Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism

The mobilization of free fatty acids from adipose triacylglycerol (TG) stores requires the activities of triacylglycerol lipases. In this study, we demonstrate that adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major enzymes contributing to TG breakdown in in vitro assays and in organ cultures of murine white adipose tissue (WAT). To differentiate between ATGL- and HSL-specific activities in cytosolic preparations of WAT and to determine the relative contribution of these TG hydrolases to the lipolytic catabolism of fat, mutant mouse models lacking ATGL or HSL and a mono-specific, small molecule inhibitor for HSL (76-0079) were used. We show that 76-0079 had no effect on TG catabolism in HSL-deficient WAT but, in contrast, essentially abolished free fatty acid mobilization in ATGL-deficient fat. CGI-58, a recently identified coactivator of ATGL, stimulates TG hydrolase activity in wild-type and HSL-deficient WAT but not in ATGL-deficient WAT, suggesting that ATGL is the sole target for CGI-58-mediated activation of adipose lipolysis. Together, ATGL and HSL are responsible for more than 95% of the TG hydrolase activity present in murine WAT. Additional known or unknown lipases appear to play only a quantitatively minor role in fat cell lipolysis.     

Attenuation of adipocyte triacylglycerol hydrolase activity decreases basal fatty acid efflux

Fatty acids released from adipose triacylglycerol stores by lipolysis provide vertebrates with an important source of energy. We investigated the role of microsomal triacylglycerol hydrolase (TGH) in the mobilization of adipocyte triacylglycerols through inactivation of the TGH activity by RNA interference or chemical inhibition. Attenuation of TGH activity resulted in decreased basal but not isoproterenol-stimulated efflux of fatty acids from 3T3-L1 adipocytes. Lack of TGH activity was accompanied by accumulation of cellular triacylglycerols and cholesteryl esters without any changes in the expression of enzymes catalyzing triacylglycerol synthesis (diacylglycerol acyltransferases 1 and 2) or degradation (adipose triglyceride lipase and hormone-sensitive lipase). Inhibition of TGH-mediated lipolysis also did not affect insulin-stimulated Glut4 translocation from intracellular compartments to the plasma membrane or glucose uptake into adipocytes. These data suggest that TGH plays a role in adipose tissue triacylglycerol metabolism and may be a suitable pharmacological target for lowering fatty acid efflux from adipose tissue without altering glucose import.     

Effects of rosiglitazone and high fat diet on lipase/esterase expression in adipose tissue

A number of intracellular lipase/esterase have been reported in adipose tissue either by functional assays of activity or through proteomic analysis. In the current work, we have studied the relative expression level of 12 members of the lipase/esterase family that are found in white adipose tissue. We found that the relative mRNA levels of ATGL and HSL are the most abundant, being 2-3 fold greater than TGH or ADPN; whereas other intracellular neutral lipase/esterases were expressed at substantially lower levels. High fat feeding did not alter the mRNA expression levels of most lipase/esterases, but did reduce CGI-58 and WBSCR21. Likewise, rosiglitazone treatment did not alter the mRNA expression levels of most lipase/esterases, but did increase ATGL, TGH, CGI-58 and WBSCR21, while reducing ADPN. WAT from HSL-/- mice showed no compensatory increase in any lipase/esterases, rather mRNA levels of most lipase/esterases were reduced. In contrast, BAT from HSL-/- mice showed an increase in ATGL expression, as well as a decrease in ES-1, APEH and WBSCR21. Analysis of the immunoreactive protein levels of some of the lipases confirmed the results seen with mRNA. In conclusion, these data highlight the complexity of the regulation of the expression of intracellular neutral lipase/esterases involved in lipolysis.     

