Triacylglycerols: 2. Biosynthesis and Metabolism
All eukaryotic organisms and even a few prokaryotes are able to synthesise triacylglycerols, and in animals, many cell types and organs have this ability, but the liver, intestines and adipose tissue are most active with most of the body stores in the last of these (see our web page on triacylglycerol structure and composition). Within all cell types, even those of the brain, triacylglycerols are stored as cytoplasmic 'lipid droplets' enclosed by a monolayer of phospholipids and hydrophobic proteins such as the perilipins in adipose tissue or oleosins in seeds. These lipid droplets are now treated as distinctive organelles, with their own characteristic metabolic pathways and associated enzymes - no longer boring blobs of fat. However, they are not unique to animals and plants as Mycobacteria and yeasts have similar lipid inclusions.
The lipid serves as a store of fatty acids for energy, which can be released rapidly on demand, and as a reserve of fatty acids for structural purposes or as precursors for eicosanoids. In addition, lipid droplets serve as a protective agency in cells to sequester any excess of biologically active and potentially harmful lipids such as free fatty acids, oxylipins, diacylglycerols, cholesterol (as cholesterol esters), retinol esters and coenzyme A esters.
2.1. Biosynthesis of Triacylglycerols
Three main pathways for triacylglycerol biosynthesis are known, the sn-glycerol-3-phosphate and dihydroxyacetone phosphate pathways, which predominates in liver and adipose tissue, and a monoacylglycerol pathway in the intestines. In maturing plant seeds and some animal tissues, a fourth pathway has been recognized in which a diacylglycerol transferase is involved. The most important route to triacylglycerols is the sn-glycerol-3-phosphate or Kennedy pathway, first described by Professor Eugene Kennedy and colleagues in the 1950s, by means of which more than 90% of liver triacylglycerols are produced.
In this pathway, the main source of the glycerol backbone has long been believed to be sn-glycerol-3-phosphate produced by the catabolism of glucose (glycolysis) or to a lesser extent by the action of the enzyme glycerol kinase on free glycerol. However, there is increasing evidence that a significant proportion of the glycerol is produced de novo by a process known as glyceroneogenesis via pyruvate. Indeed, this may be the main source in adipose tissue.
Subsequent reactions occur primarily in or at the endoplasmic reticulum. First, the precursor sn-glycerol-3-phosphate is esterified by a fatty acid coenzyme A ester in a reaction catalysed by a glycerol-3-phosphate acyltransferase (GPAT) at position sn-1 to form lysophosphatidic acid, and this is in turn acylated by an acylglycerophosphate acyltransferase (AGPAT) in position sn-2 to form a key intermediate in the biosynthesis of all glycerolipids - phosphatidic acid, reactions described in greater detail in our web page on this lipid. Numerous isoforms of these enzymes are known; they are expressed with specific tissue and membrane distributions and they are regulated in different ways.
Then, the phosphate group is removed by a family of enzymes - phosphatidic acid phosphohydrolases (PAPs or ‘phosphatidate phosphatases’ or ‘lipid phosphate phosphatases’). PAPs are also important as they produce sn-1,2-diacylglycerols as essential intermediates in the biosynthesis not only of triacylglycerols but also of phosphatidylcholine and phosphatidylethanolamine (and of monogalactosyldiacylglycerols in plants). This is a key branch-point in lipid biosynthesis as it may dictate the flow of lipids for storage or membrane biogenesis.
Much of this phosphatase activity leading to triacylglycerol biosynthesis in animals resides in three related cytoplasmic proteins, termed lipins, i.e. lipin-1, lipin-2 and lipin-3, which have tissue-specific roles in glycerolipid synthesis. Unusually, these were characterized and named before the nature of their enzymatic activities were determined. Each of the lipins appears to have distinctive expression and functions, but lipin-1 (PAP1) in three isoforms (designated 1α, 1β and 1γ) accounts for most of the PAP activity in adipose tissue and skeletal muscle in humans. Lipin 2 is the most abundant lipin in liver, but is also expressed substantially in the small intestine, macrophages and some regions of the brain, while lipin 3 activity overlaps with that of lipin 1 and lipin 2. Lipins are cytosolic enzymes but associate transiently with membranes to access their substrate, i.e. they are translocated to the endoplasmic reticulum in response to elevated levels of fatty acids within cells, although they do not have trans-membrane domains. Lipin-1 activity requires Mg2+ ions and is inhibited by N-ethylmaleimide, whereas the membrane-bound activity responsible for synthesising diacylglycerols as a phospholipid intermediate is independent of Mg2+ concentration and is not sensitive to the inhibitor.
Perhaps surprisingly, lipin-1 has a dual role in that it operates in collaboration with known nuclear receptors as a transcriptional coactivator to modulate lipid metabolism (lipin 1α) while lipin 1β is associated with induction of lipogenic genes such as fatty acid synthase, stearoyl CoA desaturase and DGAT. They can have profound effects on signalling in a variety of cell types. Abnormalities in lipin-1 expression are known to be involved in some human disease states that may lead to the metabolic syndrome and inflammatory disorders. Lipin 2 is a similar phosphatidate phosphohydrolase, which is present in liver and brain and is regulated dynamically by fasting and obesity (in mice), while lipin 3 is found in the gastrointestinal tract and liver.
In the final step in this pathway, the resultant 1,2-diacyl-sn-glycerol is acylated by diacylglycerol acyltransferases (DGAT), which can utilize a wide range of fatty acyl-CoA esters to form the triacyl-sn-glycerol. In fact there are two DGAT enzymes, which are structurally and functionally distinct. In animals, DGAT1 is located mainly in the endoplasmic reticulum and is expressed in skeletal muscle, skin and intestine, with lower levels of expression in liver and adipose tissue. It is believed to have dual topology contributing to triacylglycerol synthesis on both sides of the membrane of the endoplasmic reticulum, but esterifying only pre-formed fatty acids of exogenous origin. Perhaps surprisingly, DGAT1 is the only one present in the epithelial cells that synthesise milk fat in the mammary gland. Also DGAT1 can utilize a wider range of substrates, including monoacylglycerols, long-chain alcohols (for wax synthesis) and retinol, and it is reported to have an important role in protecting the endoplasmic reticulum from the lipotoxic effects of high-fat diets. Orthologues of this enzyme are present in most eukaryotes, other than yeasts, and it is especially important in plants.
DGAT2 is the main form of the enzyme in hepatocytes and adipocytes (lipid droplets), although it is expressed much more widely in tissues. It is associated with distinct regions of the endoplasmic reticulum, at the surface of lipid droplets and in mitochondria, and it esterifies fatty acids of both endogenous and exogenous origin. DGAT2 is believed to have a targeting domain that enables it to tether between the endoplasmic reticulum and lipid droplet thereby channelling triacylglycerols from the synthesis site in the endoplasmic reticulum to the nascent lipid droplet, where they accumulate and lead to the expansion of the latter (see below). Both enzymes are important modulators of energy metabolism, although DGAT2 appears to be especially important in controlling the homeostasis of triacylglycerols in vivo. As the glycerol-3-phosphate acyltransferase (GPAT) has the lowest specific activity of these enzymes, this step may be the rate-limiting one. However, DGATs are the dedicated triacylglycerol-forming enzymes, and they are seen as the best target for pharmaceutical intervention in obesity and attendant ailments; clinical studies of DGAT1 inhibitors are at an early stage.
