Lipolysis and lipogenesis

Triglyceride, a fatty acyl ester derivative of glycerol, is the major energy depot of all eukaryotic cells. Lipolysis is the enzymic process by which triacylglycerol, stored in cellular lipid droplets, is hydrolytically cleaved to generate glycerol and free fatty acids. The free fatty acids can be subsequently used as energy substrates, essential precursors for lipid and membrane synthesis, or mediators in cell signaling processes. The complete oxidation of free fatty acids to generate ATP occurs in the mitochondria by the processes of β-oxidation which is described in the related article Fatty acid oxidation and synthesis. It involves the sequential degradation of fatty acids to multiple units of acetyl-CoA which can then be completely oxidized via the tricarboxylic acid cycle (Krebs Cycle) and electron transport chain.

Lipogenesis is the process by which glycerol is esterified with free fatty acids to form triglyceride. Dietary fat (triglycerides), when ingested with food, is absorbed by the gut. Being apolar (poorly water-soluble), triglycerides are transported in the form of plasma-lipoproteins called chylomicrons. Lipids are released from their carrier lipoproteins through the local activity of lipoprotein lipase (LPL) and subsequently split into their constituent fatty acids and glycerol. These are taken up by adipose tissue where the triglycerides are resynthesized and stored in cytoplasmic lipid droplets. Lipogenesis also includes the anabolic process by which triglycerides are formed in the liver from excess glucose. Here fatty acids of varying length are synthesised by the sequential addition of two-carbon units derived from acetyl CoA as discussed in the related article Fatty acid oxidation and synthesis. Fatty acids generated by lipogenesis in the liver, are subsequently esterified with glycerol to form triglycerides that are packaged, not in chylomicrons, but in very low density lipoproteins (VLDLs) and secreted into the circulation. Once in the circulation, VLDLs come in contact with lipoprotein lipase (LPL) in the capillary beds in the body (adipose, cardiac, and skeletal muscle) where LPL releases the triglycerides for intracellular storage or energy production.

Lipolysis

The cellular concentration of free fatty acids is tightly controlled by the balance between fatty acid esterification (described below) and triacylglycerol hydrolysis. Fat stores of white adipose tissue represent the major energy reserves in mammals. Triacylglycerol storage and mobilization is a general biological process in essentially all cells of the body and is not restricted to adipose tissue. However, whereas adipocytes are able to secrete free fatty acids and provide them as systemic energy substrates, non-adipose cells do not secrete fatty acids but utilize triacylglycerol-derived fatty acids in a cell autonomous manner for local energy production or lipid synthesis. Consistent with this local utilization, the triacylglycerol storage capacity of non-adipose tissues and cells is relatively minor compared to the importance of adipose tissue providing fatty acids for the whole organism. In fact, excessive ectopic lipid deposition in non-adipose tissues leads to lipotoxicity and is associated with prevalent metabolic diseases, such as type-2 diabetes[1].

Enzymes involved in lipolysis

Figure 1. Schematic delineation of the coordinate breakdown of triacylglycerols. Abbreviations: ATGL, adipose triacylglyceride lipase; DAG, diacylglycerol; G, glycerol; HSL, hormone-sensitive lipase; MAG, monoacylglycerol; MGL, monoglyceride lipase; NEFA, non-esterified fatty acids (referred to throughout this article as free fatty acids, FFAs). Reproduced from Lass et al., 2011[1] with permission. [Click to enlarge]
Figure 1. Schematic delineation of the coordinate breakdown of triacylglycerols. Abbreviations: ATGL, adipose triacylglyceride lipase; DAG, diacylglycerol; G, glycerol; HSL, hormone-sensitive lipase; MAG, monoacylglycerol; MGL, monoglyceride lipase; NEFA, non-esterified fatty acids (referred to throughout this article as free fatty acids, FFAs). Reproduced from Lass et al., 2011[1] with permission. [Click to enlarge]
The hydrolysis of the primary and secondary ester bonds between long chain fatty acids and the glycerol backbone in triacylglycerol is called “lipolysis” and depends on specific hydrolases commonly designated lipases[1]. To date, three enzymes: adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL) have been implicated in the complete hydrolysis of triacylglycerol molecules in cellular lipid stores (Figure 1).

