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• W2055651091 abstract "Fatty acids (FAs) are essential components of all lipid classes and pivotal substrates for energy production in all vertebrates. Additionally, they act directly or indirectly as signaling molecules and, when bonded to amino acid side chains of peptides, anchor proteins in biological membranes. In vertebrates, FAs are predominantly stored in the form of triacylglycerol (TG) within lipid droplets of white adipose tissue. Lipid droplet-associated TGs are also found in most nonadipose tissues, including liver, cardiac muscle, and skeletal muscle. The mobilization of FAs from all fat depots depends on the activity of TG hydrolases. Currently, three enzymes are known to hydrolyze TG, the well-studied hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL), discovered more than 40 years ago, as well as the relatively recently identified adipose triglyceride lipase (ATGL). The phenotype of HSL- and ATGL-deficient mice, as well as the disease pattern of patients with defective ATGL activity (due to mutation in ATGL or in the enzyme's activator, CGI-58), suggest that the consecutive action of ATGL, HSL, and MGL is responsible for the complete hydrolysis of a TG molecule. The complex regulation of these enzymes by numerous, partially uncharacterized effectors creates the “lipolysome,” a complex metabolic network that contributes to the control of lipid and energy homeostasis. This review focuses on the structure, function, and regulation of lipolytic enzymes with a special emphasis on ATGL. Fatty acids (FAs) are essential components of all lipid classes and pivotal substrates for energy production in all vertebrates. Additionally, they act directly or indirectly as signaling molecules and, when bonded to amino acid side chains of peptides, anchor proteins in biological membranes. In vertebrates, FAs are predominantly stored in the form of triacylglycerol (TG) within lipid droplets of white adipose tissue. Lipid droplet-associated TGs are also found in most nonadipose tissues, including liver, cardiac muscle, and skeletal muscle. The mobilization of FAs from all fat depots depends on the activity of TG hydrolases. Currently, three enzymes are known to hydrolyze TG, the well-studied hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL), discovered more than 40 years ago, as well as the relatively recently identified adipose triglyceride lipase (ATGL). The phenotype of HSL- and ATGL-deficient mice, as well as the disease pattern of patients with defective ATGL activity (due to mutation in ATGL or in the enzyme's activator, CGI-58), suggest that the consecutive action of ATGL, HSL, and MGL is responsible for the complete hydrolysis of a TG molecule. The complex regulation of these enzymes by numerous, partially uncharacterized effectors creates the “lipolysome,” a complex metabolic network that contributes to the control of lipid and energy homeostasis. This review focuses on the structure, function, and regulation of lipolytic enzymes with a special emphasis on ATGL. Lipid homeostasis reflects a balance of processes, designed to generate fatty acids (FAs) and lipids, deliver them from their site of origin to target tissues, and catabolize them for metabolic purposes. Innumerable genes and signal components are responsible for an integrated communication network between many tissues and organs, including adipose tissue, liver, muscles, the digestive tract, pancreas, and the nervous system. This network ultimately accounts for the accurate regulation of lipid and energy homeostasis. Despite the central physiological importance of these processes for human health, many basic mechanisms regulating the synthesis, uptake, storage, and utilization of lipids remain insufficiently characterized. FAs are vital components of essentially all known organisms. They are important substrates for oxidation and the production of cellular energy. FAs are essential precursors for all lipid classes, including those forming biological membranes. Finally, they are important for protein function in acylated proteins and as ligands for nuclear receptor transcription factors. In contrast to these “beneficial” characteristics, unesterified FAs can become deleterious for cells when present even at relatively low concentrations. The chronic exposure of nonadipose cells and tissues to elevated concentrations of FAs triggers adverse effects subsumed under the term of “lipotoxicity” (1Schaffer J.E Lipotoxicity: when tissues overeat..Curr. Opin. Lipidol. 