In a second pathway for triacylglycerol biosynthesis, dihydroxyacetone-phosphate in peroxisomes or endoplasmic reticulum can be acylated by a specific acyltransferase to form 1-acyl dihydroxyacetone-phosphate, which is reduced by dihydroxyacetone-phosphate oxido-reductase to lysophosphatidic acid, which can then enter the pathway above to triacylglycerols. The precursor dihydroxyacetone-phosphate is important also as part of the biosynthetic route to plasmalogens, and neutral plasmalogens can be significant components of cytoplasmic droplets in many mammalian cells types but not adipose tissue.
In the enterocytes of intestines after a meal, up to 75% of the triacylglycerols are formed via a monoacylglycerol pathway. 2-Monoacyl-sn-glycerols and free fatty acids released from dietary triacylglycerols by the action of pancreatic lipase within the intestines (see below) are taken up by the enterocytes. There, the monoacylglycerols are first acylated by an acyl coenzyme A:monoacylglycerol acyltransferase with formation of sn-1,2-diacylglycerols mainly as the first intermediate in the process, though some sn-2,3-diacylglycerols (~10%) are also produced (DGAT1 can also acylate monoacylglycerols). 1-Monoacylglycerols can also be synthesised by the acylation of glycerol and these can also be acylated. There are three isoforms of the monoacylglycerol acyltransferase in humans of which MGAT2 is most active in the intestines and liver and MGAT1 in adipose tissue. Finally, the acyl coenzyme A:diacylglycerol acyltransferase (DGAT1) reacts with the sn-1,2-diacylglycerols only to form triacylglycerols.
In a fourth biosynthetic pathway, which is less well known, triacylglycerols are synthesised by a transacylation reaction between two racemic diacylglycerols that is independent of acyl-CoA. The reaction was first detected in the endoplasmic reticulum of intestinal micro villus cells and is catalysed by a diacylglycerol transacylase. Both diacylglycerol enantiomers participate in the reaction with equal facility to transfer a fatty acyl group with formation of triacylglycerols and a 2-monoacyl-sn-glycerol. A similar reaction has been observed in seed oils.
It has been suggested that this enzyme may function in remodelling triacylglycerols post synthesis, especially in oil seeds, and it is possible that it may be involved in similar processes in the liver and adipose tissue, where extensive hydrolysis/re-esterification is known to occur. There is evidence for selectivity in the biosynthesis of different molecular species in a variety of tissues and organisms, which may be a consequence of the varying biosynthetic pathways. Also in adipose tissue, fatty acids synthesised de novo are utilized in different ways from those from external sources in that they enter positions sn-1 and 2 predominantly, while a high proportion of the oleic acid synthesised in the tissue by desaturation of exogenous stearic acid is esterified to position sn-3.
In prokaryotes, the glycerol-3-phosphate pathway of triacylglycerol biosynthesis only occurs, but in yeast both glycerol-3-phosphate and dihydroxyacetone-phosphate can be the primary precursors and synthesis takes place in cytoplasmic lipid droplets and the endoplasmic reticulum. In plants, the glycerol-3-phosphate pathway is most important, but these process are discussed below in greater detail.
Among other potential routes to the various intermediates, lysophosphatidic acid and phosphatidic acid can be synthesised in mitochondria, but must then be transported to the endoplasmic reticulum before they enter the pathway for triacylglycerol production. 1,2-Diacyl-sn-glycerols are also produced by the action of phospholipase C on phospholipids.
In the glycerol-3-phosphate and other pathways, the starting material is of defined stereochemistry and each of the enzymes catalysing the various steps in the process is distinctive and can have preferences for particular fatty acids (as their coenzyme A esters) and for particular fatty acid combinations in the partially acylated intermediates. It should not be surprising, therefore, that natural triacylglycerols exist in enantiomeric forms with each position of the sn-glycerol moiety esterified by different fatty acids, as discussed in Triacylglycerols - Part 1.
While triacylglycerols are essential for normal physiology, an excessive accumulation in human adipose tissue and other organs results in obesity and other health problems, including insulin resistance, steatohepatitis and cardiomyopathy. Accordingly, there is considerable pharmaceutical interest in drugs that affect triacylglycerol biosynthesis and metabolism.
2.2. Triacylglycerol Metabolism in the Intestines, Liver and Mammary Gland
Fat comprises up to 40% of the energy intake in the human diet in Western countries, and a high proportion of this is triacylglycerols. The process of fat digestion is begun in the stomach by acid-stable gastric or lingual lipases, the extent of which depending on species but may be important for efficient emulsification. However, this is insignificant in quantitative terms in comparison to the reaction with pancreatic lipase, which occurs in the duodenum. Entry of triacylglycerol degradation products into the duodenum stimulates synthesis of the hormone cholecystokinin and causes the gall bladder to release bile acids, which are strong detergents and act to emulsify the hydrophobic triacylglycerols so increasing the available surface area. In turn, cholecystokinin stimulates the release of the hydrolytic enzyme pancreatic lipase together with a co-lipase, which is essential for the activity of the enzyme. Pancreatic lipase, co-lipase, bile salts and calcium ions act together in a complex at the surface of the emulsified fat droplets to hydrolyse triacylglycerols. The process is regiospecific and results in the release of the fatty acids from the 1 and 3 positions with formation of 2-monoacyl-sn-glycerols. Isomerization of the latter to 1(3)-monoacyl-sn-glycerols occurs to some extent, and these can be degraded completely by the enzyme to glycerol and free fatty acids. Other lipases hydrolyse the phospholipids and other complex lipids in foods at the same time.
This process is somewhat different in neonates and young infants, in whom pancreatic lipase is less active but is effectively replaced by lipases in breast milk and by an acid gastric lipase (pH optimum 4-6).
There is evidence that the regiospecific structure of dietary triacylglycerols has an effect on the uptake of particular fatty acids and may influence further the lipid metabolism in humans. In particular, incorporation of palmitic acid into the position sn-2 of milk fat may be of benefit to the human infant (as a source of energy for growth and development), although it increases the atherogenic potential for adults. In addition, 2-monoacylglycerols and 2-oleoylglycerol especially have a signalling function in the intestines by activating a specific G-protein coupled receptor GPR119, sometimes termed the ‘fat sensor’. When stimulated, this causes a reduction in food intake and body weight gain in rats and regulates glucose-stimulated insulin secretion. The free fatty acids released have a similar effect, though by a very different mechanism, via the receptor GPR40. Overall, it has become evident that triacylglycerol metabolism in the intestine has regulatory effects on the secretion of gut hormones and on systemic lipid metabolism and energy balance.