Lipase-selective functional domains of perilipin A differentially regulate constitutive and protein kinase A-stimulated lipolysis

Perilipin (Peri) A is a lipid droplet-associated phosphoprotein that acts dually as a suppressor of basal (constitutive) lipolysis and as an enhancer of cyclic AMP-dependent protein kinase (PKA)-stimulated lipolysis by both hormone-sensitive lipase (HSL) and non-HSL(s). To identify domains of Peri A that mediate these multiple actions, we introduced adenoviruses expressing truncated or mutated Peri A and HSL into NIH 3T3 fibroblasts lacking endogenous perilipins and HSL but overexpressing acyl-CoA synthetase 1 and fatty acid transporter 1. We identified two lipase-selective functional domains: 1) Peri A (amino acids 1-300), which inhibits basal lipolysis and promotes PKA-stimulated lipolysis by HSL, and 2) Peri A (amino acids 301-517), which inhibits basal lipolysis by non-HSL and promotes PKA-stimulated lipolysis by both HSL and non-HSL. PKA site mutagenesis revealed that PKA-stimulated lipolysis by HSL requires phosphorylation of one or more sites within Peri 1-300 (Ser81, Ser222, and Ser276). PKA-stimulated lipolysis by non-HSL additionally requires phosphorylation of one or more PKA sites within Peri 301-517 (Ser433, Ser492, and Ser517). Peri 301-517 promoted PKA-stimulated lipolysis by HSL yet did not block HSL-mediated basal lipolysis, indicating that an additional region(s) within Peri 301-517 promotes hormone-stimulated lipolysis by HSL. These results suggest a model of Peri A function in which 1) lipase-specific "barrier" domains block basal lipolysis by HSL and non-HSL, 2) differential PKA site phosphorylation allows PKA-stimulated lipolysis by HSL and non-HSL, respectively, and 3) additional domains within Peri A further facilitate PKA-stimulated lipolysis, again with lipase selectivity.     

Hormone-sensitive lipase-independent adipocyte lipolysis during beta-adrenergic stimulation, fasting, and dietary fat loading

In white adipose tissue, lipolysis can occur by hormone-sensitive lipase (HSL)-dependent or HSL-independent pathways. To study HSL-independent lipolysis, we placed HSL-deficient mice in conditions of increased fatty acid flux: beta-adrenergic stimulation, fasting, and dietary fat loading. Intraperitoneal administration of the beta(3)-adrenergic agonist CL-316243 caused a greater increase in nonesterified fatty acid level in controls (0.33 +/- 0.05 mmol/l) than in HSL(-/-) mice (0.12 +/- 0.01 mmol/l, P < 0.01). Similarly, in isolated adipocytes, lipolytic response to CL-316243 was greatly reduced in HSL(-/-) mice compared with controls. Fasting for 相似文献   

Lipolytic stimulation modulates the subcellular distribution of hormone-sensitive lipase in 3T3-L1 cells

3T3-L1 cells have been a useful model system for studying adipocyte differentiation and metabolism. They acquire a hormone-sensitive lipase during differentiation (Kawamura, M., et al. 1981. Proc. Natl. Acad. Sci. USA. 78: 732-735). In the present study the control of lipolysis in these cells was investigated. Basal glycerol release from cell monolayers was 437 nmol/mg protein per hr, and could be stimulated approximately 6-fold by exposure to 1 microM isoproterenol. Subcellular fractionation of stimulated cells revealed a redistribution of triglyceride lipase activity: loss from the infranatant fraction and increase in the pellet fraction. The redistribution was dosage-dependent and reversible. Treatment of intact cells with 8-bromoadenosine 3':5' cyclic monophosphate elicited similar redistribution of the lipase activity; however, disruption and incubation of untreated cells in the presence of ATP and either cyclic AMP or the catalytic subunit from cAMP-dependent protein kinase did not. The lipase activity in the pellet fraction was increased 3- to 4-fold after maximal lipolytic stimulation of intact cells, whereas phosphorylation of the enzyme in vitro yielded 1.4- to 1.6-fold stimulation in all subcellular fractions from untreated cells. The lipase found in the particulate fraction has the same properties as the previously characterized infranatant enzyme. It is suggested that interaction of the lipase with substrate and associated intracellular membranes may be a novel feature of the regulation of lipolysis.     