Adipose triglyceride lipase (ATGL) selectively performs the first and rate-limiting step, hydrolyzing triacylglycerols to generate diacylglycerols (DAGs) and free fatty acids. Compared to its hydrolytic activity towards triacylglycerol (TAG), ATGL exhibits only minor or no activity against other lipids, such as diacylglycerol (DAG), monoacylglycerol (MAG), cholesterylesters, or retinylesters[1].

Hormone-sensitive lipase (HSL) is a multifunctional enzyme capable of hydrolyzing a variety of acylesters including triacylglycerol (TAG), diacylglycerol (DAG, and monoacylglycerol (MAG). Within the triacylglycerol hydrolysis cascade this enzyme is rate-limiting for DAG catabolism. Finally, monoglyceride lipase (MGL) efficiently cleaves MAG into glycerol and non-esterified fatty acids (free fatty acids)[1].

The important role of adipose triglyceride lipase (ATGL) for triacylglycerol catabolism became evident from the analysis and examination of ATGL-deficient mice and human patients with mutations in the ATGL gene. ATGL mutations in humans are associated with systemic triacylglycerol accumulation and cardiac myopathy with this rare inherited disease referred as “neutral lipid storage disease with myopathy”[1].

In contrast to ATGL deficiency, hormone-sensitive lipase (HSL)-deficient mice do not show increased fat deposition, are not overweight or obese, and lose white adipose tissue mass with increasing age. Adipocytes of HSL-deficient mice exhibit only a moderate decrease in stimulated lipolysis. Notably, these mice accumulate diacylglycerol (DAG) in several tissues indicating that HSL is rate-limiting for DAG hydrolysis. Mutations in the HSL gene of humans leading to enzyme dysfunction or deficiency have not been reported. The physiological role of monoglyceride lipse (MGL) in lipolysis has not been evaluated so far[1].

The tissue-specific expression pattern of hormone-sensitive lipase (HSL) resembles the one for adipose triglyceride lipase(ATGL). Highest expression is observed in white adipose tissue and brown adipose tissue. Low HSL expression is found in many other tissues and cells particularly in steroidogenic cells, muscle, pancreatic β-cells, and macrophages[1].