The free fatty acids and 2-monoacyl-sn-glycerols are rapidly taken up by the intestinal cells, from the distal duodenum to the jejunum, via specific carrier molecules but also by passive diffusion. A specific fatty acid binding protein prevents a potentially toxic build-up of unesterified fatty acids and targets them for triacylglycerol biosynthesis. The long-chain fatty acids are converted to the CoA esters and esterified into triacylglycerols by the monoacylglycerol pathway as described above. In contrast, short and medium-chain fatty acids (C12 and below) are absorbed in unesterified form and pass directly into the portal blood stream, where they are transported to the liver to be oxidized.
Subsequently, the triacylglycerols are incorporated into lipoprotein complexes termed chylomicrons in the enterocytes by processes discussed in greater detail in our web page dealing with lipoproteins.. In brief, these consist of a core of triacylglycerols together with some cholesterol esters that is stabilized and rendered compatible with an aqueous environment by a surface film consisting of phospholipids, free cholesterol and one molecule of a truncated form of apoprotein B (48 kDa). These particles are secreted into the lymph and thence into the plasma for transport to the peripheral tissues for storage or structural purposes. Adipose tissue in particular exports appreciable amounts of the enzyme lipoprotein lipase, which binds to the luminal membrane of endothelial cells facing into the blood, where it rapidly hydrolyses the passing triacylglycerols at the cell surface releasing free fatty acids, most of which are absorbed into the adjacent adipocytes and re-utilized for triacylglycerol synthesis within the cell.
The chylomicrons remnants eventually reach the liver, where the remaining lipids are hydrolysed at the external membranes by a hepatic lipase and absorbed. The fatty acids within the liver can be utilized for a variety of purposes, from oxidation to the synthesis of structural lipids, but a proportion is re-converted into triacylglycerols, and some of this is stored as lipid droplets within the cytoplasm of the cells (see next section). In addition, phosphatidylcholine from the high-density lipoproteins is taken up by the liver, and a high proportion of this is eventually converted to triacylglycerols. In healthy liver, the levels of triacylglycerols are low (<5% of the total lipids), because the rates of acquisition of fatty acid from plasma and synthesis de novo within the liver are balanced by rates of oxidation and secretion into plasma. On the other hand, excessive accumulation of storage triacylglycerols is associated with fatty liver, insulin resistance and type 2 diabetes.
Most of the newly synthesised triacylglycerols are exported into the plasma in the form of very-low-density lipoproteins (VLDL), consisting again of a triacylglycerol and cholesterol ester core, surrounded by phospholipids and free cholesterol, together with one molecule of full-length apoprotein B (100 kDa), apoprotein C and sometimes apoprotein E. These particles in turn are transported to the peripheral tissues, where they are hydrolysed and the free acids absorbed. Eventually, the remnants are returned to the liver.
In the mammary gland, triacylglycerols are synthesised in the endoplasmic reticulum and large lipid droplets are produced with a monolayer of phospholipids derived from this membrane. These are transported to the plasma membrane and bud off into the milk with an envelope comprised of the phospholipid membrane to form milk fat globules as food for the newborn. The process is thus very different from that involved in the secretion of triacylglycerol-rich lipoproteins from other organs.
2.3. Triacylglycerol Synthesis and Catabolism (Lipolysis) in Adipocytes and Lipid Droplets
Adipose tissue and the adipocytes are characterized by accumulations of triacylglycerols, which act as the main energy store for animals, although they also cushion and insulate the body. Thus, triacylglycerols stored when there is a surplus of nutrients are mobilized for energy production during starvation. Adipose tissue also functions as a reserve of bioactive lipids, such as eicosanoids and lipid-soluble vitamins, and when required provides structural components, including fatty acids, cholesterol and retinol, for membrane synthesis and repair. Large fat depots occur around internal organs such as the liver, and also subcutaneously (see our web page on triacylglycerol composition), and each of these may react differently to metabolic constraints. Brown and beige fat have special properties and are discussed below, while bone marrow adipocytes (70% of the available space) have distinctive functions also.
Similarly, within most other animal cells, even ganglia in the brain, a proportion of the fatty acids taken up from the circulation is converted to triacylglycerols as described above and incorporated into cytoplasmic lipid droplets (also termed 'fat globules', 'oil bodies', 'lipid particles', 'adiposomes', etc). By buffering against fatty acid accumulation that might exceed their capacity, non-adipose cells defend themselves in this way against lipotoxicity while providing a rapid source of energy and essential metabolites. Acting in concert with other cellular organelles, they function in many different metabolic processes. The triacylglycerol droplets together with cholesterol esters and other neutral lipids are surrounded by a protective monolayer that includes phospholipids, cholesterol and hydrophobic proteins. The phospholipid component of the monolayer consists mainly of phosphatidylcholine and phosphatidylethanolamine derived from cytosolic leaflets of the endoplasmic reticulum and plasma membrane. Lipid droplets do not occur only in the cytoplasm of animal cells but are present in the cytoplasm of some prokaryotes and in the plastids and other organelles of plants (see below).
Among the proteins are many that function directly in lipid metabolism, and they include acyltransferases, lipases, perilipins, caveolins and the Adipose Differentiation Related Protein (ADRP or adipophilin). In adipocytes, the lipid droplets can range to up to 200 μm in diameter, while other cell types contain smaller lipid droplets of the order of 50 nm in diameter. Cytosolic lipid droplets with similar metabolic activities are found in the fruit fly Drosophila melanogaster, and many aspects of triacylglycerol processing and regulation parallel those in humans. Higher plants and yeasts also have cytosplasmic droplets (see below). Like adipose tissue cells, lipid droplets have a major function in that they sense and respond rapidly to changes in systemic energy balance. Within cells, lipid droplets facilitate the coordination and communication between different organelles and act as vital hubs of cellular metabolism.
Lipid droplet assembly: This process takes place in sub-domains of the endoplasmic reticulum, where at least one isoform of each of the enzymes of triacylglycerol biosynthesis, from acyl-CoA synthetases through to glycerol-3-phosphate acyltransferases, is located probably in a protein assembly or 'interactome'. As triacylglycerols accumulate, they reach a critical level when a spontaneous condensation or nucleation by phase separation occurs, leading to formation of an oil blister within the hydrophobic bilayer region so attracting perilipins and other proteins that allow lipid droplets to grow further in patches of the membrane as lens-like swellings between the two membrane leaflets. A non-enzymatic protein seipin stabilizes the nascent droplets with minimal disruption to the membrane and enables them to mature by a mechanism that is still uncertain but may involve regulation of protein and lipid trafficking into the droplet.
As they grow, lipid droplets bud toward the cytosol, a process that is believed to be directed and aided by surface proteins such as perilipin, while the triacylglycerol core attracts and is largely surrounded by phospholipids from the outer leaflet of the endoplasmic reticulum. Growth continues through an extended endoplasmic reticulum/droplet junction or bridge until finally with the involvement of membrane curvature-inducing coat proteins, fat storage-inducing transmembrane ('FIT') proteins that bind diacylglycerols, lysophospholipids and phosphatidic acid (non-bilayer forming lipids), the droplets bud off into the cytoplasm with their surface monolayer of phospholipids and proteins, including the enzymes of triacylglycerol biosynthesis. There is an excellent diagrammatic illustration of lipid droplet formation in the paper by Olzmann and Carvalho cited below. Similar process occur in yeast, nematodes and plants.