2003; 14: 281-287Crossref PubMed Scopus (0) Google Scholar, 2Unger R.H Lipotoxic diseases..Annu. Rev. Med. 2002; 53: 319-336Crossref PubMed Scopus (796) Google Scholar). Accordingly, when supplied with excessive nutrients, essentially all eukaryotes reesterify and deposit FAs as triacylglycerol (TG) droplets to provide an energy reserve for times of nutrient deprivation and to detoxify otherwise harmful compounds. Until recently, lipid droplets were viewed as an inert storage pool of TG. It is now known that essentially all cells in the body generate lipid droplets composed of neutral lipids (TG and cholesteryl esters), phospholipids, and unesterified cholesterol at varying, tissue-specific concentrations. Additionally, numerous proteins are associated with lipid droplets (3Brasaemle D.L Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis..J. Lipid Res. 2007; 48: 2547-2559Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 4Brasaemle D.L Dolios G. Shapiro L. Wang R. Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3T3–L1 adipocytes..J. Biol. Chem. 2004; 279: 46835-46842Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 5Londos C. Brasaemle D.L. Schultz C.J. Segrest J.P. Kimmel A.R. Perilipins, ADRP, and other proteins that associate with intracellular neutral lipid droplets in animal cells..Semin. Cell Dev. Biol. 1999; 10: 51-58Crossref PubMed Google Scholar). These include structural proteins, lipid-modifying enzymes, and proteins that regulate enzyme activities. To date, the physiological role of many of these factors remains elusive. However, from the limited knowledge that is available, it is apparent that lipid droplets represent remarkably flexible, dynamic organelles that are used for the production of membrane components, energy substrates, and signaling molecules, including lipotoxic compounds (6Beckman M. Cell biology. Great balls of fat..Science. 2006; 311: 1232-1234Crossref PubMed Scopus (76) Google Scholar, 7Martin S. Parton R.G Lipid droplets: a unified view of a dynamic organelle..Nat. Rev. Mol. Cell Biol. 2006; 7: 373-378Crossref PubMed Scopus (0) Google Scholar). Although lipid droplets are observed in many cell types, the majority of fat in mammals is found in adipocytes of white adipose tissue (WAT). The central contribution of WAT to the regulation of energy homeostasis is due to both the enormous lipid storage capacity as well as its function as an endocrine organ secreting numerous hormones and adipo-cytokines (8Ahima R.S Lazar M.A. Adipokines and the peripheral and neural control of energy balance..Mol. Endocrinol. 2008; 22: 1023-1031Crossref PubMed Scopus (0) Google Scholar). Prevalent metabolic diseases such as obesity and type 2 diabetes emerge when TG synthesis and catabolism lose synchrony. The key process in fat catabolism and the provision of energy substrate during times of nutrient deprivation (fasting) or enhanced energy demand (e.g., exercise) is the hydrolytic cleavage of stored TG, the generation of FAs and glycerol, and their release from adipocytes. A complex, hormonally controlled regulatory network controls the initiation of this process, called lipolysis, and ultimately activates key intracellular lipases to hydrolyze TG. Currently, three enzymes are known to have an established function in the lipolytic breakdown of fat in adipose and nonadipose tissues: adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL). Numerous lipolytic and antilipolytic effectors control the catabolism of stored fat in various tissues (9Langin D. Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome..Pharmacol. Res. 2006; 53: 482-491Crossref PubMed Scopus (0) Google Scholar, 10Holm C. Osterlund T. Laurell H. Contreras J.A. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis..Annu. Rev. Nutr. 2000; 20: 365-393Crossref PubMed Scopus (331) Google Scholar). These include hormones, cytokines, and adipokines. In adipose tissue, the most potent stimulatory signals are catecholamines acting on β-adrenergic receptors (11Lafontan M. Berlan M. Fat cell adrenergic receptors and the control of white and brown fat cell function..J. Lipid Res. 1993; 34: 1057-1091Abstract Full Text PDF PubMed Google Scholar). Mouse adipocytes express three subtypes of β-adrenergic receptors (β-ARs): β1-AR, β2-AR, and β3-AR. In human adipose tissue, only β1 and β2 receptors induce lipolysis. When catecholamines bind to these receptors, stimulatory Gs proteins activate adenylate cyclase, causing a rise in cAMP levels and elevated activity of cAMP-dependent protein kinase-A (PKA) (10Holm C. Osterlund T. Laurell H. Contreras J.A. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis..Annu. Rev. Nutr. 2000; 20: 365-393Crossref PubMed Scopus (331) Google Scholar, 12Collins S. Cao W. Robidoux J. Learning new tricks from old dogs: beta-adrenergic receptors teach new lessons on firing up adipose tissue metabolism..Mol. Endocrinol. 2004; 18: 2123-2131Crossref PubMed Scopus (0) Google Scholar, 13Holm C. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis..Biochem. Soc. Trans. 2003; 31: 1120-1124Crossref PubMed Scopus (354) Google Scholar). PKA-mediated phosphorlylation of target proteins, including lipolytic enzymes and lipid droplet-associated proteins, induces an increased release of FAs and glycerol from adipose tissue up to 100-fold. Other hormones that stimulate PKA via Gs protein-coupled receptors include glucagon, parathyroid hormone, thyrotropin, α-melanocyte-stimulating hormone, and adrenocorticotropin. Several antilipolytic factors have been shown to act through inhibitory Gi protein-coupled receptors (10Holm C. Osterlund T. Laurell H. Contreras J.A. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis..Annu. Rev. Nutr. 2000; 20: 365-393Crossref PubMed Scopus (331) Google Scholar). These factors include catecholamines acting through α2-adrenergic receptors (11Lafontan M. Berlan M. Fat cell adrenergic receptors and the control of white and brown fat cell function..J. Lipid Res. 1993; 34: 1057-1091Abstract Full Text PDF PubMed Google Scholar), adenosine (A1-adenosine receptor) (14Larrouy D. Galitzky J. Lafontan M. A1 adenosine receptors in the human fat cell: tissue distribution and regulation of radioligand binding..Eur. J. Pharmacol. 1991; 206: 139-147Crossref PubMed Google Scholar), prostaglandin (E2 receptor) (15Richelsen B. Release and effects of prostaglandins in adipose tissue..Prostaglandins Leukot. Essent. Fatty Acids. 1992; 47: 171-182Abstract Full Text PDF PubMed Scopus (0) Google Scholar), NPY (NPY-1 receptor) (16Bradley R.L Mansfield J.P. Maratos-Flier E. Neuropeptides, including neuropeptide Y and melanocortins, mediate lipolysis in murine adipocytes..Obes. Res. 2005; 13: 653-661Crossref PubMed Google Scholar), and nicotinic acid (GPR109A receptor) (17Offermanns S. The nicotinic acid receptor GPR109A (HM74A or PUMA-G) as a new therapeutic target..Trends Pharmacol. Sci. 2006; 27: 384-390Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The relative distribution of α- and β-adrenergic receptors therefore determines the lipolytic activity in a tissue- and cell type-specific manner. Insulin and insulin-like growth factor represent the most potent inhibitory hormones in lipolysis (9Langin D. Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome..Pharmacol. Res. 2006; 53: 482-491Crossref PubMed Scopus (0) Google Scholar, 18Degerman E. Landstrom T.R. Wijkander J. Holst L.S. Ahmad F. Belfrage P. Manganiello V. Phosphorylation and activation of hormone-sensitive adipocyte phosphodiesterase type 3B..Methods. 