Regulation of lipolysis

Figure 2. Regulation of adipocyte lipolysis. Epinephrine and glucagon stimulate fatty acid release from triglycerides stored in adipocyte fat droplets, whereas insulin action is to counter the responses to these two hormones, and conversely, to induce fat storage. Epinephrine and glucagon, binding to their respective receptors, triggers activation of adenylate cylcase (AC) and subsequently, PKA. Activated PKA phosphorylates both perilipin-1 and hormone-sensitive lipase (HSL). The phosphorylation of perilipin-1, leads to the release of the ATGL co-activator α/β hydrolase domain-containing protein-5 (ABHD5), which now binds and activates adipose triglyceride lipase (ATGL), providing free fatty acid (FFA) and DAG substrate for PKA-activated HSL. HSL then hydrolyzes DAG to an FFA and MAG. Free fatty acids are transported to the plasma membrane bound to adipocyte fatty acid-binding protein (aP2: also known as FABP4) and transported across the plasma membrane into the circulation by one of several fatty acid transport proteins. The glycerol released through the action of monoglyceride lipase (MGL) is transported across the plasma membrane via the action of aquaporin 7, (AQP7). The actions of insulin, which counter the effects of epinephrine or glucagon, are primarily the result of the activation of PKB which then phosphorylates and activates phosphodiesterase (PDE) leading to a reduced level of cAMP and consequent reduced activity of PKA. Reproduced with permission of themedicalbiochemistrypage, LLC [2]. [Click to enlarge].
Figure 2. Regulation of adipocyte lipolysis. Epinephrine and glucagon stimulate fatty acid release from triglycerides stored in adipocyte fat droplets, whereas insulin action is to counter the responses to these two hormones, and conversely, to induce fat storage. Epinephrine and glucagon, binding to their respective receptors, triggers activation of adenylate cylcase (AC) and subsequently, PKA. Activated PKA phosphorylates both perilipin-1 and hormone-sensitive lipase (HSL). The phosphorylation of perilipin-1, leads to the release of the ATGL co-activator α/β hydrolase domain-containing protein-5 (ABHD5), which now binds and activates adipose triglyceride lipase (ATGL), providing free fatty acid (FFA) and DAG substrate for PKA-activated HSL. HSL then hydrolyzes DAG to an FFA and MAG. Free fatty acids are transported to the plasma membrane bound to adipocyte fatty acid-binding protein (aP2: also known as FABP4) and transported across the plasma membrane into the circulation by one of several fatty acid transport proteins. The glycerol released through the action of monoglyceride lipase (MGL) is transported across the plasma membrane via the action of aquaporin 7, (AQP7). The actions of insulin, which counter the effects of epinephrine or glucagon, are primarily the result of the activation of PKB which then phosphorylates and activates phosphodiesterase (PDE) leading to a reduced level of cAMP and consequent reduced activity of PKA. Reproduced with permission of themedicalbiochemistrypage, LLC [2]. [Click to enlarge].
Regulation of ATGL - The complex regulation of lipolysis is summarized in Figure 2. The activity of adipose triglyceride lipase (ATGL) activity can be drastically increased by an activator protein called α/β hydrolase domain-containing protein-5 (ABHD5). It was originally named comparative gene identification-58 (CGI-58) following a comparative gene sequence screen of humans and the nematode C. elegans[2]. This activation involves direct protein-protein interaction with ABHD5 with maximal stimulation achieved at approximately equimolar concentrations of enzyme and activator protein. Currently, it is unknown whether ABHD5 binding affects ATGL conformation, facilitates substrate presentation, or enhances ATGL’s lipolytic activity by removing reaction products from the active site. The direct interaction by itself is not sufficient since ABHD5 variants, which were capable of binding ATGL, failed to stimulate enzyme activity. ATGL activation in living cells additionally requires the binding of ABHD5 to the lipid droplet. Truncated variants of ABHD5, which fail to localize to the lipid droplet, but bind to ATGL, are unable to stimulate ATGL activity[1][2].

Recently, a cell-cycle regulatory protein called G0G1 switch protein (GOS2) was identified as a selective inhibitor of adipose triglyceride lipase (ATGL)[1][2]. It is predominantly expressed in adipose tissue and liver and to a lesser extent in muscle, ovary, and kidney. Overexpression of G0S2 in cells causes massive lipid accumulation indicating a role for G0S2 in lipid/energy metabolism. In adipocytes, its expression is induced by insulin and inhibited by TNF-α or isoproterenol, both factors that stimulate lipolysis. Furthermore G0S2 has been identified as a peroxisome proliferator-activated receptor gamma (PPARγ) target gene containing a PPAR-response element (PPRE) in its promoter sequence. In contrast to PPARγ, PPARα down-regulates G0S2 mRNA expression. The N-terminal domain of G0S2 directly interacts with the patatin domain of ATGL facilitating AGTL’s binding to lipid droplets[2]. GOS2 appears not to directly compete with ATGL binding of α/β hydrolase domain-containing protein-5 (ABHD5) as both ATGL and G0S2 translocate to lipid droplets upon stimulation of lipolysis[1][2].