Subsequently, mitochondria, peroxisomes and other organelles may contribute or exchange lipids at inter-organelle contact sites and effect changes in protein composition, although the lipid droplets remain close to the endoplasmic reticulum, and presumably this enables a dynamic response to any change in metabolic status sensed by the this organelle. Seipin appears to be essential for maintaining functional junctions between lipid droplets with other organelles in addition to its role in the initial steps of their formation; it is essential for lipid droplet formation in nuclei. In adipocytes, lipid droplets can also grow by fusion of smaller droplets, although again the mechanism is not fully understood.
Some of the surface proteins on lipid droplets can extend long helical hairpins of hydrophobic peptides deep into the lipid core. For example, perilipins constitute a family of at least five phosphorylated proteins that bind to droplets in animals and share a common region, the so-called ‘PAT’ domain, named for the three original members of the family that include perilipin and ADRP. Proteins related evolutionarily to these are found in more primitive organisms, including insects, slime moulds and fungi, but not in the nematode Caenorhabditis elegans. In mammals, perilipin A (or 'PLIN1' or more accurately the splice variant 'PLIN1a') is a well-established regulator of lipolysis in adipocytes, and it is believed to be involved in the formation of the large lipid droplets in white adipose tissue. The perilipins PLIN1 and PLIN2 have functions in triacylglycerol metabolism in tissues other than adipocytes, and PLIN2 in particular is the main perilipin in hepatocytes; PLIN5 operates in tissues that oxidize fatty acids such as the heart. Other surface proteins of lipid droplets are enzymes intimately involved in triacylglycerol metabolism, although there is a suggestion that cytoplasmic droplets may act as a storage organelle for hydrophobic proteins whose function is elsewhere in the cell.
On the basis of profiling of the surface proteins and phospholipids, lipid droplets in cells are now considered to be complex, metabolically active organelles that function in the supply of fatty acids for various purposes, including membrane trafficking and possibly in the recycling of both simple and complex lipids. Although they originate in the endoplasmic reticulum, lipid droplets can associate with most other cellular organelles through membrane contact sites in a highly dynamic manner. For example, within the liver, triacylglycerols are stored as lipid droplets in the cytoplasm adjacent to the endoplasmic reticulum where a triacylglycerol hydrolase can effect lipolysis to di- and monoacylglycerols that are more soluble in the membrane, which they are able to cross. They are then available for re-synthesis into triacylglycerols by luminally oriented acyltransferases before assembly into nascent lipoprotein complexes. Similar organelles can be found in most eukaryotic cells and in bacteria, and they provide a reservoir not only for triacylglycerols and their fatty acid constituents but also for eicosanoids, and cholesterol and retinol esters, for example. Lipid droplets even occur in the nuclei of cells where their constituents interact with numerous proteins and are involved in the regulation of nuclear events.
Lipolysis: When fatty acids are required by other tissues for energy or other purposes, they are released from the triacylglycerols by the sequential actions of three cytosolic enzymes at neutral pH, i.e. adipose triacylglycerol lipase (ATGL), hormone-sensitive lipase (HSL) and monoacylglycerol lipase, which cycle between the cytoplasmic surfaces of the endoplasmic reticulum and the surface layer of lipid droplets. Simplistically, ATGL hydrolyses triacylglycerols to diacylglycerols, which are hydrolysed by HSL to monoacylglycerols before these are hydrolysed by the monoacylglycerol lipase to complete the process. A protein perilipin (PLIN1) has been described as "the gatekeeper of the adipocyte lipid storehouse". Thus, the lipolytic process is regulated by perilipin, which acts as a barrier to lipolysis in non-stimulated cells, but on β-adrenergic stimulation as during fasting it is phosphorylated by the cAMP-protein kinase. This changes its shape and reduces its hydrophobicity, and in the process activates lipolysis. An isoform, perilipin A, is the main regulatory factor in white adipose tissue. However, many other proteins interact with the three enzymes to modulate their activity, location and stability.
The adipose triacylglycerol lipase, which initiates the process, was discovered surprisingly recently. It is structurally related to the plant acyl-hydrolases in that it has a patatin-like domain in the NH2-terminal region (patatin is a non-specific acyl-hydrolase in potato) and is located on the surface of the lipid droplet both in the basal and activated states. This lipase is specific for triacylglycerols containing long-chain fatty acids, preferentially cleaving ester bonds in the sn-1 or sn-2 position (but not sn-3), and yields diacylglycerols and free fatty acids as the main products, with low activity only towards diacylglycerols, and none to monoacylglycerols and cholesterol esters. However, it also has transacylase and phospholipase activities, and it hydrolyses retinol esters in hepatic stellate cells. Adipose triacylglycerol lipase can be activated at the same time as hormone-sensitive lipase and is now believed to be rate limiting for the first step in triacylglycerol hydrolysis.
Regulation of the enzymatic activity is a complex process, and for example, a lipid droplet protein designated Gene identification-58 (CGI-58 or ABHD5), is known to be an important activating factor and is required for hydrolysis of fatty acids from position sn-1. In the resting state this protein binds to perilipin (PLIN1), but on hormonal stimulation, the latter is phosphorylated leading to dissociation and interaction of CGI-58 with phosphorylated ATGL to commence the first step in triacylglycerol hydrolysis. Mutations in adipose triacylglycerol lipase or CGI-58 are believed to be responsible for a syndrome in humans known as ‘neutral lipid storage disease’. A second protein (G0S2) inhibits the enzyme.
Hormone-sensitive lipase is regulated by the action of the hormones insulin and noradrenaline by a mechanism that ultimately involves phosphorylation of the enzyme by cAMP-protein kinase (as with perilipin), thereby increasing its activity and causing it to translocate from the cytosol to the lipid droplet to initiate the second step in hydrolysis. Its activity is regulated further by a variety of proteins that include PLINs and fatty acid binding proteins (FABP). Hormone-sensitive lipase has a broad substrate specificity compared to other neutral lipases, and in addition to its activity towards triacylglycerols, it will rapidly hydrolyse diacylglycerols, monoacylglycerols, retinol esters and cholesterol esters. In fact, diacylglycerols are hydrolysed ten times as rapidly as triacylglycerols. Within the triacylglycerol molecule, hormone-sensitive lipase preferentially hydrolyses ester bonds in the sn-1 and sn-3 positions, leaving free acids and 2-monoacylglycerols as the main end products.
