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Information on EC 3.1.1.79 - hormone-sensitive lipase and Organism(s) Mus musculus and UniProt Accession P54310
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3.1.1.79 hormone-sensitive lipaseIUBMB Comments
This enzyme is a serine hydrolase. Compared with other lipases, hormone-sensitive lipase has a uniquely broad substrate specificity. It hydrolyses all acylglycerols (triacylglycerol, diacylglycerol and monoacylglycerol) [2,3,4] as well as cholesteryl esters [2,4], steroid fatty acid esters , retinyl esters and p-nitrophenyl esters [4,7]. It exhibits a preference for the 1- or 3-ester bond of its acylglycerol substrate compared with the 2-ester bond . The enzyme shows little preference for the fatty acids in the triacylglycerol, although there is some increase in activity with decreasing chain length. The enzyme activity is increased in response to hormones that elevate intracellular levels of cAMP.
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Word Map
- 3.1.1.79
- adipose
-
lipolysis
- adipocytes
- triglyceride
- lipoprotein
- obesity
- triacylglycerols
- peroxisome
- droplet
- lipases
-
perilipin
-
proliferator-activated
-
obese
-
lipogenesis
-
high-fat
- leptin
- camp
- epididymal
- catecholamine
-
cholesteryl
- carnitine
- abdominal
-
antilipolytic
-
lipogenic
- adiponectin
- nefas
- preadipocytes
- esterases
-
amp-activated
- isoproterenol
-
depot
-
nonesterified
- monoglyceride
-
3.1.1.3
- synthesis
- drug development
-
isoproterenol-stimulated
-
intramyocellular
-
catecholamine-stimulated
- triolein
- protein-1c
-
droplet-associated
- diagnostics
-
antiobesity
-
palmitoyltransferase-1
-
catecholamine-induced
- monoacylglycerols
-
retroperitoneal
-
pnpla2
-
gxsxg
-
adipocyte-specific
- medicine
-
re-esterification
-
beta3-adrenergic
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Reaction Schemes
Synonyms
hormone-sensitive lipase, alpha/beta hydrolase, hsl protein, secreted lipase, est22, est25, mgmdl2, cardiac hsl, est06, mglip2, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
HSL
HSL
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
diacylglycerol acylhydrolase
This enzyme is a serine hydrolase. Compared with other lipases, hormone-sensitive lipase has a uniquely broad substrate specificity. It hydrolyses all acylglycerols (triacylglycerol, diacylglycerol and monoacylglycerol) [2,3,4] as well as cholesteryl esters [2,4], steroid fatty acid esters [5], retinyl esters [6] and p-nitrophenyl esters [4,7]. It exhibits a preference for the 1- or 3-ester bond of its acylglycerol substrate compared with the 2-ester bond [8]. The enzyme shows little preference for the fatty acids in the triacylglycerol, although there is some increase in activity with decreasing chain length. The enzyme activity is increased in response to hormones that elevate intracellular levels of cAMP.
CAS REGISTRY NUMBER
COMMENTARY
9001-62-1
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
cholesteryl ester + H2O
cholesterol + a carboxylate
-
overexpression of HSL increases the supply of free cholesterol as a ligand for liver X receptor, thereby stimulates the expression of ABCA1 gene in macrophages
-
-
?
additional information
?
-
hormone-sensitive lipase is a key enzyme of acylglycerol metabolism in white adipose tissue. The hormone-sensitive lipase activity in white adipose tissue is important for metabolic plasticity and inflammation. Hormone-sensitive lipase-mediated lipolysis and subsequent downstream free fatty acid signaling are important components of adipose tissue remodeling following acute and chronic beta3-adrenergic receptor activation
-
-
?
additional information
?
-
-
hormone-sensitive lipase is required for high-density lipoprotein cholesteryl ester-supported adrenal steroidogenesis
-
-
?
additional information
?
-
-
hypothesis that HSL functions as a cholesterol ester hydrolase rather than as a lipase with regard to GSIS and beta-cells
-
-
?
additional information
?
-
-
sn-1,3-diacylglycerol is the preferred substrate for the consecutive hydrolysis by hormone-sensitive lipase, the enzyme is less active with sn-1,2-diacylglycerol
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
additional information
?
-
hormone-sensitive lipase is a key enzyme of acylglycerol metabolism in white adipose tissue. The hormone-sensitive lipase activity in white adipose tissue is important for metabolic plasticity and inflammation. Hormone-sensitive lipase-mediated lipolysis and subsequent downstream free fatty acid signaling are important components of adipose tissue remodeling following acute and chronic beta3-adrenergic receptor activation
-
-
?
additional information
?