Adipose triglyceride lipase (ATGL) is a hormone-sensitive lipase and β-adrenergic (eg. epinephrine/adrenaline) activation of ATGL activity is required for full hormone-activated lipolysis in white adipose tissue. In the absence of ATGL, free fatty acid and glycerol mobilization in response to β-adrenergic stimulation were decreased by ∼70%. The molecular mechanisms that regulate ATGL activity in response to β-adrenergic stimulation are incompletely understood. Recent evidence suggests an indirect mechanism involving perilipin-1 and α/β hydrolase domain-containing protein-5 (ABHD5). Perilipin-1 expression is restricted to β-adrenergic stimulatable cells, such as adipocytes and steroidogenic cells, and is essential for β-adrenergic stimulatable lipolysis. Perilipin-1 governs the ATGL- and HSL-mediated breakdown of fat in white adipose tissue in multiple ways (see below). As discussed above ATGL activity is regulated by the availability of its co-activator ABHD5. In non-stimulated adipocytes, ABHD5 is located at the surface of lipid droplets and is mostly bound to perilipin-1. In the activated state, perilipin-1 is phosphorylated by cAMP-dependent protein kinase A (PKA) which causes the dissociation of ABHD5 from perilipin-1, which is now available for the activation of ATGL (Figure 2). Thus perilipin-1 controls the activation of ATGL in white adipose tissue by interacting with its co-activator ABHD5 in a cAMP-dependent fashion[1][2].

In non-adipose tissues, the activation of lipolysis is less well characterized because these tissues express little or no perilipin-1. Yet, adipose triglyceride lipase (ATGL) and α/β hydrolase domain-containing protein-5 (ABHD5) play an essential role in triacylglycerol (TAG) hydrolysis, particularly in tissues with high free fatty acid demand, such as skeletal muscle, heart, and liver. Thus, alternative, perilipin-1-independent mechanisms must exist to regulate ATGL activity in non-adipose tissues and could involve perilipin-2, the ubiquitously expressed protein that regulates the access of ATGL to lipid droplets in various cell lines. Whether the regulation of ATGL activity by perilipin-2 in adipose and non-adipose tissues involves the reversible binding of ABHD5 by perilipin-2 is currently unknown. Perilipin-3 is also expressed in virtually all cell types and tissues. In murine hepatocytes, downregulation of perilipin-3 expression leads to a dramatic increase of lipid droplet size and a decrease in lipid droplet number. In addition, these cells show increased lipolysis associated with increased ATGL localization on lipid droplets. Thus, perilipin-3 exerts a protective role for lipid droplet via preventing ATGL access to the lipid droplet. Perilipin-4 is found primarily in white adipose tissue and to a lesser degree in skeletal muscle and heart but nothing is known about its involvement in the lipolytic pathway. A fifth member of the family, perilipin-5 was identified as a lipid droplet binding protein that may regulate fatty acid mobilization and oxidation in tissues with high oxidative capacity such as liver and muscle[1].

Human adipose triglyceride lipase (ATGL) is phosphorylated at two serine residues (Ser404 and Ser428). However, the relevance of phosphorylation for the regulation of enzyme activity is unclear. In contrast to hormone-sensitive lipase (HSL) (see below), phosphorylation of ATGL does not involve PKA. Furthermore, the known phosphorylation sites are not critical for lipid droplet localization or in vitro triacylglycerol (TAG) hydrolysis. Interestingly, the ATGL orthologue in C. elegans ATGL-1 is phosphorylated at multiple sites by the protein serine kinase AMPK thereby inactivating enzyme activity. ATGL-1 inhibition via enzyme phosphorylation prolongs the life span of C. elegans larvae during the dormant state of dauer. Whether matching regulatory phosphorylation sites exist on mammalian ATGL orthologues and whether they are involved in enzyme inactivation during hibernation, long-term fasting, etc. is not known[1].

Adipose triglyceride lipase (ATGL) expression and activity is upregulated during adipose differentiation and is a target for transcription factors PPARγ and insulin-responsive transcription factor forkhead box O1 (FoxO1). Furthermore, fasting and glucocorticoids such as dexamethasone, the PPARγ agonists thiazolidinediones, induce mRNA expression. In contrast, insulin, TNF-α, mTor complex 1, and feeding repress ATGL mRNA expression. Interestingly, the β-adrenergic agonist isoproterenol reduces ATGL (and HSL) mRNA levels in adipocytes although the enzyme activity is induced at the same time. The role of leptin in the regulation of ATGL is controversial. Leptin is known to restrain energy intake and to promote lipolysis, a process involving upregulation of PPARγ expression. Yet, a study on porcine adipocyte lipolysis found that leptin decreased ATGL protein expression while it increased mRNA expression. Insulin resistance and obesity have also been correlated with changes in ATGL mRNA or protein levels[1].