The monoacylglycerol lipase is believed to be the rate-limiting enzyme in lipolysis, i.e. the final step in triacylglycerol catabolism releasing free glycerol and fatty acids, and is found in the cytoplasm, the plasma membrane, and in lipid droplets. It is specific for monoacylglycerols and has no activity against di- or triacylglycerols. As it is the enzyme mainly responsible for deactivation of the endocannabinoid 2-arachidonoylglycerol and is highly active in malignant cancers, it is attracting pharmaceutical interest. Further lipolytic enzymes, including carboxylesterases, are believed to operate against triacylglycerols in cytoplasmic lipid droplets in the liver.
Unesterified fatty acids released by the combined action of these three lipases are exported into the plasma for transport to other tissues in the form of albumin complexes, while the glycerol released is transported to the liver for metabolism by either glycolysis or gluconeogenesis. Eventually, the whole organelle can disappear, including the proteins, when they undergo a process of autophagy ('lipophagy'), i.e. the delivery of the organelles to lytic compartments for degradation. This process is especially important during starvation and is also relevant to tumorigenesis and cancer metastasis, and while it is mechanistically distinct from lipolysis, there is cross-talk between the two.
Not only does the adipocyte provide a store of energy but it manages the flow of energy through the formation of the hormone leptin, which stimulates secretion of various factors that communicate with other tissues, including cytokines, adiponectin and resistin. The synthesis of leptin is tightly controlled by adipocytes and its main function is believed to be the provision of information on the state of fat stores to other tissues. Lipid droplets may play a role in this process, since perilipin is required for the sensing function. As caveolae, which contain the proteins caveolins (and presumably sphingolipids) and are particularly abundant in adipocytes, modulate the flux of fatty acids across the plasma membrane and are involved in signal transduction and membrane trafficking pathways, it is evident that they have a major role in this aspect of lipid metabolism.
In addition, insulin is the main hormone that affects metabolism and its receptor at the plasma membrane is located in caveolae. Release of proinflammatory cytokines can stimulate lipolysis and cause insulin resistance, in turn leading to dysfunction of adipose tissue and systemic disruption of metabolism. Thus, adipose tissue metabolism has profound effects on whole-body metabolism, and defects in these processes can have severe implications for such severe pathological conditions as diabetes, obesity, cardiovascular disease, fatty liver disease and cancer in humans. It is hoped that development of specific inhibitors for hormone sensitive lipase will improve the treatment of such metabolic complications.
Functions other than energy management: Lipid droplets accumulate within many cell types other than adipocytes, including leukocytes, epithelial cells, hepatocytes and even astrocytes, especially during infections, cancer and other inflammatory conditions. They are important for the cellular storage and release of hydrophobic vitamins, signalling precursors and other lipids that are not related to energy homeostasis, while reducing the dangers of lipotoxicity. A variety of enzymes are associated with lipid droplets, including protein kinases, which are involved in many different aspects of lipid metabolism, such as cell signalling, membrane trafficking and control of the production of inflammatory mediators like the eicosanoids. Lipolysis enables secretion of lipid species termed lipokines (more generally 'adipokines') from adipocytes that may signal in a hormone-like fashion to other tissues, thereby modulating gene expression and physiological function, including food intake, insulin sensitivity, insulin secretion and related processes. These include palmitoleic acid (9-16:1) and fatty acid esters of hydroxy fatty acids (FAHFA), though the circulating proteins adiponectin and leptin have been studied more intensively. Adiponectin is a powerful insulin sensitizer and suppressor of apoptosis and inflammation with anti-diabetic and anti-atherosclerotic functions, often operating through its effects on sphingolipids, while leptin exerts most of its effects on the brain to trigger behavioral, metabolic, and endocrine responses to control the body's fuel reserves.
Indeed, there are now suggestions that lipid droplets in all cell types are essential for the response mechanisms to cellular stress, including autophagy, inflammation and immunity, and act as hubs to integrate metabolic and inflammatory processes. Via their lipolytic machinery, they regulate the availability of fatty acids for the activation of signalling pathways and for the production of oxylipins from polyunsaturated fatty acids. For example, triacylglycerols in cytoplasmic lipid droplets of human mast cells, which are potent mediators of immune reactions and influence many inflammatory diseases, have a high content of arachidonic acid and this can be released by adipose triacylglycerol lipases as a substrate for production of specific eicosanoids when the cells are stimulated appropriately. During apoptosis, triacylglycerols enriched in polyunsaturated fatty acids accumulate in lipid droplets, possibly as a protective mechanism against membrane damage caused by oxidative stress and hydroperoxide formation in this process. Triacylglycerols in lipid droplets of the skin are a highly specific source of the linoleic acid that is required for the formation of the O-acylceramides, which are essential for epidermal barrier function. An organelle termed the midbody in dividing cells in humans and rodents contains a unique triacylglycerol that is a single molecular species consisting of three fatty acids 16:1-12:0-18:1, but its function is not known.
Vitamin E (tocopherols) and vitamin A in the form of retinyl esters are stored in cytoplasmic lipid droplets, and the latter are present in appreciable concentrations in the stellate cells of liver, for example. In endocrine cells of the gonads and adrenals, cholesterol esters stored in lipid droplets are an important source of cholesterol for the mitochondrial biosynthesis of various steroid hormones. In the nucleus of the cell, in addition to providing a reservoir of fatty acids for membrane remodelling, lipid droplets can sequester transcription factors and chromatin components and generate the lipid ligands for certain nuclear receptors.
In addition to their role in lipid biochemistry, lipid droplets participate in protein degradation and glycosylation. Their metabolism can be manipulated by pathogenic viruses and bacteria such as Mycobacterium tuberculosis with unfortunate consequences for the host, but they also serve as reservoirs for proteins that fight intracellular pathogens. In consequence, such lipid droplets and their enzyme systems may be markers for disease states and are also considered to be targets for pharmaceutical intervention.
Insects: In insects, the fat body is a multifunctional tissue that is the main metabolic organ. It integrates signals that control the immune system, molting and metamorphosis, and synthesises hormones that regulate innumerable aspects of metabolism. In fat body cells, lipids, carbohydrates and proteins are the substrates and products of many pathways for use in energy production or to act as reserves for mobilization at the appropriate stage of life (diapause, metamorphosis and flight). In relation to innate and acquired humoral immunity, the fat body produces bactericidal proteins and polypeptides, i.e., lysozyme. It is also important in the early stages of an insect's life due to the production of vitellogenin, the yolk protein needed for the development of oocytes. There is further discussion in our web page on lipoproteins.
2.4. Brown Adipose Tissue
Most adipose tissue depots ('white fat') serve primarily as storage and endocrine organs that provide a reservoir of nutrients for release when the food supply is low. However, a second specialized form of adipose tissue, brown fat, is multilocular, highly vascularized and rich in mitochondria and the iron-containing pigments that transport oxygen and give the tissue its colour and name. Brown adipocytes arise from progenitor cells that are closer to those of skeletal muscle than white adipocytes. In humans, these depots tend to be located in specific anatomical regions such as subcutaneous areas around the neck, where its function may be to supply warm venous blood directly to the spinal cord and brain, and elsewhere to the heart, kidney, pancreas and liver. Brown fat is able to oxidize fat so rapidly that heat is generated (“non-shivering thermogenesis”), and it is especially important in young animals and in those recovering from hibernation.