1998; 14: 43-53Crossref PubMed Scopus (0) Google Scholar). Their effects are primarily communicated through the insulin receptor (IR), polyphosphorylation of insulin receptor substrates 1–4 (IRS1–4), activation of phosphatidylinositol-3 kinase (PI3K), and the induction of the protein kinase B/AKT(PKB/AKT). Complexity in this essentially linear pathway is added by the divergence at so-called critical nodes that interact with other signaling cascades (19Taniguchi C.M Emanuelli B. Kahn C.R. Critical nodes in signalling pathways: insights into insulin action..Nat. Rev. Mol. Cell Biol. 2006; 7: 85-96Crossref PubMed Scopus (0) Google Scholar). Critical nodes in the IR pathway include the IR and IRS interacting with cytokine and extracellular signal-regulated kinase (ERK) signaling and PI3K activating both 3-phosphoinositide-dependent protein kinases (PDK1 and 2) as well as atypical protein kinases C (PKCλ and ζ). At this point, a signaling network is established that regulates innumerable biological processes (possibly more than 1,000). Lipolysis is affected in multiple steps, including the phosphorylation of phosphodiesterase 3B, causing the degradation of cAMP and loss of PKA activation (18Degerman E. Landstrom T.R. Wijkander J. Holst L.S. Ahmad F. Belfrage P. Manganiello V. Phosphorylation and activation of hormone-sensitive adipocyte phosphodiesterase type 3B..Methods. 1998; 14: 43-53Crossref PubMed Scopus (0) Google Scholar). The mechanisms through which other effectors regulate lipolysis are less well characterized. These include tumor necrosis factor-α (TNFα), growth hormone, the Cide domain-containing proteins (CideN) family of proteins (CIDEA, -B, and -C), and the CopI-ARF vesicle transport machinery described below. The first enzyme discovered to facilitate the hormone-induced catabolism of fat was HSL. Although the initial observations of fasting-induced lipolytic activity in WAT of dogs (20Quagliarello G. Scoz G. The existence of a lipase in adipose tissue..Arch. Sci. Biol. 1932; 17: 513-529Google Scholar) and man (21Renold A.E Marble A. Lipolytic activity of adipose tissue in man and rat..J. Biol. Chem. 1950; 185: 367-375Abstract Full Text PDF PubMed Google Scholar) were reported as early as 1932 and 1950, respectively, it was not until the early 1960s that a WAT-associated lipase was shown to be regulated by hormones and found to be different from lipoprotein lipase (22Bjorntorp P. Furman R.H. Lipolytic activity in rat heart..Am. J. Physiol. 1962; 203: 323-326Crossref PubMed Google Scholar, 23Bjorntorp P. Furman R.H. Lipolytic activity in rat epididymal fat pads..Am. J. Physiol. 1962; 203: 316-322Crossref PubMed Google Scholar, 24Hollenberg C.H Raben M.S. Astwood E.B. The lipolytic response to corticotropin..Endocrinology. 1961; 68: 589-598Crossref PubMed Google Scholar, 25Rizack M.A Activation of an epinephrine-sensitive lipolytic activity from adipose tissue by adenosine 3′,5′-phosphate..J. Biol. Chem. 1964; 239: 392-395Abstract Full Text PDF PubMed Google Scholar). In a landmark study, Vaughan, Berger, and Steinberg (26Vaughan M. Berger J.E. Steinberg D. Hormone-sensitive lipase and monoglyceride lipase activities in adipose tissue..J. Biol. Chem. 1964; 239: 401-409Abstract Full Text PDF PubMed Google Scholar) discovered two independent lipolytic activities in WAT of various mammals and designated these enzymes HSL and MGL. The purification of HSL, cloning of the corresponding cDNA and gene, and high-level heterologous expression of the protein permitted an extensive study of the biochemical properties of the enzyme, its tissue-specific function, and its regulation by various agonists and antagonists. Several comprehensive reviews have been published recently to summarize these results (13Holm C. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis..Biochem. Soc. Trans. 2003; 31: 1120-1124Crossref PubMed Scopus (354) Google Scholar, 27Donsmark M. Langfort J. Holm C. Ploug T. Galbo H. Hormone-sensitive lipase as mediator of lipolysis in contracting skeletal muscle..Exerc. Sport Sci. Rev. 2005; 33: 127-133Crossref PubMed Scopus (18) Google Scholar, 28Haemmerle G. Zimmermann R. Zechner R. Letting lipids go: hormone-sensitive lipase..Curr. Opin. Lipidol. 2003; 14: 289-297Crossref PubMed Scopus (0) Google Scholar, 29Kraemer F.B Shen W.J. Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis..J. Lipid Res. 2002; 43: 1585-1594Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 30Yeaman S.J Hormone-sensitive lipase—new roles for an old enzyme..Biochem. J. 2004; 379: 11-22Crossref PubMed Scopus (0) Google Scholar). HSL exhibits broad substrate specificity capable of hydolyzing TG, diacylglycerol (DG), monoacylglycerol (MG), cholesteryl esters (CEs), retinyl esters (REs), and other ester substrates such as p-nitrophenyl butyrate (31Yeaman S.J Hormone-sensitive lipase—a multipurpose enzyme in lipid metabolism..Biochim. Biophys. Acta. 1990; 1052: 128-132Crossref PubMed Scopus (0) Google Scholar). The relative maximal hydrolysis rates are in the range of 1: 10: 1: 4: 2 for TG: DG: MG:CE: RE. Thus, TGs are actually the worst substrate for HSL among all these natural lipid esters, whereas DGs are the best. HSL slightly favors unsaturated medium-chain FAs over saturated long-chain FAs in TG substrates (32Haemmerle G. Zimmermann R. Hayn M. Theussl C. Waeg G. Wagner E. Sattler W. Magin T.M. Wagner E.F. Zechner R. Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis..J. Biol. Chem. 2002; 277: 4806-4815Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar). However, the substrate specificity toward the length or saturation grade of acyl chains within lipid esters is not very pronounced. Within the TG molecule, HSL preferentially hydrolyzes primary ester bonds in the sn-1 and sn-3 positions (33Fredrikson G. Belfrage P. Positional specificity of hormone-sensitive lipase from rat adipose tissue..J. Biol. Chem. 1983; 258: 14253-14256Abstract Full Text PDF PubMed Google Scholar). Phosphorylation of HSL in vitro modestly increases enzyme activity for TG and CE hydrolysis by 1.5- to 2-fold (34Cook K.G Yeaman S.J. Stralfors P. Fredrikson G. Belfrage P. Direct evidence that cholesterol ester hydrolase from adrenal cortex is the same enzyme as hormone-sensitive lipase from adipose tissue..Eur. J. Biochem. 1982; 125: 245-249Crossref PubMed Scopus (0) Google Scholar, 35Fredrikson G. Stralfors P. Nilsson N.O. Belfrage P. Hormone-sensitive lipase of rat adipose tissue. Purification and some properties..J. Biol. Chem. 1981; 256: 6311-6320Abstract Full Text PDF PubMed Google Scholar). The activity for DG or MG hydrolysis is not affected. The gene for human HSL (LIPE) spans a genomic region of 26 kb and is located on chromosome 19q13.2 (36Holm C. Kirchgessner T.G. Svenson K.L. Fredrikson G. Nilsson S. Miller C.G. Shively J.E. Heinzmann C. Sparkes R.S. Mohandas T. et al.Hormone-sensitive lipase: sequence, expression, and chromosomal localization to 19 cent-q13.3..Science. 1988; 241: 1503-1506Crossref PubMed Google Scholar). In addition to 10 exons that are transcribed into HSL mRNA in all human and mouse tissues, alternative exon usage results in a significant variation in the 5′-region of HSL transcripts (37Blaise R. Grober J. Rouet P. Tavernier G. Daegelen D. Langin D. Testis expression of hormone-sensitive lipase is conferred by a specific promoter that contains four regions binding testicular nuclear proteins..J. Biol. Chem. 1999; 274: 9327-9334Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 38Blaise R. Guillaudeux T. Tavernier G. Daegelen D. Evrard B. Mairal A. Holm C. Jegou B. Langin D. Testis hormone-sensitive lipase expression in spermatids is governed by a short promoter in transgenic mice..J. Biol. Chem. 2001; 276: 5109-5115Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 39Grober J. Laurell H. Blaise R. Fabry B. Schaak S. Holm C. Langin D. Characterization of the promoter of human adipocyte hormone-sensitive lipase..Biochem. J. 1997; 328: 453-461Crossref PubMed Scopus (44) Google Scholar, 40Langin D. Laurell H. Holst L.S. Belfrage P. Holm C. Gene organization and primary structure of human hormone-sensitive lipase: possible significance of a sequence homology with a lipase of Moraxella TA144, an antarctic bacterium..Proc. Natl. Acad. Sci. USA. 1993; 90: 4897-4901Crossref PubMed Google Scholar). In adipose tissue, adrenal gland, and ovary, HSL transcription starts from multiple exons (exons A, B, C, D, or exon 1) within a 13 kb region. Because exons B, C, and D are noncoding, the alternative exon usage does not change the amino acid composition of the enzyme. In contrast, exon A contains coding information for 43 additional amino acids, leading to an alternative enzyme isoform. In testis, two tissue-specific exons (T1 and T2) are used as transcriptional