Regulation of HSL - Adipose HSL activity is controlled by two distinct mechanisms in response to β-adrenergic stimulation. Firstly, the enzyme is phosphorylated by cAMP-dependent PKA at at least five distinct serine residues. Besides PKA, other protein kinases have also been shown to phosphorylate HSL and regulate enzyme activity. The list includes extracellular signal-regulated kinase, glycogen synthase kinase-4, Ca2+/calmodulin-dependent kinase II, and AMP-activated kinase. Secondly, phosphorylated HSL interacts with the lipid droplet protein perilipin-1, which itself is a target of PKA phosphorylation. The translocation of phosphorylated HSL to the lipid droplet in white adipose tissue is mediated by the phosphorylated form of perilipin-1. In the basal, non-hormonally stimulated state, perilipin-1 is not phosphorylated and prevents the binding of HSL to lipid droplets. In response to β-adrenergic stimulation, perilipin-1 is phosphorylated on six consensus serine residues by PKA. Specifically the phosphorylation of serines 81, 222, and 276 induce the binding of HSL to perilipin-1 and access to the lipid droplet. After full hormonal stimulation, HSL phosphorylation and the perilipin-1-mediated translocation of the enzyme to the lipid droplet causes a ∼100-fold induction of HSL activity in white adipose tissue. In non-adipose cells lacking perilipin-1, the role of HSL is less well characterized[1][2].

Regulation of MGL - To date, no evidence exists that cellular monoglyceride lipse (MGL) mRNA concentrations or enzyme activities are regulated by either hormones or the energy state of the cell. MGL is highly expressed in many tissues. High MAG hydrolase activity levels are constitutively present in adipocytes, hepatocytes, and muscle cells suggesting that this activity is not subject to extensive regulation. Other enzymes such as HSL and α/β hydrolase domain containing protein 6 (ABHD6) also exhibit MAG hydrolase activity and it is therefore not clear whether in vivo MGL is the only relevant MAG hydrolase[1].

Lipogenesis and exogenous and endogenous triglycerides

Dietary fat (triglyceride) is hydrolyzed to free fatty acids and monoglycerol in the intestine by pancreatic lipase and the released free fatty acids and monoacylglycerols are absorbed by intestinal epithelial cells. Short chain fatty acids can enter the circulation directly, but most fatty acids are re-esterified to triacylglycerols in the mucosa (the lining) of the intestine and packaged with other lipids and apoprotein B-48 to form small fat globules called chylomicrons. These are released into the lymph system and then into the blood[3]. The word chylomicron is composed of "chylo" - milky and "micron" - small; ie small milky (globules)[4]. After a fatty meal, the blood is so full of chylomicrons that it looks milky. Chylomicrons bind to membrane-bound lipoprotein lipases, primarily at adipose tissue and muscle, where the triacylglycerols are once again hydrolysed into free fatty acids and monoacylglycerol for transport into the tissue. The triacylglycerols are then resynthesized inside the cell and stored as fat in adipose tissue or used for energy by the process called β-oxidation in any tissue with mitochondria and an ample supply of oxygen.

An alternative source of triglycerides comes from their endogenous production in the liver. Lipogenesis is the process by which end products of glucose catabolism are converted to fatty acids, which are subsequently esterified with glycerol to form the triacylglycerols that are packaged in very-low-density lipoproteins (VLDLs) and secreted from the liver[5]. The major function of glycolysis in the liver is to provide carbons from glucose for de novo lipid synthesis[6]. Lipogenesis encompasses both de novo fatty acid synthesis and triglyceride synthesis. The former is discussed in the companion article Fatty acid synthesis and oxidation. This article will focus on the details of triglyceride synthesis only.