In brief, during cold exposure, release of noradrenaline and stimulation of β-adrenergic receptors in the nervous system initiate a catabolic program that commences with rapid breakdown of cellular triacylglycerol stores and release of unesterified fatty acids and transient activation of a co-activator of peroxisome proliferator-activated receptor gamma (PPARγ). These set in motion a signalling process that results in the efficient β-oxidation of fatty acids to produce heat. The key molecule is believed to be the uncoupling protein-1 (UCP1), which acts as a valve to uncouple electron transport in the respiratory chain from ATP production with a highly exothermic release of chemical energy, i.e. as heat rather than as ATP. Although many aspects of the mechanism are uncertain, it is clear that proton conductance by UCP1 is highly regulated and inducible. It is activated by free long-chain fatty acids and inhibited by purine nucleotides, i.e. fatty acids are not only the substrate for thermogenesis, but act also as self-regulating second messengers. The mitochondrial phospholipid cardiolipin, which is intimately involved in oxidative phosphorylation, is indispensable for stimulating and sustaining the function of thermogenic fat. There is evidence also that acylcarnitines produced in the liver from fatty acids released from white adipose tissue in response to cold exposure are transported in plasma to brown adipose tissue and can serve as a substrate for thermogenesis. Upon activation of brown adipose tissue, the dense vasculature increases the delivery of fatty acids and glucose to the brown adipocytes and warms the blood passing through the tissue.
The activities of acyl-CoA synthetases and acyl-CoA thioesterases determine the availability of substrates for β-oxidation and consequently the thermogenic capacity. Synthesis of the lipokine octadecanoid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), is induced by cold also, and this stimulates the activity of brown adipose tissue by promoting the uptake of fatty acids, acting via G-protein-coupled receptors. Similarly, there are suggestions that n-3 polyunsaturated fatty acids may promote adaptive thermogenesis, for example through the activity of the 12-lipoxygenase metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE), and fatty acid esters of hydroxy fatty acids (FAHFA) are relevant in this context. Peroxisomal synthesis of plasmenyl-phospholipids is believed to regulate adipose tissue thermogenesis by mediating mitochondrial fission.
In hibernating mammals, brown adipose tissue is especially important metabolically, and even in laboratory animals such as mice, it can consume about 50% of dietary lipids and glucose when the animals are exposed to cold. Similarly, in even humans, the activity of brown adipose tissue is induced acutely by cold and is stimulated via the sympathetic nervous system, and the relevance of this tissue to human metabolism is now becoming apparent. For example, there are suggestions that brown adipose tissue can behave as an endocrine system to secrete endocrine factors ('batokines') that may be favourable towards cardiovascular risk. For obvious reasons, there are efforts to determine whether sustained activation of brown fat by pharmaceutical means could be beneficial towards a number of human disease states, including obesity, diabetes and cardiovascular disease.
Such research has been stimulated by the observation that clusters of distinct adipocytes with thermogenic capacity in addition to their storage function can be present in white adipose tissue and emerge in response to various physiological signals, especially reactive oxygen species. They are termed 'beige or brite' adipocytes and arise from multipotent preadipocytes. Brown adipose tissue is a discrete organ in animals, but beige adipose tissue is interspersed with white and the two forms have different developmental origins. In adult humans, most of the deposits once thought to be classical brown adipose tissue do not contain the genetic markers for this tissue and are now recognized to be beige/brite fat, although brown adipose tissue per se is present in significant amounts in human newborns and infants. However, beige adipocytes utilize the same machinery to release heat by oxidation of fatty acids under β-adrenergic stimulation.
2.5. Other Functions of Triacylglycerol Depots
Subcutaneous depots act as a cushion around joints and serve as insulation against cold in many terrestrial animals, as is obvious in the pig, which is surrounded by a layer of fat, and it is especially true for marine mammals such as seals. Those adipocytes embedded in the skin differ from the general subcutaneous depots and support the growth of hair follicles and regenerating skin, and they may also have a defensive role both as a physical barrier and by responding metabolically to bacterial infection.
In marine mammals and fish, the fat depots are less dense than water and so aid buoyancy with the result that less energy is expended in swimming. More surprisingly perhaps, triacylglycerols together with the structurally related glyceryl ether diesters and wax esters are the main components of the sonar lens used in echo-location by dolphins and toothed whales. The triacylglycerols are distinctive in that they contain two molecules of 3-methylbutyric (isovaleric) acid with one long-chain fatty acid. It appears that the relative concentrations of the various lipids in an organ in the head of the animals (termed the ‘melon’) are arranged anatomically in a three-dimensional topographical pattern to enable them to focus sound waves.
In cold climates, many insects do not feed over winter and must manage their energy stores to meet the energetic demands of development and reproduction in the spring. Some insect species that are tolerant of freezing produce triacylglycerols containing acetic acid, and these remain liquid at low temperatures; by interacting with water, they may play a role in cryoprotection.
2.6. Triacylglycerol Metabolism in Plants and Yeasts
Seed oils: Fruit and seed oils are major agricultural products with appreciable economic and nutritional value to humans. The mesocarp of fruits is a highly nutritious energy source that attracts animals that help to disperse the seeds, and in plants such as the oil palm and olive trees a high proportion of the fruit flesh contains triacylglycerols. Similarly in seeds, triacylglycerols are the main storage lipid and can comprise as much as 60% of their weight. Fruit lipids are not intended for use by the plant per se and are stored in lipid droplets in large irregular structures that break down readily, but seed lipids are required for the development of the plant embryo so their metabolism is of particular importance. However, triacylglycerol biosynthesis and metabolism are required also for pollen viability and to maintain lipid homeostasis in chloroplasts (see the note on plastoglobules below).
In plants, fatty acids synthesised in the plastid compartment are stored in the embryo or endosperm tissues of seeds as triacylglycerols in lipid droplets with a coherent surface layer of proteins and lipids. In addition to the common range of fatty acids synthesised in plastids, some plant species produce novel fatty acids, including medium- and very-long-chain components and those with oxygenated and other functional moieties. Some very specific means of diverting these to seeds and triacylglycerol production must exist to prevent disruption of the plant membranes. Seed development occurs in three stages - rapid cell division with no accumulation of storage material, rapid deposition of triacylglycerols and other energy-rich metabolites, and finally desiccation.
During the period of oil accumulation in seeds, there must be a mechanism to hydrolyse the newly formed ACP esters of fatty acids and export the unesterified fatty acids to the endoplasmic reticulum, where they are converted to the CoA esters and triacylglycerols are synthesised by the Kennedy and other pathways described above. In yeast and plants, diacylglycerol esterification is the only committed step in triacylglycerol production and this occurs by mechanisms that can be both dependent or independent of acyl-CoA esters. The acyl-CoA-dependent route is catalysed by diacylglycerol:acyl-CoA acyltransferases (DGATs) with acyl-CoA and diacylglycerols as substrates. In plants, two membrane-bound enzymes (DGAT1 and DGAT2) and a cytosolic enzyme (DGAT3) are known, while the acyl-CoA-independent reaction utilizes a phospholipid:diacylglycerol acyltransferase with phospholipids as acyl donor and diacylglycerol as acyl acceptor to produce triacylglycerols and lysophospholipids. DGAT2 is especially important in those plant species with unusual fatty acid compositions.