Triacylglycerol hydrolase is localized to the endoplasmic reticulum by an unusual retrieval sequence where it participates in VLDL assembly without utilizing VLDL lipids as substrates

The majority of hepatic intracellular triacylglycerol (TG) is mobilized by lipolysis followed by reesterification to reassemble TG before incorporation into a very-low-density lipoprotein (VLDL) particle. Triacylglycerol hydrolase (TGH) is a lipase that hydrolyzes TG within hepatocytes. Immunogold electron microscopy in transfected cells revealed a disparate distribution of this enzyme within the endoplasmic reticulum (ER), with particularly intense localization in regions surrounding mitochondria. TGH is localized to the lumen of the ER by the C-terminal tetrapeptide sequence HIEL functioning as an ER retention signal. Deletion of HIEL resulted in secretion of catalytically active TGH. Mutation of HIEL to KDEL, which is the consensus ER retrieval sequence in animal cells, also resulted in ER retention and conservation of lipolytic activity. However, KDEL-TGH was not as efficient at mobilizing lipids for VLDL secretion and exhibited an altered distribution within the ER. TGH is a glycoprotein, but glycosylation is not required for catalytic activity. TGH does not hydrolyze apolipoprotein B-associated lipids. This suggests a mechanism for vectored movement of TGs onto developing VLDL in the ER as TGH may mobilize TG for VLDL assembly, but will not access this lipid once it is associated with VLDL.     

Apolipoprotein B and triacylglycerol secretion in human triacylglycerol hydrolase transgenic mice

Apolipoprotein B (apoB)-containing lipoproteins play a critical role in whole body lipid homeostasis and the pathogenesis of atherosclerosis. The assembly of hepatic apoB-containing lipoproteins, VLDL, is governed by the availability of lipids, including triacylglycerol (TG). The majority of TG associated with VLDL is derived from the hepatic cytoplasmic lipid stores by a process involving lipolysis followed by reesterification. Microsomal triacylglycerol hydrolase (TGH) has been demonstrated to play a role in the lipolysis/reesterification process. To evaluate the potential regulatory role of TGH in hepatic VLDL assembly, we developed inducible transgenic mice expressing a human TGH minigene under the control of the mouse metallothionein promoter. Induction of human TGH by zinc resulted in liver-specific expression of the enzyme associated with 3- to 4-fold increases in lipolytic activity that could be attenuated with a TGH-specific inhibitor. Augmented TGH activity led to increased secretion of newly synthesized apoB and plasma TG levels. These results suggest that increased hepatic expression of TGH leads to a more proatherogenic plasma lipid and apoB profile.     

Increased norepinephrine by medium-chain triglyceride attributable to lipolysis in white and brown adipose tissue of C57BL/6J mice

A further investigation of the lipolysis induced by medium-chain triglyceride (MCT) was conducted on C57BL/6J mice fed with a diet containing 2% MCT or 2% long-chain triglyceride (LCT). Blood norepinephrine, body fat and blood lipid variables, and the protein or mRNA expression of the genes relevant to lipolysis were measured and analyzed in the white and brown adipose tissue (WAT, BAT). Decreased body fat and improved blood lipid profiles attributable to MCT were confirmed. A higher level of blood norepinephrine was observed with the MCT diet. The adipose triglyceride lipase (ATGL) activity and its mRNA expression, the expression of protein and mRNA of the beta 3 adrenergic receptor (β3-AR) in both WAT and BAT, and the hormone-sensitive lipase (HSL) activity and its mRNA expression in BAT were significantly increased in the mice with MCT feeding. The lipolysis induced by MCT might be partially mediated by increasing norepinephrine, thereafter signaling the up-regulation of β3-AR, ATGL, and HSL in WAT and BAT.     

Human hormone-sensitive lipase (HSL): expression in white fat corrects the white adipose phenotype of HSL-deficient mice

In white adipose tissue (WAT), hormone-sensitive lipase (HSL) can mediate lipolysis, a central pathway in obesity and diabetes. Gene-targeted HSL-deficient (HSL-/-) mice with no detectable HSL peptide or activity (measured as cholesteryl esterase) have WAT abnormalities, including low mass, marked heterogeneity of cell diameter, increased diacylglycerol content, and low beta-adrenergic stimulation of adipocyte lipolysis. Three transgenic mouse strains preferentially expressing human HSL in WAT were bred to a HSL-/- background. One, HSL-/- N, expresses normal human HSL (41.3 +/- 9.1% of normal activity); two express a serine-to-alanine mutant (S554A) initially hypothesized to be constitutively active: HSL-/- ML, 50.3 +/- 12.3% of normal, and HSL-/- MH, 69.8 +/- 15.8% of normal. In WAT, HSL-/- N mice resembled HSL+/+ controls in WAT mass, histology, diacylglyceride content, and lipolytic response to beta-adrenergic agents. In contrast, HSL-/- ML and HSL-/- MH mice resembled nontransgenic HSL-/- mice, except that diacylglycerol content and perirenal and inguinal WAT masses approached normal in HSL-/- MH mice. Therefore, 1) WAT expression of normal human HSL markedly improves HSL-/- WAT biochemically, physiologically, and morphologically; 2) similar levels of S554A HSL have a low physiological effect despite being active in vitro; and 3) diacylglycerol accumulation is not essential for the development of the characteristic WAT pathology of HSL-/- mice.     