Two pathways of triglyceride synthesis

In mammals, the synthesis of triacylglycerol serves critical functions in multiple physiological processes, including intestinal dietary fat absorption, intracellular storage of surplus energy, lactation, attenuation of lipotoxicity, lipid transportation, and signal transduction. There are two major biochemical pathways for triacylglycerol synthesis (Figure 3). The monoacylglycerol pathway begins with the acylation of monoacylglycerol with a fatty acyl-CoA by monoacylglycerol acyltransferase. This pathway plays a predominant role in enterocytes (columnar epithelial absorptive cells of the small intestine) after feeding, where large amounts of 2- monoacylglycerol and fatty acids are released from the digestion of dietary lipids. The monoacylglycerol pathway is also active in adipose tissue, likely playing a role in storing excess energy in the form of triacylglycerol[7].

Figure 3. The two metabolic pathways involved in the synthesis of triacylglycerol (TAG). The monoacylglycerol (MAG) pathway, begins with the acylation of MAG with fatty acyl-CoA catalyzed by monoacylglycerol acyltransferase (MGAT). This pathway dominates in the small intestine, a tissue primarily responsible for dietary fat absorption. The glycerol 3-phosphate (G-3-P) pathway is a de novo pathway involved in triacylglycerol (TAG) synthesis in most tissues. The G-3-P pathway begins with the acylation (with fatty acyl-CoA), of G-3-P by glycerol-3-phosphate acyltransferase (GPAT), producing lysophosphatidic acid (LPA). This is followed sequentially by further acylation by LPA acyltransferase (LPAAT) and dephosphorylation by phosphatidic acid (PA) phosphorylase (PAP) to yield diacylgycerol (DAG). The 2 pathways share the final step in converting diacylglycerol DAG into TAG, which is catalyzed by diacylglycerol acyltransferase (DGAT). DAG is also used as a substrate for the synthesis of phosphatidic choline (PC) and phosphatidic ethanolamine (PE). Reproduced from Shi and Cheng, 2009[7] with permission. [Click to enlarge]
Figure 3. The two metabolic pathways involved in the synthesis of triacylglycerol (TAG). The monoacylglycerol (MAG) pathway, begins with the acylation of MAG with fatty acyl-CoA catalyzed by monoacylglycerol acyltransferase (MGAT). This pathway dominates in the small intestine, a tissue primarily responsible for dietary fat absorption. The glycerol 3-phosphate (G-3-P) pathway is a de novo pathway involved in triacylglycerol (TAG) synthesis in most tissues. The G-3-P pathway begins with the acylation (with fatty acyl-CoA), of G-3-P by glycerol-3-phosphate acyltransferase (GPAT), producing lysophosphatidic acid (LPA). This is followed sequentially by further acylation by LPA acyltransferase (LPAAT) and dephosphorylation by phosphatidic acid (PA) phosphorylase (PAP) to yield diacylgycerol (DAG). The 2 pathways share the final step in converting diacylglycerol DAG into TAG, which is catalyzed by diacylglycerol acyltransferase (DGAT). DAG is also used as a substrate for the synthesis of phosphatidic choline (PC) and phosphatidic ethanolamine (PE). Reproduced from Shi and Cheng, 2009[7] with permission. [Click to enlarge]
A second pathway to triacylglycerol synthesis is the glycerol 3-phosphate (G-3-P) pathway (Figure 3), a de novo pathway in most tissues, including the small intestine. This pathway begins with the acylation of glycerol 3-phosphate with a fatty acyl-CoA, producing lysophosphatidic acid, followed by further acylation and dephosphorylation to yield diacylglycerol. These two pathways share the final step in converting diacylglycerol to triacylglycerol, a reaction catalyzed by diacylglycerol acyltransferase[7].