In addition, a substantial proportion in some species is synthesised by a flux through the membrane phospholipid phosphatidylcholine, produced by both the eukaryotic and prokaryotic pathways with differing positional distributions (see our web-page on galactosyldiacylglycerols), in which diacylglycerols are generated by the action of a phosphatidate phosphatase as an intermediate. Direct transfer of one fatty acid from phosphatidylcholine to diacylglycerol by the action of the phospholipid:1,2-diacyl-sn-glycerol-acyltransferase (PDAT) enzyme also occurs, possibly to remove damaged or unusual membrane components. As phosphatidylcholine undergoes extensive remodelling and its fatty acid components are subject to modification, for example by desaturation to form linoleic and linolenic acids, the compositions and especially the positional distributions of triacylglycerols produced in this way can be very different from those synthesised by the ‘classical’ pathways. Phosphatidylcholine may also function as a carrier for the trafficking of acyl groups between organelles and membrane subdomains, and it has been suggested that an assembly of interacting enzymes may facilitate the transfer of polyunsaturated fatty acids from this phospholipid to triacylglycerols in seeds.
As triacylglycerol synthesis continues, oil droplets accumulate between the leaflets of the endoplasmic reticulum and are surrounded by a monolayer of phospholipids and proteins, which in Arabidopsis include oleosins, a caleosin, a steroleosin, a putative aquaporin and a glycosylphosphatidylinositol-anchored protein. These eventually “bud off” from the endoplasmic reticulum with their monolayer of phospholipids and proteins and are released into the cytosol by a yet-to-be defined mechanism.
At the onset of germination, water is absorbed and lipases are activated. The process of lipolysis begins at the surface of oil bodies, where the oleosins, which are the most abundant structural proteins, are believed to serve to assist the docking of lipases. They also control the size and stability of lipid droplets in seeds. A number of lipases have been cloned from various plant species and are typical α/β-hydrolases, with a conserved catalytic triad of Ser, His, and Asp or Glu as in patatin (an especially abundant lipolytic protein in potatoes), which are able to hydrolyse triacylglycerols but not phospho- or galactolipids. The most important of these is believed to be the 'sugar-dependent lipase 1 (SDP1)', which is a patatin-like lipase similar to the mammalian adipose triacylglycerol lipase discussed above, and is located on the surface of the oil body. This is active mainly against triacylglycerols to generate diacylglycerols, but presumably works in conjunction with di- and monoacylglycerol lipases to generate free fatty acids and glycerol.
The lipid droplets in seeds exist in close proximity with glyoxysomes (broadly equivalent to peroxisomes). These are the membrane-bound organelles that contain most of the enzymes required to oxidize fatty acids derived from the triacylglycerols via acetyl-CoA to four-carbon compounds, such as succinate, which are then converted to soluble sugars to provide germinating seeds with energy to fuel the growth of the seedlings and to produce shoots and leaves. In addition, they supply structural elements before the seedlings develop the capacity to photosynthesise. How the products of lipolysis are transported to the glyoxysomes for further metabolism has still to be determined, but a specific ‘ABC’ transporter is required to import fatty acids into the glyoxysomes in Arabidopsis. The free acids are converted to their coenzyme A esters by two long-chain acyl-CoA synthetases located on the inner face of the peroxisome membrane before entry into the β-oxidation pathway. All of these processes are controlled by an intricate regulatory network, involving transcription factors that crosstalk with signalling events from the seed maturation phase through to embryo development. After about two days of the germination process, the glycoxysomes begin to break down, but β-oxidation can continue in peroxisomes in leaf tissue.
Lipid droplets - plastoglobules: Triacylglycerol-rich lipid droplets (LD) have been observed in most cell types in vegetative tissues of plants as well as in seeds, and although their origin and function are poorly understood, they contain all the enzymes required for triacylglycerol metabolism together with phospholipases, lipoxygenases and other oxidative enzymes. Rather than oleosins, these lipid droplets in plants and algae contain a family of ubiquitously expressed 'LD-associated proteins' on the surface, together with a monolayer of phospholipids (mainly phosphatidylcholine), galactolipids such as sulfoquinovosyldiacylglycerol and in some species betaine lipids. As in yeast and humans, seipins (three in Arabidopsis) are necessary for normal LD biogenesis. Again, LD form within the bilayer of the endoplasmic reticulum and pinch off into the cytoplasm. Abiotic stresses can induce remodelling of lipid membranes through lipase action with the formation of toxic lipid intermediates, and these can be sequestered by triacylglycerols in lipid droplets to inhibit membrane damage and potentially prevent cell death. While they are believed to be involved mainly in stress responses, lipid droplets may have other specialized roles, for example in anther and pollen development, where triacylglycerols serve as a source of fatty acids for membrane biosynthesis. Fatty acids derived from triacylglycerols in lipid droplets are believed to be subjected to peroxisomal β-oxidation to produce the ATP required for stomatal opening and no doubt many other purposes.
In addition, lipid droplets that have been termed 'plastoglobules' are produced by localized accumulation of triacylglycerols and other neutral lipids between the membrane leaflets of the thylakoid cisternae and then pinch off into the stroma, where they are involved in a wide range of biological functions from biogenesis to senescence via the recruitment of specific proteins. During senescence for example, lipid droplets accumulate rapidly in leaves of A. thaliana. In reproductive tissues, may have a more direct function by recruiting and transporting proteins, both for organ formation and successful pollination. Antifungal compounds such as 2-hydroxy-octadecatrienoic acid and other oxylipins are produced from α-linolenic acid in these organelles, and it has been suggested that the latter function as intracellular factories to produce stable metabolites via unstable intermediates by concentrating the enzymes and hydrophobic substrates in an efficient manner. Plastoglobules are also implicated in the biosynthesis and metabolism of vitamins E and K.
Microalgae: Triacylglycerol metabolism in lipid droplets in microalgae is under intensive study because of their potential for biodiesel production. It seems that similar processes occur as in higher plants, but with a simpler genome encoding few redundant proteins. In the unicellular green model microalga Chlamydomonas reinhardtii, for example, key lipid droplet proteins, lipases and enzymes of β-oxidation have been characterized.
Yeasts: Lipid droplets in yeast are considered to be a highly dynamic and functionally diverse hub that ensures stress resistance and cell survival by promoting membrane and organelle homeostasis. As most of the important biosynthetic and catabolic enzymes involved in triacylglycerol metabolism are conserved between yeasts and mammals, the former are proving to be useful models for the study of triacylglycerol production. The size and triacylglycerol content of lipid droplets in yeasts change appreciably in different stages of growth and development, and Saccharomyces cerevisiae contains a single phosphatidic acid phosphatase (Pah1), which has an essential role in this process. During vegetative growth, Pah1 in the cytosol is phosphorylated by multiple protein kinases, and this enables the synthesis of phospholipids rather than triacylglycerols. As cells progress into stasis, the Pah1 is dephosphorylated and translocates to the endoplasmic reticulum, which ultimately leads to triacylglycerol synthesis for storage in lipid droplets. Some fatty acids derived from phospholipids are utilized for triacylglycerol biosynthesis at the inner nuclear membrane, and this is important for nuclear integrity.
