growth can be induced by various stimuli including growth factors, long-chain unsaturated fatty acids (including oleic acid and arachidonic acid), oxidative stress and inflammatory stimuli such bacterial lipopolysaccharides, various microbial pathogens, platelet-activating factor, eicosanoids, and cytokines. [19]

An example is the endocannabinoids that are unsaturated fatty acid derivatives, which mainly are considered to be synthesised “on demand” from phospholipid precursors residing in the cell membrane, but may also be synthesised and stored in intracellular lipid droplets and released from those stores under appropriate conditions. [20]

It is possible to observe the formation of lipid droplets, live and label-free, using label-free live-cell imaging.

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Related Research Articles

<span class="mw-page-title-main">Lipid</span> Substance of biological origin that is soluble in nonpolar solvents

Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins, monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing energy, signaling, and acting as structural components of cell membranes. Lipids have applications in the cosmetic and food industries, and in nanotechnology.

<span class="mw-page-title-main">Lipolysis</span> Metabolism involving breakdown of lipids

Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important regulatory hormone in lipolysis is insulin; lipolysis can only occur when insulin action falls to low levels, as occurs during fasting. Other hormones that affect lipolysis include glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.

<span class="mw-page-title-main">Adipocyte</span> Cells that primarily compose adipose tissue, specialized in storing energy as fat

Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. In cell culture, adipocyte progenitors can also form osteoblasts, myocytes and other cell types.

Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.

<span class="mw-page-title-main">Glycerophospholipid</span> Class of lipids

Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the main component of biological membranes in eukaryotic cells. They are a type of lipid, of which its composition affects membrane structure and properties. Two major classes are known: those for bacteria and eukaryotes and a separate family for archaea.

Triacsin C is an inhibitor of long fatty acyl CoA synthetase that has been isolated from Streptomyces aureofaciens. It blocks β-cell apoptosis, induced by fatty acids (lipoapoptosis) in a rat model of obesity. In addition, it blocks the de novo synthesis of triglycerides, diglycerides, and cholesterol esters, thus interfering with lipid metabolism.

<span class="mw-page-title-main">Perilipin-1</span> Protein in humans

Perilipin, also known as lipid droplet-associated protein, perilipin 1, or PLIN, is a protein that, in humans, is encoded by the PLIN gene. The perilipins are a family of proteins that associate with the surface of lipid droplets. Phosphorylation of perilipin is essential for the mobilization of fats in adipose tissue.

Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In animals, these fats are obtained from food and are synthesized by the liver. Lipogenesis is the process of synthesizing these fats. The majority of lipids found in the human body from ingesting food are triglycerides and cholesterol. Other types of lipids found in the body are fatty acids and membrane lipids. Lipid metabolism is often considered as the digestion and absorption process of dietary fat; however, there are two sources of fats that organisms can use to obtain energy: from consumed dietary fats and from stored fat. Vertebrates use both sources of fat to produce energy for organs such as the heart to function. Since lipids are hydrophobic molecules, they need to be solubilized before their metabolism can begin. Lipid metabolism often begins with hydrolysis, which occurs with the help of various enzymes in the digestive system. Lipid metabolism also occurs in plants, though the processes differ in some ways when compared to animals. The second step after the hydrolysis is the absorption of the fatty acids into the epithelial cells of the intestinal wall. In the epithelial cells, fatty acids are packaged and transported to the rest of the body.

<span class="mw-page-title-main">Hormone-sensitive lipase</span> Enzyme

Hormone-sensitive lipase (EC 3.1.1.79, HSL), also previously known as cholesteryl ester hydrolase (CEH), sometimes referred to as triacylglycerol lipase, is an enzyme that, in humans, is encoded by the LIPE gene, and catalyzes the following reaction:

<span class="mw-page-title-main">Fatty acid-binding protein</span>

The fatty-acid-binding proteins (FABPs) are a family of transport proteins for fatty acids and other lipophilic substances such as eicosanoids and retinoids. These proteins are thought to facilitate the transfer of fatty acids between extra- and intracellular membranes. Some family members are also believed to transport lipophilic molecules from outer cell membrane to certain intracellular receptors such as PPAR. The FABPs are intracellular carriers that “solubilize” the endocannabinoid anandamide (AEA), transporting AEA to the breakdown by FAAH, and compounds that bind to FABPs block AEA breakdown, raising its level. The cannabinoids are also discovered to bind human FABPs that function as intracellular carriers, as THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. Levels of fatty-acid-binding protein have been shown to decline with ageing in the mouse brain, possibly contributing to age-associated decline in synaptic activity.

<span class="mw-page-title-main">Stearoyl-CoA 9-desaturase</span> Class of enzymes

Stearoyl-CoA desaturase (Δ-9-desaturase) is an endoplasmic reticulum enzyme that catalyzes the rate-limiting step in the formation of monounsaturated fatty acids (MUFAs), specifically oleate and palmitoleate from stearoyl-CoA and palmitoyl-CoA. Oleate and palmitoleate are major components of membrane phospholipids, cholesterol esters and alkyl-diacylglycerol. In humans, the enzyme is encoded by the SCD gene.