Inhibition of adipocyte lipolysis by papaverine: papaverine can inhibit the redistribution of hormone-sensitive lipase

Papaverine, despite being a potent phosphodiesterase inhibitor, actually blocks adipocyte lipolysis. The present study was designed to clarify the mechanism of the inhibitory effect of papaverine on lipolysis. Lipolysis, stimulated by either 10 microM isoproterenol or 5 mM dibutyryl cAMP, was significantly inhibited by papaverine (100 microM and above). Papaverine, however, did not affect the isoproterenol-induced increase in the protein kinase A (A-kinase) activity ratio. In cell-free extract from non-stimulated adipocytes, cAMP-stimulated A-kinase activities were almost completely blocked by H-89, a potent inhibitor of A-kinase, but not by papaverine. Thus, the inhibitory effect of papaverine on lipolysis could be responsible for a deficit in step(s) distal to A-kinase activity. Hormone-sensitive lipase activities in the infranatant fraction of centrifuged homogenates of cells, which were maximally stimulated with isoproterenol were significantly reduced. This result indicates that hormone-sensitive lipase redistributes from cytosol to its substrate in lipolytically stimulated cells. Papaverine completely blocked the isoproterenol-induced decrease in lipase activity in the infranatant fraction. These results suggest that papaverine blocks lipolysis through its inhibitory effect on the redistribution of hormone-sensitive lipase.     

Triglyceride with medium-chain fatty acids increases the activity and expression of hormone-sensitive lipase in white adipose tissue of C57BL/6J mice

We have previously shown that medium-chain triglyceride (MCT) resulted in significantly less body fat mass than long-chain triglyceride (LCT) did in hypertriglyceridimic subjects. The possible mechanism for this was investigated by measuring and analyzing changes in the body fat, blood lipid profile, enzymatic level and activity of hormone-sensitive lipase (HSL) and its mRNA expression, and levels of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) in white adipose tissue (WAT) of C57BL/6J mice fed for 16 weeks on an MCT or LCT diet. MCT induced lower body weight and body fat, and an improved blood lipid profile than LCT did. The enzymatic level and activity of HSL and its mRNA expression, and the levels of cAMP and PKA were significantly higher in WAT of mice fed with the MCT diet. No significant differences in the levels of lipoprotein lipase and peroxisome proliferator-activated receptor-γ in WAT were apparent between the effects of MCT and LCT. It is concluded that lipolysis by the increased level and activity of HSL, which was induced by the activation of cAMP-dependent PKA in WAT, was partially responsible for the lower fat accumulation in C57BL/6J mice fed with MCT.     

Structure-function analysis of human triacylglycerol hydrolase by site-directed mutagenesis: identification of the catalytic triad and a glycosylation site

Triacylglycerol hydrolase is a microsomal enzyme that hydrolyzes stored cytoplasmic triacylglycerol in the liver and participates in the lipolysis/re-esterification cycle during the assembly of very-low-density lipoproteins. The structure-activity relationship of the enzyme was investigated by site-directed mutagenesis and heterologous expression. Expression of human TGH in Escherichia coli yields a protein without enzymatic activity, which suggests that posttranslational processing is necessary for the catalytic activity. Expression in baculovirus-infected Sf-9 cells resulted in correct processing of the N-terminal signal sequence and yielded a catalytically active enzyme. A putative catalytic triad consisting of a nucleophilic serine (S221), glutamic acid (E354), and histidine (H468) was identified. Site-directed mutagenesis of the residues (S221A, E354A, and H468A) yielded a catalytically inactive enzyme. CD spectra of purified mutant proteins were very similar to that of the wild-type enzyme, which suggests that the mutations did not affect folding. Human TGH was glycosylated in the insect cells. Mutagenesis of the putative N-glycosylation site (N79A) yielded an active nonglycosylated enzyme. Deletion of the putative C-terminal endoplasmic reticulum retrieval signal (HIEL) did not result in secretion of the mutant protein. A model of human TGH structure suggested a lipase alpha/beta hydrolase fold with a buried active site and two disulfide bridges (C87-C116 and C274-C285).     