Enzymes involved in triglyceride synthesis

MGATs - Monoacylglycerol acyltransferase (MGAT) catalyzes the first step in triacylglycerol synthesis involved in dietary absorption by enterocytes. Three isoforms of MGAT enzymes, known as MGAT1, MGAT2, and MGAT3, have been identified so far. All three possess strong monoacylglycerol acyltransferase enzyme activity and are localized in the endoplasmic reticulum (ER). However, they differ in tissue expression patterns and in catalytic properties. The MGAT1 mRNA has been detected mainly in stomach, kidney, and adipose tissue, whereas MGAT2 and MGAT3 exhibit highest expression in the small intestine. Among the MGAT isoforms, MGAT3 (which is found only in higher mammals and humans but not in rodents) possesses some unique features. Although named after its enzyme activity, MGAT3 shares higher sequence homology and some catalytic properties with DGAT2 than with the other MGAT isoforms, suggesting MGAT3 also functions as a triacylglycerol synthase[7].

DGATs – As discussed above diacylglycerol, the obligate precursor to triglycerol, is derived either from the glycerol-3-phosphate pathway or the monoacylglycerol pathway and is esterified to triglycerol by a diacylglycerol acyltransferase (DGAT) reaction. There are at least two independent mammalian enzymes known to catalyze this reaction, DGAT1 and DGAT2, both of which show little preference in terms of the fatty acyl-CoA substrate[8]. In humans, DGAT1 is highly expressed in human small intestine, colon, testis, and skeletal muscle but has notably lower levels of expression in adipose and liver. In contrast DGAT2 while showing widespread expression in humans, is found in particularly high levels in liver and adipose tissue. These expression patterns of the DGATs indicate that they may have different functions in different tissues. DGAT1 likely plays a role in intestinal repackaging of free fatty acids using the monoacylglycerol pathway, whereas DGAT2 may function primarily in triglyceride synthesis and export from the liver and deposition in adipose tissue [8].

Aberrant DGAT expression in any of several tissues or organ systems may play a role in disorders such as obesity and nonalcoholic fatty liver disease. Glucose preferentially enhances DGAT1 mRNA expression, whereas insulin increases the level of DGAT2 mRNA. Interestingly when fasted mice are fed a high-carbohydrate meal, DGAT2 but not DGAT1 mRNA is increased in liver, adipose, and small intestine[8].

Mice lacking DGAT1 (Dgat1−/−) exhibit 50% less body fat but are otherwise healthy and fertile with normal serum triglyceride. Their observable phenotypes include lower plasma glucose levels associated with increased insulin and leptin sensitivity; poor milk production - due to deficient triglyceride production in mammary glands; and dry fur and hair associated with atrophy of sebaceous glands. Dgat1−/− mice are resistant to hepatic steatosis and diet-induced obesity, when placed on a high-fat diet, the decreased body fat and lack of weight gain being due to an increase in total energy expenditure due to physical activity and thermogenesis[8].

Mice deficient in DGAT2 (Dgat2−/−) are severely depleted of triglycerides in their tissues and plasma, leading to neonatal death from metabolic disarray and poor skin barrier function. DGAT1 was unable to compensate for the loss of DGAT2, suggesting different roles for the two enzymes, and that DGAT2 is the enzyme responsible for the majority of triglyceride synthesis in mice[8].

Little is known about DGAT expression and regulation within the liver and the precise role of DGAT1 in the development of fatty liver syndromes such as nonalcoholic fatty liver disease remains to be determined. DGAT1 expression was found to be upregulated in the livers of individuals with this syndrome[8].