start sites. Exon T1 codes for an additional 300 amino acids, whereas T2 contains no coding sequences. The high variability in exon usage results in various HSL mRNA and protein sizes in adipose tissue, pancreatic β-cells, ovaries, and testis. Multiple potential transcription factor binding elements upstream of each transcriptional start site suggest the possibility of differential transcriptional regulation of HSL in different tissues and under various physiological conditions. According to the HSL domain structure model [the three-dimensional (3D) structure of the enzyme remains to be elucidated], the enzyme can be subdivided into three functional regions (41Holm C. Davis R.C. Osterlund T. Schotz M.C. Fredrikson G. Identification of the active site serine of hormone-sensitive lipase by site-directed mutagenesis..FEBS Lett. 1994; 344: 234-238Crossref PubMed Scopus (55) Google Scholar, 42Osterlund T. Beussman D.J. Julenius K. Poon P.H. Linse S. Shabanowitz J. Hunt D.F. Schotz M.C. Derewenda Z.S. Holm C. Domain identification of hormone-sensitive lipase by circular dichroism and fluorescence spectroscopy, limited proteolysis, and mass spectrometry..J. Biol. Chem. 1999; 274: 15382-15388Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 43Osterlund T. Contreras J.A. Holm C. Identification of essential aspartic acid and histidine residues of hormone-sensitive lipase: apparent residues of the catalytic triad..FEBS Lett. 1997; 403: 259-262Crossref PubMed Scopus (0) Google Scholar, 44Osterlund T. Danielsson B. Degerman E. Contreras J.A. Edgren G. Davis R.C. Schotz M.C. Holm C. Domain-structure analysis of recombinant rat hormone-sensitive lipase..Biochem. J. 1996; 319: 411-420Crossref PubMed Scopus (137) Google Scholar). The N-terminal domain (amino acids 1–300) is believed to mediate enzyme dimerization (45Shen W.J Patel S. Hong R. Kraemer F.B. Hormone-sensitive lipase functions as an oligomer..Biochemistry. 2000; 39: 2392-2398Crossref PubMed Scopus (0) Google Scholar) and interaction with FABP4, a fatty acid binding protein known to enhance HSL enzyme activity (46Shen W.J Liang Y. Hong R. Patel S. Natu V. Sridhar K. Jenkins A. Bernlohr D.A. Kraemer F.B. Characterization of the functional interaction of adipocyte lipid-binding protein with hormone-sensitive lipase..J. Biol. Chem. 2001; 276: 49443-49448Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 47Shen W.J Sridhar K. Bernlohr D.A. Kraemer F.B. Interaction of rat hormone-sensitive lipase with adipocyte lipid-binding protein..Proc. Natl. Acad. Sci. USA. 1999; 96: 5528-5532Crossref PubMed Scopus (0) Google Scholar, 48Smith A.J Thompson B.R. Sanders M.A. Bernlohr D.A. Interaction of the adipocyte fatty acid-binding protein with the hormone-sensitive lipase: regulation by fatty acids and phosphorylation..J. Biol. Chem. 2007; 282: 32424-32432Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The C-terminal domain contains the catalytic triad composed of serine 423, aspartate 703, and histidine 733 (numbering relates to rat HSL, isoform 2) within an α/β hydrolase fold typically found in many lipases and esterases. The third domain represents the regulatory module of the enzyme. This loop region (amino acids 521–669) contains all known phosphorylation sites of HSL. Two major mechanisms determine HSL activity: enzyme phosphorylation by protein kinases and interaction with auxiliary proteins. The pathway of β-adrenergic stimulation involves the PKA-mediated phosphorylation of HSL. Originally it was believed that phosphorylation at two serine residues (563 and 565) (numbering relates to rat HSL, isoform 2) was sufficient to mediate the cAMP-dependent activation of HSL (49Stralfors P. Belfrage P. Phosphorylation of hormone-sensitive lipase by cyclic AMP-dependent protein kinase..J. Biol. Chem. 1983; 258: 15146-15152Abstract Full Text PDF PubMed Google Scholar, 50Stralfors P. Bjorgell P. Belfrage P. Hormonal regulation of hormone-sensitive lipase in intact adipocytes: identification of phosphorylated sites and effects on the phosphorylation by lipolytic hormones and insulin..Proc. Natl. Acad. Sci. USA. 1984; 81: 3317-3321Crossref PubMed Google Scholar). Serine 565 was considered the basal phosphorylation site and serine 563 the regulatory site (51Garton A.J Campbell D.G. Cohen P. Yeaman S.J. Primary structure of the site on bovine hormone-sensitive lipase phosphorylated by cyclic AMP-dependent protein kinase..FEBS Lett. 1988; 229: 68-72Crossref PubMed Scopus (0) Google Scholar, 52Garton A.J Yeaman S.J. Identification and role of the basal phosphorylation site on hormone-sensitive lipase..Eur. J. Biochem. 