Mutation of F417 but not of L418 or L420 in the lipid binding domain decreases the activity of triacylglycerol hydrolase

Human triacylglycerol hydrolase (hTGH) has been shown to play a role in hepatic lipid metabolism. Triacylglycerol hydrolase (TGH) hydrolyzes insoluble carboxylic esters at lipid/water interfaces, although the mechanism by which the enzyme adsorbs to lipid droplets is unclear. Three-dimensional modeling of hTGH predicts that catalytic residues are adjacent to an alpha-helix that may mediate TGH/lipid interaction. The helix contains a putative neutral lipid binding domain consisting of the octapeptide FLDLIADV (amino acid residues 417-424) with the consensus sequence FLXLXXXn (where n is a nonpolar residue and X is any amino acid except proline) identified in several other proteins that bind or metabolize neutral lipids. Deletion of this alpha-helix abolished the lipolytic activity of hTGH. Replacement of F417 with alanine reduced activity by 40% toward both insoluble and soluble esters, whereas replacement of L418 and L420 with alanine did not. Another potential mechanism of increasing TGH affinity for lipid is via reversible acylation. Molecular modeling predicts that C390 is available for covalent acylation. However, neither chemical modification of C390 nor mutation to alanine affected activity. Our findings indicate that F417 but not L418, L420, or C390 participates in substrate hydrolysis by hTGH.     

Partial Inhibition of Adipose Tissue Lipolysis Improves Glucose Metabolism and Insulin Sensitivity Without Alteration of Fat Mass

When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet–fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity.     

Regulation of triacylglycerol hydrolase expression by dietary fatty acids and peroxisomal proliferator-activated receptors

Triacylglycerol hydrolase (TGH) is an enzyme that catalyzes the lipolysis of intracellular stored triacylglycerol (TG). Peroxisomal proliferator-activated receptors (PPAR) regulate a multitude of genes involved in lipid homeostasis. Polyunsaturated fatty acids (PUFA) are PPAR ligands and fatty acids are produced via TGH activity, so we studied whether dietary fats and PPAR agonists could regulate TGH expression. In 3T3-L1 adipocytes, TGH expression was increased 10-fold upon differentiation, compared to pre-adipocytes. 3T3-L1 cells incubated with a PPARγ agonist during the differentiation process resulted in a 5-fold increase in TGH expression compared to control cells. Evidence for direct regulation of TGH expression by PPARγ could not be demonstrated as TGH expression was not affected by a 24-h incubation of mature 3T3-L1 adipocytes with the PPARγ agonist. Feeding mice diets enriched in fatty acids for 3 weeks did not affect hepatic TGH expression, though a 3-week diet enriched in fatty acids and cholesterol increased hepatic TGH expression 2-fold. Two weeks of clofibrate feeding did not significantly affect hepatic TGH expression or microsomal lipolytic activities in wild-type or PPARα-null mice, indicating that PPARα does not regulate hepatic TGH expression. Therefore, TGH expression does not appear to be directly regulated by PPARs or fatty acids in the liver or adipocytes.     

Insulin, glucagon and fatty acid treatment of hepatocytes does not result in phosphorylation or changes in activity of triacylglycerol hydrolase

It is recognized that the majority of very low density lipoprotein (VLDL) associated triacylglycerol (TG) is synthesized from fatty acids and partial acylglycerols generated by lipolysis of intra-hepatic storage rather than made de novo. Triacylglycerol hydrolase (TGH) is involved in mobilizing stored TG. Modulating the ability of TGH to hydrolyze stored lipids represents a potentially regulated and rate limiting step in VLDL assembly. Phosphorylation of lipases and carboxylesterases trigger diverse but functionally significant events. We explored the potential for regulating the mobilization of hepatic TG through phosphorylation of TGH. Insulin is known to suppress VLDL secretion from liver, and glucagon can be considered an opposing hormone. However, neither insulin nor glucagon treatment of hepatocytes led to phosphorylation of TGH or changes in its activity. Augmenting intracellular TG stores by incubations with oleic acid also did not lead to changes in TGH activity. Therefore, changes in phosphorylation state are not a mechanism for regulating TGH activity, access to TG substrate pools or for TGH-mediated contributions to VLDL assembly and secretion.     

Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome

Adipose triglyceride lipase (ATGL) was recently identified as an important triacylglycerol (TG) hydrolase promoting the catabolism of stored fat in adipose and nonadipose tissues. We now demonstrate that efficient ATGL enzyme activity requires activation by CGI-58. Mutations in the human CGI-58 gene are associated with Chanarin-Dorfman Syndrome (CDS), a rare genetic disease where TG accumulates excessively in multiple tissues. CGI-58 interacts with ATGL, stimulating its TG hydrolase activity up to 20-fold. Alleles of CGI-58 carrying point mutations associated with CDS fail to activate ATGL. Moreover, CGI-58/ATGL coexpression attenuates lipid accumulation in COS-7 cells. Antisense RNA-mediated reduction of CGI-58 expression in 3T3-L1 adipocytes inhibits TG mobilization. Finally, expression of functional CGI-58 in CDS fibroblasts restores lipolysis and reverses the abnormal TG accumulation typical for CDS. These data establish an important biochemical function for CGI-58 in the lipolytic degradation of fat, implicating this lipolysis activator in the pathogenesis of CDS.     

Possible mechanisms by which adipocyte lipolysis is enhanced in exercise-trained rats

A possible mechanism(s) behind exercise training-enhanced lipolysis was investigated in rat adipocytes. Exercise training (9 weeks; running) enhanced the activity of cAMP-dependent protein kinase (PKA) and the protein expressions of PKA subunits (catalytic, RII alpha, and RII beta) in P(40) fraction (sedimenting at 40,000g), but not in I(40) fraction (infranatant of 40,000g) of adipocyte homogenate. The expression of PKA-anchoring protein 150 (AKAP150) in P(40) fraction was greater in exercise-trained (TR) than in control (C) rats. Hormone-sensitive lipase (HSL) activities in both fractions were also greater in TR. On the other hand, stimulated lipolysis was accompanied by increased activities of HSL in P(40) but not in I(40) fraction. The decreases in stimulated lipolysis due to St-Ht31 were greater in TR rats. Thus, the mechanisms behind exercise training-enhanced adipocyte lipolysis could involve the increased activities of PKA and HSL with enhanced expressions of AKAP150 and some subunits of PKA, all of which may be compartmentalized within adipocytes.     

Lipolysis: pathway under construction

PURPOSE OF REVIEW: The lipolytic catabolism of stored fat in adipose tissue supplies tissues with fatty acids as metabolites and energy substrates during times of food deprivation. This review focuses on the function of recently discovered enzymes in adipose tissue lipolysis and fatty acid mobilization. RECENT FINDINGS: The characterization of hormone-sensitive lipase-deficient mice provided compelling evidence that hormone-sensitive lipase is not uniquely responsible for the hydrolysis of triacylglycerols and diacylglycerols of stored fat. Recently, three different laboratories independently discovered a novel enzyme that also acts in this capacity. We named the enzyme 'adipose triglyceride lipase' in accordance with its predominant expression in adipose tissue, its high substrate specificity for triacylglycerols, and its function in the lipolytic mobilization of fatty acids. Two other research groups showed that adipose triglyceride lipase (named desnutrin and Ca-independent phospholipase A2zeta, respectively) is regulated by the nutritional status and that it might exert acyl-transacylase activity in addition to its activity as triacylglycerol hydrolase. Adipose triglyceride lipase represents a novel type of 'patatin domain-containing' triacylglycerol hydrolase that is more closely related to plant lipases than to other known mammalian metabolic triacylglycerol hydrolases. SUMMARY: Although the regulation of adipose triglyceride lipase and its physiological function remain to be determined in mouse lines that lack or overexpress the enzyme, present data permit the conclusion that adipose triglyceride lipase is involved in the cellular mobilization of fatty acids, and they require a revision of the concept that hormone-sensitive lipase is the only enzyme involved in the lipolysis of adipose tissue triglycerides.