-
-
hormone-sensitive lipase is required for high-density lipoprotein cholesteryl ester-supported adrenal steroidogenesis
-
-
?
additional information
?
-
-
sn-1,3-diacylglycerol is the preferred substrate for the consecutive hydrolysis by hormone-sensitive lipase, the enzyme is less active with sn-1,2-diacylglycerol
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
L-methionine
-
L-methionine enhances the enzyme activaty in absence of tumor necrosis factor-alpha, but inhibits it in presence of TNF-alpha
additional information
-
incubation with LDL augments the accumulation of cholesteryl ester in the HSL-deficient hepatocytes
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
L-methionine
-
L-methionine enhances the enzyme activity in absence of tumor necrosis factor-alpha, but inhibits it in presence of TNF-alpha
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
postmeiotic germ cells express a specific HSL isoform that includes a 313 amino acid N-terminus encoded by a testis-specific exon T1
-
HSL accounts for the entire neutral cholesteryl ester hydrolase activity of enterocytes
-
adipocytes retrovirally engineered from murine embryonic fibroblasts
-
the beta-cell isoform of HSL is involved in maintaining lipid homeostasis in islets and contributes to the proper control of glucose stimulated insulin secretion
-
located in close association to insulin granules in beta-cells
-
adipose triglyceride lipase and hormone-sensitive lipase are responsible for more than 95% of the triglyceride hydrolase activity present in murine white adipose tissue
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
hyperleptinemia equally suppresses the food intake in wild-type and Hsl KO mice. Leptin-mediated fat loss and glucose-lowering are significantly blunted in the absence of HSL when leptin is overexpressed by recombinant adenovirus carrying leptin. Hsl KO mice have a tendency to retain more fat than wild-type mice in the face of hyperleptinemia
malfunction
physiological function
additional information
malfunction
-
depletion of the enzyme affects lipoprotein-derived cellular cholesterol influx, diminishes the supply of cholesterol to the mitochondria, and results in the repression of steroidogenic acute regulatory protein and phospho-steroidogenic acute regulatory protein levels
malfunction
-
enzyme-deficient mice accumulate sn-1,3-diacylglycerol and sn-2,3-diacylglycerol in white adipose tissue
malfunction
-
in male mice, deficiency of hormone sensitive lipase causes deficient spermatogenesis, azoospermia, and infertility
physiological function
-
hormone-sensitive lipase modulates adipose metabolism by providing intrinsic ligands or pro-ligands for PPARgama, mechanism, overview
physiological function
-
the catalytic function of hormone-sensitive lipase is essential for spermatogenesis in male mice, while the presence of the enzyme's N-terminal testis-specific fragment is not essential
physiological function
-
the enzyme is crucial for the hydrolysis of diacylglycerol within the lipolytic cascade
physiological function
-
the enzyme is primarily involved in catalyzing cholesteryl ester hydrolysis and plays an important role in the regulation of cAMP-mediated steroidogenic acute regulatory protein expression and steroidogenesis through modulation of liver X receptor pathways. The enzyme-dependent regulation of steroidogenesis predominantly involves liver X recetor signaling. Enzyme-mediated steroidogenesis entails enhanced oxysterol production. Hormonal control of the enzyme activity is primarily mediated by the phosphorylation of serine residues, Ser563, Ser659, and Ser660
physiological function
-
adipose triglyceride lipase Atgl and hormone-sensitive lipase Hsl mRNA expression is time-dependently increased by fasting, along with other fatty acid metabolism genes (Pparx02, Cd36, and Aox). ATGL and HSL protein levels are induced by 239 and 322%, respectively. There is an increase in ATGL phosphorylation at the AMPK-regulated serine 406 site in the 14-3-3 binding motif, and an increase in HSL phosphorylation at serines 565 and 660 that are regulated by AMPK and PKA, respectively
additional information
-
hormone-sensitive lipase is significantly increased in white adipose tissue of fasted JunB-KO mice, after JunB silencing through knockdown via lentiviruses harboring a shRNA construct targeted against JunB, the effect might be due to a systemic effect/factor in JunB-KO mice, like the significantly decreased insulin levels, metbaolic phenotype, overview
additional information
-
cells deficient in liver X receptors exhibit decreased enzyme responsiveness
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). LIPS_MOUSE
759
0
83348
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
phosphoprotein
-
perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms
phosphoprotein
-
reversible phosphorylation, the enzyme is phosphorylated at Ser660, Ser563, and Ser565, activation of the protein kinase A pathway, by a cAMP analogue dibutyryl cyclic AMP, enhances expression of the enzyme and its phosphorylationat Ser660 and Ser563, but not at Ser565
phosphoprotein
-
fasting induces an increase in HSL phosphorylation at serines 565 and 660 that is regulated by PKA
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
HSL(-/-) mice
-
feeding with a high-cholesterol diet induces hepatic cholesteryl ester accumulation, show reduced activity of cholesteryl ester hydrolase, but not of TG lipase. Hepatocytes show reduced activity of cholesteryl ester hydrolase and contain more cholesteryl ester than those from HSL(+/+) mice even without the incubation with lipoproteins
Lep(ob/ob)/HSL(-/-)
-
mice lacking both leptin and HSL (Lep(ob/ob)/HSL(-/-)) show massive accumulation of cholesteryl ester in the liver compared with Lep(ob/ob)/HSL(+/+) mice, while triacylglycerol accumulation was modest
additional information
additional information
beta cell-specific knockout of hormone-sensitive lipase fasting basal plasma glucose levels are significantly elevated in mice lacking HSL in beta cells. Insulin content and beta cell mass are increased in beta HSL KO mice
additional information
-
beta cell-specific knockout of hormone-sensitive lipase fasting basal plasma glucose levels are significantly elevated in mice lacking HSL in beta cells. Insulin content and beta cell mass are increased in beta HSL KO mice
additional information
-
generation of HSL-/- mice, rosiglitazone, a synthetic antidiabetic drug, treatment leads to restoration of reduced body weight of the mutant mice, and to an increase in body weight compared to controls, overview
additional information
-
cells overexpressing the enzyme increase the efficacy of liver X receptor ligands on steroidogenic acute regulatory protein expression and steroid synthesis, suggesting enzyme-mediated steroidogenesis entails enhanced oxysterol production
additional information
-
generation of mice that express mutant enzyme transgenes only in postmeiotic germ cells on an enzyme-deficient background: one transgene expressed's human enzyme lacking enzyme activity but containing the testis-specific N-terminus, resulting in infertile HSL-/-muttg mice. The other transgene expresses catalytically inactive enzyme with the testis-specific N-terminal peptide, resulting in HSL-/-atg mice. Infertile HSL-/-muttg mice show abnormal histology of the seminiferous epithelium and absence of spermatozoa in the epididymal lumen. In contrast, HSL-/-atg mice have normal fertility and normal testicular morphology
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene Lipe, encodes a specific HSL isoform including a 313 amino acid N-terminus encoded by the testis-specific exon T1
-
heart-specific HSL-overexpressing mice, transgenic (Tg) mice with heart-specific HSL overexpression are generated, and cardiac histology, function, lipid profile, and gene expressions are analyzed after induction of diabetes by streptozotocin. HSL overexpression inhibits cardiac steatosis in streptozotocin (STZ)-induced diabetic mice
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
activation of the protein kinase A pathway, by a cAMP analogue dibutyryl cyclic AMP, enhances expression of the enzyme and its phosphorylation at Ser660 and Ser563, but not at Ser565, concomitant with increased enzyme activity. An increase in enzyme is correlated with the liver X receptor target genes, steroid receptor element-binding protein 1c, and ATP binding cassette transporter A1
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
hyperleptinemia equally suppresses the food intake in wild-type and Hsl KO mice. Leptin-mediated fat loss and glucose-lowering are significantly blunted in the absence of HSL when leptin is overexpressed by recombinant adenovirus carrying leptin. Hsl KO mice have a tendency to retain more fat than wild-type mice in the face of hyperleptinemia
medicine
medicine
-
cardiac HSL can be a therapeutic target for regulating diabetic cardiomyopathy
medicine
-
adipose triglyceride lipase Atgl and hormone-sensitive lipase Hsl mRNA expression is time-dependently increased by fasting, along with other fatty acid metabolism genes (Pparx02, Cd36, and Aox). ATGL and HSL protein levels are induced by 239 and 322%, respectively. There is an increase in ATGL phosphorylation at the AMPK-regulated serine 406 site in the 14-3-3 binding motif, and an increase in HSL phosphorylation at serines 565 and 660 that are regulated by AMPK and PKA, respectively
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Yeaman, S.J.
Hormone-sensitive lipase - new roles for an old enzyme
Biochem. J.