<span class="mw-page-title-main">Phosphatidate phosphatase</span>

The enzyme phosphatidate phosphatase (PAP, EC 3.1.3.4) is a key regulatory enzyme in lipid metabolism, catalyzing the conversion of phosphatidate to diacylglycerol:

<span class="mw-page-title-main">Perilipin-2</span> Protein-coding gene in the species Homo sapiens

Adipose differentiation-related protein, also known as perilipin 2, ADRP or adipophilin, is a protein which belongs to the perilipin (PAT) family of cytoplasmic lipid droplet (CLD)–binding proteins. In humans it is encoded by the ADFP gene. This protein surrounds the lipid droplet along with phospholipids and is involved in assisting the storage of neutral lipids within the lipid droplets.

<span class="mw-page-title-main">Adipose triglyceride lipase</span> Mammalian protein found in Homo sapiens

Adipose triglyceride lipase, also known as patatin-like phospholipase domain-containing protein 2 and ATGL, is an enzyme that in humans is encoded by the PNPLA2 gene. ATGL catalyses the first reaction of lipolysis, where triacylglycerols are hydrolysed to diacylglycerols.

<span class="mw-page-title-main">Carbohydrate-responsive element-binding protein</span> Protein-coding gene in the species Homo sapiens

Carbohydrate-responsive element-binding protein (ChREBP) also known as MLX-interacting protein-like (MLXIPL) is a protein that in humans is encoded by the MLXIPL gene. The protein name derives from the protein's interaction with carbohydrate response element sequences of DNA.

<span class="mw-page-title-main">PNPLA3</span> Protein-coding gene in the species Homo sapiens

Patatin-like phospholipase domain-containing protein 3 (PNPLA3) also known as adiponutrin (ADPN), acylglycerol O-acyltransferase or calcium-independent phospholipase A2-epsilon (iPLA2-epsilon) is an enzyme that in humans is encoded by the PNPLA3 gene.

Fat globules are individual pieces of intracellular fat in human cell biology. The lipid droplet's function is to store energy for the organism's body and is found in every type of adipocytes. They can consist of a vacuole, droplet of triglyceride, or any other blood lipid, as opposed to fat cells in between other cells in an organ. They contain a hydrophobic core and are encased in a phospholipid monolayer membrane. Due to their hydrophobic nature, lipids and lipid digestive derivatives must be transported in the globular form within the cell, blood, and tissue spaces.

Lipotoxicity is a metabolic syndrome that results from the accumulation of lipid intermediates in non-adipose tissue, leading to cellular dysfunction and death. The tissues normally affected include the kidneys, liver, heart and skeletal muscle. Lipotoxicity is believed to have a role in heart failure, obesity, and diabetes, and is estimated to affect approximately 25% of the adult American population.

<span class="mw-page-title-main">Perilipin-4</span> Protein-coding gene in the species Homo sapiens

Perilipin 4, also known as S3-12, is a protein that in humans is encoded by the PLIN4 gene on chromosome 19. It is highly expressed in white adipose tissue, with lower expression in heart, skeletal muscle, and brown adipose tissue. PLIN4 coats lipid droplets in adipocytes to protect them from lipases. The PLIN4 gene may be associated with insulin resistance and obesity risk.

<span class="mw-page-title-main">Perilipin-5</span> Mammalian protein found in Homo sapiens

Perilipin 5, also known as Oxpatperilipin 5 or PLIN5, is a protein that belongs to perilipin family. This protein group has been shown to be responsible for lipid droplet's biogenesis, structure and degradation. In particular, Perilipin 5 is a lipid droplet-associated protein whose function is to keep the balance between lipolysis and lipogenesis, as well as maintaining lipid droplet homeostasis. For example, in oxidative tissues, muscular tissues and cardiac tissues, PLIN5 promotes association between lipid droplets and mitochondria.

