Lipid droplet
Lipid droplets, also known as lipid bodies, oil bodies, or adiposomes, are endoplasmic reticulum-derived neutral lipid storage organelles consisting of a core of hydrophobic neutral lipids enveloped by a protein-studded phospholipid monolayer. Lipid droplets are conserved across almost all species, from bacteria to archaea through fungi, plants, algae, insects, and all mammals, including humans.
As organelles, lipid droplets function as a storage compartment for a cell’s metabolic energy reserves. Lipid droplets are the only cellular compartment dedicated to the storage of TAGs and other neutral lipids, making these organelles crucial for both energy storage functions and for the aversion of cellular lipotoxicity. Lipid droplets also serve as a reservoir for cholesterol esters and fat-soluble vitamins, as well as many other polymeric lipids.
Both the appearance and the distribution of lipid droplets changes by cell type, and may reflect the specialized functions of a given type of cell. Generally, the diameter of lipid droplets ranges from 0.1-5 µm in non-adipocyte cells, but increases to over 100 µm in white adipocytes. Research on lipid droplet function has proved crucial in both health and disease, as these organelles are known to support many large-scale biological processes such as development and aging.
The role of lipid droplets outside of neutral lipid storage remains a topic of ongoing research.
Significance
Everyday, cells within the human body rely on the metabolic energy stores found in lipid droplets to survive. Sufficient levels of energy reserves are found and kept in specialized cells called adipocytes, which are crucial for human survival. Unlike other cells, adipocytes are specialized for storage of metabolic energy reserves, and as such, an abundance of lipid droplets are typically found within them. During times of starvation, these lipid droplet reserves decrease within adipocytes and are scarcely found. However, sustained caloric excess stimulates the growth of these lipid droplet reserves as they accumulate excess lipids from caloric surplus. Caloric excess stimulates not only the expansion of lipid droplets, but also the expansion of adipocytes, in a process known as adipose hypertrophy.In humans, excess lipid droplet stores are associated with significant health issues, including increased risk of chronic conditions such as Type 2 diabetes, heart disease, stroke, high blood pressure, high cholesterol, atherosclerosis, and many cancers. Generally, obesity also leads to musculoskeletal issues such as osteoarthritis, sleep apnea, liver disease, gallbladder disease, kidney problems, infertility, pregnancy complications, and depression. Conversely, a lack of lipid droplet reserves as seen in conditions like anorexia lead to a variety of serious health complications, such as anemia, heart failure, bone loss, muscle wasting, vitamin deficiencies, stomach problems, and kidney disease. Serious health risks increase as a person’s weight approaches either extreme, and as such, weight must be taken seriously to ensure a healthy life.
Structure
Notably, lipid droplets bear a unique structure relative to all other cellular organelles. LDs emerge from the endoplasmic reticulum, where many remain continuous within cytoplasmic leaflets of the endoplasmic reticulum phospholipid bilayer itself. LDs thus bear a phospholipid monolayer, which envelopes a highly dynamic core of hydrophobic neutral lipids. While all LDs are known to share this structure, the behavior and morphologies of these organelles are both diverse and extremely dynamic.Outer Membrane Monolayer
Unlike other organelles, the outer membrane of lipid droplets is composed of a phospholipid monolayer. LD formation begins within the phospholipid bilayer of the endoplasmic reticulum, where a cytoplasmic leaflet of the phospholipid bilayer "buds" as neutral lipids accumulate at its center. This phospholipid monolayer ultimately becomes the LD droplet surface, and remains continuous with the phospholipid bilayer of ER. Hydrophobic neutral lipids enveloped by the phospholipid monolayer remain highly dynamic at its core, where they are stored or hydrolyzed in accordance with cellular energetic needs. Throughout further LD maturation, the outer phospholipid monolayer of the organelle is thought to remain connected to the endoplasmic reticulum via a hairpin-like "stalk" formation between the two organelles.Membrane Surface Proteins
The surface of the LD monolayer is decorated with a vast and diverse repertoire of proteins, the number of which varies from species to species. In yeast, approximately 40 different LD proteins have been cataloged using proteomics-based approaches, while the mammalian LD proteome is known to consist of over 100 proteins to date. LD surface proteins are known to regulate and dictate several aspects of the LD life-cycle, including LD budding, growth, turnover, and interaction with other cellular organelles, such as mitochondria. Inherently, the LD proteome is highly dynamic and represents a key area of interest in modern lipid research.The first and best-characterized family of lipid droplet associated proteins is the perilipin protein family, consisting of five proteins. These include perilipin 1, perilipin 2, perilipin 3, perilipin 4 and perilipin 5. Proteomics studies have elucidated the association of many other families of proteins to the lipid surface, including those involved in membrane trafficking, vesicle docking, endocytosis and exocytosis.