1990; 191: 245-250Crossref PubMed Scopus (0) Google Scholar, 53Olsson H. Belfrage P. The regulatory and basal phosphorylation sites of hormone-sensitive lipase are dephosphorylated by protein phosphatase-1, 2A and 2C but not by protein phosphatase-2B..Eur. J. Biochem. 1987; 168: 399-405Crossref PubMed Google Scholar). However, PKA-mediated enzyme activation in an HSL variant in which Ser 563 was replaced by alanine led to the discovery of additional PKA phosphorylation sites (54Anthonsen M.W Ronnstrand L. Wernstedt C. Degerman E. Holm C. Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro..J. Biol. Chem. 1998; 273: 215-221Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The identification of these additional serines that are targets for phosphorylation by PKA (Ser 659 and Ser 660) (54Anthonsen M.W Ronnstrand L. Wernstedt C. Degerman E. Holm C. Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro..J. Biol. Chem. 1998; 273: 215-221Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), ERK (Ser 600) (55Greenberg A.S Shen W.J. Muliro K. Patel S. Souza S.C. Roth R.A. Kraemer F.B. Stimulation of lipolysis and hormone-sensitive lipase via the extracellular signal-regulated kinase pathway..J. Biol. Chem. 2001; 276: 45456-45461Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar), glycogen synthase kinase-4 (Ser 563) (56Olsson H. Stralfors P. Belfrage P. Phosphorylation of the basal site of hormone-sensitive lipase by glycogen synthase kinase-4..FEBS Lett. 1986; 209: 175-180Crossref PubMed Scopus (0) Google Scholar), Ca2+/calmodulin-dependent kinase II (Ser 565) (57Garton A.J Campbell D.G. Carling D. Hardie D.G. Colbran R.J. Yeaman S.J. Phosphorylation of bovine hormone-sensitive lipase by the AMP-activated protein kinase. A possible antilipolytic mechanism..Eur. J. Biochem. 1989; 179: 249-254Crossref PubMed Google Scholar), and AMP-activated kinase (Ser 565) (57Garton A.J Campbell D.G. Carling D. Hardie D.G. Colbran R.J. Yeaman S.J. Phosphorylation of bovine hormone-sensitive lipase by the AMP-activated protein kinase. A possible antilipolytic mechanism..Eur. J. Biochem. 1989; 179: 249-254Crossref PubMed Google Scholar) has markedly increased the complexity of posttranslational HSL modification and regulation. Enzymes involved in the dephosphorylation of HSL include protein phosphatases 1, 2A, and 2C (58Olsson H. Belfrage P. Phosphorylation and dephosphorylation of hormone-sensitive lipase. Interactions between the regulatory and basal phosphorylation sites..FEBS Lett. 1988; 232: 78-82Crossref PubMed Scopus (0) Google Scholar). HSL phosphorylation by PKA in response to β-adrenergic stimulation induces the intrinsic HSL enzyme activity only moderately (approximately 2-fold). This is in sharp contrast to findings in intact cells where β-adrenergic stimulation and activation of PKA cause up to a 100-fold induction of FA and glycerol release. Thus, in addition to HSL modification, other mechanisms must contribute to hormone-induced lipolysis. This finding led to the discovery of perilipin (3Brasaemle D.L Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis..J. Lipid Res. 2007; 48: 2547-2559Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 59Granneman J.G Moore H.P. Location, location: protein trafficking and lipolysis in adipocytes..Trends Endocrinol. Metab. 2008; 19: 3-9Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 60Londos C. Szta" @default.
• W2055651091 created "2016-06-24" @default.
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• W2055651091 date "2009-01-01" @default.
• W2055651091 modified "2023-10-16" @default.
• W2055651091 title "Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores" @default.
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