References

  1. ↑ Martin, Sally; Parton, Robert G. (8 March 2006). "Lipid droplets: a unified view of a dynamic organelle". Nature Reviews Molecular Cell Biology. 7 (5): 373–378. doi:10.1038/nrm1912. PMID   16550215. S2CID   34926182.
  2. 1 2 3 Mobilization and cellular uptake of stored fats and triacylglycerol (with Animation)
  3. ↑ Bozza, PT; Viola, JP (Apr–Jun 2010). "Lipid droplets in inflammation, cancer". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 82 (4–6): 243–50. doi:10.1016/j.plefa.2010.02.005. PMID   20206487.
  4. ↑ Melo, Rossana C. N.; Dvorak, Ann M.; Chitnis, Chetan E. (5 July 2012). "Lipid Body–Phagosome Interaction in Macrophages during Infectious Diseases: Host Defense or Pathogen Survival Strategy?". PLOS Pathogens. 8 (7): e1002729. doi: 10.1371/journal.ppat.1002729 . PMC   3390411 . PMID   22792061.
  5. ↑ Greenberg, Andrew S.; Coleman, Rosalind A.; Kraemer, Fredric B.; McManaman, James L.; Obin, Martin S.; Puri, Vishwajeet; Yan, Qing-Wu; Miyoshi, Hideaki; Mashek, Douglas G. (1 June 2011). "The role of lipid droplets in metabolic disease in rodents and humans". Journal of Clinical Investigation. 121 (6): 2102–2110. doi:10.1172/JCI46069. PMC   3104768 . PMID   21633178.
  6. ↑ Bosma, M; Kersten, S; Hesselink, MKC; Schrauwen, P (2012). "Re-evaluating lipotoxic triggers in skeletal muscle: Relating intramyocellular lipid metabolism to insulin sensitivity" (PDF). Prog Lipid Res. 51 (1): 36–49. doi:10.1016/j.plipres.2011.11.003. PMID   22120643.
  7. ↑ Heaton, N.S.; Randall, G (2010). "Dengue virus-induced autophagy regulates lipid metabolism". Cell Host Microbe. 8 (5): 422–32. doi:10.1016/j.chom.2010.10.006. PMC   3026642 . PMID   21075353.
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  9. ↑ Bosma, M; Hesselink, MKC; Sparks, LM; Timmers, S; Ferraz, MJ; Mattijssen, F; van Beurden, D; Schaart, G; de Baets, MH; Verheyen, FK; Kersten, S; Schrauwen, P (2012). "Perilipin 2 improves insulin sensitivity in skeletal muscle despite elevated intramuscular lipid levels". Diabetes. 61 (11): 2679–2690. doi:10.2337/db11-1402. PMC   3478528 . PMID   22807032.
  10. ↑ Martin, S; Parton, RG (Apr 2005). "Caveolin, cholesterol, and lipid bodies". Seminars in Cell & Developmental Biology. 16 (2): 163–74. doi:10.1016/j.semcdb.2005.01.007. PMID   15797827.
  11. ↑ Brasaemle, D. L. (25 August 2007). "Thematic review series: Adipocyte Biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis". The Journal of Lipid Research. 48 (12): 2547–2559. doi: 10.1194/jlr.R700014-JLR200 . PMID   17878492.
  12. ↑ Kimmel, AR; Brasaemle, DL; McAndrews-Hill, M; Sztalryd, C; Londos, C (Mar 2010). "Adoption of PERILIPIN as a unifying nomenclature for the mammalian PAT-family of intracellular lipid storage droplet proteins". Journal of Lipid Research. 51 (3): 468–71. doi:10.1194/jlr.R000034. PMC   2817576 . PMID   19638644.
  13. ↑ Goodman, JM (Oct 17, 2008). "The gregarious lipid droplet". The Journal of Biological Chemistry. 283 (42): 28005–9. doi: 10.1074/jbc.R800042200 . PMC   2568941 . PMID   18611863.
  14. ↑ Bartz, R.; Li, W.-H.; Venables, B.; Zehmer, J. K.; Roth, M. R.; Welti, R.; Anderson, R. G. W.; Liu, P.; Chapman, K. D. (22 January 2007). "Lipidomics reveals that adiposomes store ether lipids and mediate phospholipid traffic". The Journal of Lipid Research. 48 (4): 837–847. doi:10.1194/jlr.M600413-JLR200. PMID   17210984.
  15. 1 2 Guo Y, Cordes KR, Farese RV, Walther TC (Mar 15, 2009). "Lipid droplets at a glance". Journal of Cell Science. 122 (Pt 6): 749–52. doi:10.1242/jcs.037630. PMC   2714424 . PMID   19261844.
  16. ↑ Chorlay, Aymeric; Abdou Rachid Thiam (February 2018). "An Asymmetry in Monolayer Tension Regulates Lipid Droplet Budding Direction". Biophysical Journal. 114 (3): 631–640. doi: 10.1016/j.bpj.2017.12.014 . PMC   5985028 . PMID   29414709.
  17. 1 2 Wilfling, Florian; Haas, J.; Walther, T.; Farese, R. (August 2014). "Lipid droplet biogenesis". Current Opinion in Cell Biology. 29: 39–45. doi:10.1016/j.ceb.2014.03.008. PMC   4526149 . PMID   24736091.
  18. ↑ Harris, Charles; et al. (April 2011). "DGAT enzymes are required for triacylglycerol synthesis and lipid droplets in adipocytes". Journal of Lipid Research. 52 (4): 657–667. doi:10.1194/jlr.M013003. PMC   3284159 . PMID   21317108.
  19. ↑ Melo, R. C. N.; D'Avila, H.; Wan, H.-C.; Bozza, P. T.; Dvorak, A. M.; Weller, P. F. (23 March 2011). "Lipid Bodies in Inflammatory Cells: Structure, Function, and Current Imaging Techniques". Journal of Histochemistry & Cytochemistry. 59 (5): 540–556. doi:10.1369/0022155411404073. PMC   3201176 . PMID   21430261.
  20. ↑ Ayakannu, Thangesweran; Taylor, Anthony H.; Marczylo, Timothy H.; Willets, Jonathon M.; Konje, Justin C. (2013). "The Endocannabinoid System and Sex Steroid Hormone-Dependent Cancers". International Journal of Endocrinology. 2013: 259676. doi: 10.1155/2013/259676 . ISSN   1687-8337. PMC   3863507 . PMID   24369462.
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