Lipid Droplet Core
At their core, lipid droplets contain a highly dynamic, hydrophobic deposit of neutral lipids, such as triacylglycerols and cholesteryl esters. In most cells, metabolic energy is stored in the form of fatty acids, which are the building blocks of triacylglycerols or fat. Lipid droplets are the only cellular compartment dedicated to the storage of TAGs and other neutral lipids, making these organelles crucial for both energy storage functions and the aversion of lipotoxicity. In adipocytes, TAGs are the predominant component of the LD core. However, in other cell types, various ratios of TAGs and CEs are found in the LD core.Demarcation between TAGs and CEs within the LD core has not been observed by conventional electron microscopy alone, although segregation within the core may exist in certain circumstances. Some evidence exists to suggest partitioning among lipid esters in the LD core, such as concentric lipid ester layers observed by cryoelectron microscopy, and island-like fracture faces seen by freeze-fracture electron microscopy. Membrane-like structures have also been observed in the LD core in more specialized cell types.
Analysis of the lipid composition of lipid droplets has revealed the presence of a diverse set of phospholipid species; phosphatidylcholine and phosphatidylethanolamine are the most abundant, followed by phosphatidylinositol.
Lipid Droplet Heterogeneity
Generally, LD heterogeneity refers to observable differences in LD size, abundance, distribution, location, core lipid composition, or proteome composition about the organelle. Discrete combinations of these features are thought to shape general functional differences between LD populations, many of which may be present across different cell types, as well as within the same cell. Of all factors used to characterize specific LD types, the surface proteome has proven most useful. Features associated with a specific LD type are largely determined by the proteins on the LD surface, many of which facilitate LD growth or shrinkage such as lipid enzymes, as well as scaffolding proteins and factors that mediate interactions with other organelles. LD heterogeneity is best characterized within cells of a given cell type, where it may thus reflect relative changes in cellular metabolic state or become indicative of physiological disease. However, LD heterogeneity within a single cell likely reflects the discrete functions of different LD subpopulations in metabolic homeostasis, in both health and disease.Differences Across Cell Types
, the core function of the LD as a lipid storage depot is conserved across cell types and species. However, cellular identity determines the threshold for LD utility and thus caps LD heterogeneity by cell type.Lipid Droplet Biogenesis
Lipid droplet biogenesis begins at the membrane of the endoplasmic reticulum. Despite over a decade of modern research, the process of LD formation has yet to be fully understood.LD biogenesis is triggered by the accumulation of neutral lipids within the membrane of the endoplasmic reticulum, which occurs in response to elevated dietary carbohydrate or lipid intake. In simplest terms, lipid droplets form should the rate of neutral lipid synthesis at the ER exceed the ER membrane’s capacity to accommodate those lipids, causing them to phase-separate and bud into lipid droplets. To date, LD assembly appears to follow a single robust mechanism, regardless of the type of neutral lipid involved. Nevertheless, LD biogenesis has been extensively characterized for triacylglycerols. While the formation of lipid droplets remains dependent on the availability of free fatty acids and other metabolites, the general process can be nevertheless summarized by the following sections.
Availability of Fatty Acids
A number of metabolic reactions must first occur within the cell in order for synthesis of the main lipid droplet component triacylglycerol to occur. A more detailed explanation of fatty acid synthesis is available here, but the topic remains outside the scope of this article. Nevertheless, several reactions relevant to TAG synthesis are summarized below:In brief, TAG and phospholipids are generated from glucose-derived glycerol and mitochondrial-derived fatty acids. Acetyl-CoA is the precursor used for fatty acid synthesis in the cytosol; however, acetyl-CoA is unable to be shuttled directly into the cytosol in its original form. Originally, acetyl-CoA is generated in the mitochondria from pyruvate molecules derived from glucose via glycolysis. Within the mitochondria, acetyl-CoA typically combines with oxaloacetate and serves as a substrate for the synthesis of citrate as part of the well known citric acid cycle. Notably, the inner mitochondrial membrane is impermeable to acetyl-CoA, and as such, a specialized shuttle system must be used to import acetyl-CoA into the cytosol for fatty acid production. This process, known as the citrate–malate shuttle, relies on the tricarboxylate transport protein to import citrate into the cytosol, where it is then split into acetyl-CoA and oxaloacetate by the enzyme ATP citrate lyase. Cytosolic acetyl-CoA is then available for use in fatty acid and cholesterol synthesis, but oxaloacetate must be reduced to malate in order to reenter the mitochondria. Malate dehydrogenase reduces cytosolic oxaloacetate by coupling NADH oxidation to NAD+, and malate produced by this reaction can be transported back into the mitochondria, thus completing the namesake of the citrate–malate shuttle.