Additional roles for MGATs and DGATs

Figure 4. Monoacylglycerol acyltransferase (MGAT) and diacylglycerol acyltransferase (DGAT) enzymes are implicated in multiple pathways that regulate energy homeostasis. MGAT and DGAT enzymes play important roles in energy metabolism by regulating satiety in the brain (mediated by monoacylglycerol (MAG)), dietary fat absorption in the gut (in the form of triacylglycerol (TAG)), phospholipid synthesis and very-low-density lipoprotein (VLDL) secretion in the liver (in the form of DAG and TAG), fat storage in adipocytes (in the form of TAG), and insulin sensitivity in skeletal muscle (mediated by DAG). Reproduced from Shi and Cheng, 2009[7] with permission. [Click to enlarge]
Figure 4. Monoacylglycerol acyltransferase (MGAT) and diacylglycerol acyltransferase (DGAT) enzymes are implicated in multiple pathways that regulate energy homeostasis. MGAT and DGAT enzymes play important roles in energy metabolism by regulating satiety in the brain (mediated by monoacylglycerol (MAG)), dietary fat absorption in the gut (in the form of triacylglycerol (TAG)), phospholipid synthesis and very-low-density lipoprotein (VLDL) secretion in the liver (in the form of DAG and TAG), fat storage in adipocytes (in the form of TAG), and insulin sensitivity in skeletal muscle (mediated by DAG). Reproduced from Shi and Cheng, 2009[7] with permission. [Click to enlarge]
In addition to the synthesis of triacylglycerol, the monoacylglycerol acyltransferase (MGAT) and diacylglycerol acyltransferase (DGAT) enzymes also modulate intracellular levels of monoacylglycerol (MAG) and diacylglycerol (DAG), two important signaling molecules[7]. DAG is an activator for protein kinase C (PKC), which regulates insulin sensitivity in the liver and skeletal muscle. 2-Arachidonoylglycerol in the brain is a natural ligand for endocannabinoid receptors, which regulate various physiological events, including appetite. Consequently, the MGAT and DGAT families of enzymes are implicated in the regulation of various physiological functions, such as dietary fat absorption, lipid metabolism, fat storage, insulin sensitivity, satiety, and energy homeostasis (Figure 4). Details are provided in the review by Shi and Cheng[7].

Triglyceride synthesis disorders

The importance of triacylglycerol (TAG) synthesis is exemplified by severe insulin resistance in patients with lipodystrophy, a genetic condition characterized by defective TAG synthesis and storage in adipose tissues. Whereas excess TAG accumulation in adipose leads to obesity, ectopic storage of TAG in nonadipose tissues such as liver and skeletal muscle is associated with insulin resistance. Recent progress in the identification and characterization of the monoacylglycerol acyltransferase (MGAT) and diacylglycerol acyltransferase (DGAT) enzymes along with the phenotypic characterizations of mice with altered expression of these genes have provided important insights into their dynamic roles in the regulation of energy homeostasis and other physiological functions[7].

References

  1. ^ Lass A et al, Lipolysis – A highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores, Prog Lipid Res, 2011; 50:14–27, doi: 10.1016/j.plipres.2010.10.004

  2. ^ King M, Lipolysis and the oxidation of fatty acids. http://themedicalbiochemistrypage.org/fatty-acid-oxidation.php

  3. ^ Berg JM, Tymoczko JL, Stryer L, 2002, Chapter 22: ‘Fatty Acid Metabolism’ In: Biochemistry 5th Edition, New York: WH Freeman.

  4. ^  http://www.medicinenet.com/script/main/art.asp?articlekey=11296

  5. ^ Lipogenesis http://en.wikipedia.org/wiki/Lipogenesis

  6. ^ Postic C, Girard J, The role of the lipogenic pathway in the development of hepatic steatosis. Diabetes & amp; Metab, 2008; 34:643-8. http://www.em-consulte.com/en/article/200090

  7. ^ Shi Y, Cheng D, Beyond triglyceride synthesis: the dynamic functional roles of MGAT and DGAT enzymes in energy metabolism. Am J Physiol Endocrinol Metab, 2009; 297:E10-E18.

  8. ^ Turkish A, Sturley SL, Regulation of Triglyceride Metabolism. I. Eukaryotic neutral lipid synthesis: Many ways to skin ACAT or a DGAT, Amer J Physiol - Gastrointestinal and Liver Physiology, 2007; 292:G953-G957. DOI: 10.1152/ajpgi.00509.2006

Comments

Nobody has commented on this article

Commenting is only available for registered Diapedia users. Please log in or register first.