2.7. Triacylglycerol Metabolism in Prokaryotes
Study of the biosynthesis of triacylglycerols in bacteria has been stimulated by an awareness of the role of this lipid class in the pathogenesis of Mycobacterium tuberculosis and the relationship with antibiotic biosynthesis by Streptomyces coelicolor. For example, triacylglycerols are believed to be an energy reserve for the long-term survival of M. tuberculosis during the persistence phase of infection as well as a means by which unesterified fatty acids are detoxified. Increasing numbers of bacterial species, for example from the genera Mycobacterium, Nocardia, Rhodococcus, Micromonospora, Dietzia and Gordonia, are now known to produce triacylglycerols (sometimes wax esters), and these can be stored in lipid droplets in the organisms. The first three steps in triacylglycerol biosynthesis are catalysed by GPAT, LPAT and PAP enzymes comparable to those in other organisms. However, it has become apparent that the DGAT can be a dual-function CoA-dependent acyltransferase known as wax ester synthase/diacylglycerol acyltransferase, which accepts a broad diversity of acyl-CoA substrates for esterification of diacylglycerols or long-chain fatty alcohols for the synthesis of triacylglycerols or wax esters, respectively, depending on which intermediates are present in the organisms. Bacteria that lack such an enzyme are unable to produce these non-polar lipids.
Other web pages on this site dealing with triacylglycerols are Triacylglycerols: Part 1 - their structure and compositions, and Triacylglycerols: Part 3 - regio- and stereospecific analysis procedures.
- Alvarez, H.M. Triacylglycerol and wax ester-accumulating machinery in prokaryotes. Biochimie, 120, 28-39 (2016); DOI.
- Alves-Bezerra, M. and Cohen, D.E. Triglyceride metabolism in the liver. Comprehensive Physiology, 8, 1-22 (2018); DOI.
- Bhatt-Wessel, B., Jordan, T.W., Miller, J.H. and Peng, L. Role of DGAT enzymes in triacylglycerol metabolism. Arch. Biochem. Biophys., 655, 1-11 (2018); DOI.
- Bozza, P.T., Bakker-Abreu, I., Navarro-Xavier, R.A. and Bandeira-Melo, C. Lipid body function in eicosanoid synthesis: An update. Prostaglandins Leukotrienes Essential Fatty Acids, 85, 205-213 (2011); DOI.
- Cohen, P. (Editor) Brown and Beige Fat: From Molecules to Physiology. Biochim. Biophys Acta, Lipids, 1864, Issue 1, Pages 1-112 (2019) - special journal issue - several articles.
- Coleman, R.A. It takes a village: channeling fatty acid metabolism and triacylglycerol formation via protein interactomes. J. Lipid Res., 60, 490-497 (2019); DOI.
- Coleman, R.A. and Hesselink, M.K.C. (Editors) Recent advances in lipid droplet biology. Biochim.Biophys. Acta, Lipids, (Volume 1862, Issue 10, Part B, Pages 1129-1284, October 2017) - special journal issue - various articles.
- Funcke, J.B. and Scherer, P.E. Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication. J. Lipid Res., 60, 1648-1697 (2019); DOI.
- Graef, M. Lipid droplet-mediated lipid and protein homeostasis in budding yeast. FEBS Letts, 592, 1291-1303 (2018); DOI.
- Heier, C., Klishch, S., Stilbytska, O., Semaniuk, U. and Lushchak, O. The Drosophila model to interrogate triacylglycerol biology. Biochim. Biophys. Acta, Lipids, 1866, 1163-1184 (2021); DOI.
- Hertzel, A.V., Thompson, B.R., Wiczer, B.M. and Bernlohr, D.A. Lipid metabolism in adipose tissue. In: Biochemistry of Lipids, Lipoproteins and Membranes (5th Edition). pp. 277-304 (Vance, D.E. and Vance, J. (editors), Elsevier, Amsterdam) (2008) - see Science Direct.
- Hofer, P., Taschler, U., Schreiber, R., Kotzbeck, P. and Schoiswohl, G. The lipolysome - a highly complex and dynamic protein network orchestrating cytoplasmic triacylglycerol degradation. Metabolites, 10, 147 (2020); DOI.
- Lee, J. and Ridgway, N.D. Substrate channeling in the glycerol-3-phosphate pathway regulates the synthesis, storage and secretion of glycerolipids. Biochim. Biophys. Acta, Lipids, 1865, 158438 (2020); DOI.
- Li-Beisson, Y., Thelen, J.J., Fedosejevs, E. and Harwood, J.L. The lipid biochemistry of eukaryotic algae. Prog. Lipid Res., 74, 31-68 (2019); DOI.
- Maraschina, F. dos Santos, Kulcheski, F.R., Segatto, A.L.A., Trenz, T.S., Barrientos-Diaz, O., Margis-Pinheiro, M., Margis, R. and Turchetto-Zolet, A.C. Enzymes of glycerol-3-phosphate pathway in triacylglycerol synthesis in plants: Function, biotechnological application and evolution. Prog. Lipid Res., 73, 46-64 (2019); DOI.
- Nicholls, D.G. The hunt for the molecular mechanism of brown fat thermogenesis. Biochimie, 134, 9-18 (2017); DOI - and many other articles in this journal issue.
- Olzmann, J.A. and Carvalho, P. Dynamics and functions of lipid droplets. Nature Rev. Mol. Cell Biol., 20, 137-155 (2019); DOI
- Reue, K. and Wang, H. Mammalian lipin phosphatidic acid phosphatases in lipid synthesis and beyond: metabolic and inflammatory disorders. J. Lipid Res., 60, 728-733 (2019); DOI.
- Schneider, M. (Editor) 'The Biology of Lipid Droplets'. Exp. Cell Res. (Volume 340, Issue 2, pp. 171-328, January 2016) - special journal issue - various articles.
- Xiao, C.T., Stahel, P., Carreiro, A.L., Buhman, K.K. and Lewis, G.F. Recent advances in triacylglycerol mobilization by the gut. Trends Endocrinol. Metab., 29, 151-163 (2018); DOI.
- Xu, C.C., Fan, J. and Shanklin, J. Metabolic and functional connections between cytoplasmic and chloroplast triacylglycerol storage. Prog. Lipid Res., 80, 101069 (2020); DOI.
- Yang, Y. and Benning, C. Functions of triacylglycerols during plant development and stress. Curr. Opinion Biotechn., 41, 191-198 (2018); DOI.
|Credits/disclaimer||Updated: July 12
||Author: William W. Christie|