379
11-22
2004
Homo sapiens, Mus musculus, Rattus norvegicus
Shih, M.F.; Taberner, P.V.
Effects of acute and chronic ethanol administration on the response of mouse adipose tissue hormone-sensitive lipase to alpha(2)-adrenoceptor activation bu UK 14304
Alcohol Alcohol.
36
381-387
2001
Mus musculus
Haemmerle, G.; Zimmermann, R.; Zechner, R.
Letting lipids go: hormone-sensitive lipase
Curr. Opin. Lipidol.
14
289-297
2003
Mus musculus
Osterlund, T.
Structure-function relationships of hormone-sensitive lipase
Eur. J. Biochem.
268
1899-1907
2001
Homo sapiens, Mus musculus, Rattus norvegicus
Kraemer, F.B.; Shen, W.J.; Harada, K.; Patel, S.; Osuga, J.I.; Ishibashi, S.; Azhar, S.
Hormone-sensitive lipase is required for high-density lipoprotein cholesteryl ester-supported adrenal steroidogenesis
Mol. Endocrinol.
18
549-557
2004
Mus musculus
Mottillo, E.P.; Shen, X.J.; Granneman, J.G.
Role of hormone-sensitive lipase in beta-adrenergic remodeling of white adipose tissue
Am. J. Physiol. Endocrinol. Metab.
293
E1188-E1197
2007
Mus musculus (P54310)
Shen, W.J.; Liang, Y.; Wang, J.; Harada, K.; Patel, S.; Michie, S.A.; Osuga, J.; Ishibashi, S.; Kraemer, F.B.
Regulation of hormone-sensitive lipase in islets
Diabetes Res. Clin. Pract.
75
14-26
2007
Mus musculus
Miyoshi, H.; Souza, S.C.; Zhang, H.H.; Strissel, K.J.; Christoffolete, M.A.; Kovsan, J.; Rudich, A.; Kraemer, F.B.; Bianco, A.C.; Obin, M.S.; Greenberg, A.S.
Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms
J. Biol. Chem.
281
15837-15844
2006
Mus musculus
Schweiger, M.; Schreiber, R.; Haemmerle, G.; Lass, A.; Fledelius, C.; Jacobsen, P.; Tornqvist, H.; Zechner, R.; Zimmermann, R.
Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism
J. Biol. Chem.
281
40236-40241
2006
Mus musculus
Ueno, M.; Suzuki, J.; Zenimaru, Y.; Takahashi, S.; Koizumi, T.; Noriki, S.; Yamaguchi, O.; Otsu, K.; Shen, W.J.; Kraemer, F.B.; Miyamori, I.
Cardiac overexpression of hormone-sensitive lipase inhibits myocardial steatosis and fibrosis in streptozotocin diabetic mice
Am. J. Physiol. Endocrinol. Metab.
294
E1109-E1118
2008
Mus musculus, Mus musculus C57BL/6
Tazoe, F.; Yagyu, H.; Okazaki, H.; Igarashi, M.; Eto, K.; Nagashima, S.; Inaba, T.; Shimano, H.; Osuga, J.; Ishibashi, S.
Induction of ABCA1 by overexpression of hormone-sensitive lipase in macrophages
Biochem. Biophys. Res. Commun.
376
111-115
2008
Mus musculus
Larsson, S.; Wierup, N.; Sundler, F.; Eliasson, L.; Holm, C.
Lack of cholesterol mobilization in islets of hormone-sensitive lipase deficient mice impairs insulin secretion
Biochem. Biophys. Res. Commun.
376
558-562
2008
Mus musculus
Fex, M.; Haemmerle, G.; Wierup, N.; Dekker-Nitert, M.; Rehn, M.; Ristow, M.; Zechner, R.; Sundler, F.; Holm, C.; Eliasson, L.; Mulder, H.
A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis
Diabetologia
52
271-280
2009
Mus musculus (P54310), Mus musculus
Sekiya, M.; Osuga, J.; Yahagi, N.; Okazaki, H.; Tamura, Y.; Igarashi, M.; Takase, S.; Harada, K.; Okazaki, S.; Iizuka, Y.; Ohashi, K.; Yagyu, H.; Okazaki, M.; Gotoda, T.; Nagai, R.; Kadowaki, T.; Shimano, H.; Yamada, N.; Ishibashi, S.
Hormone-sensitive lipase is involved in hepatic cholesteryl ester hydrolysis
J. Lipid Res.
49
1829-1838
2008
Mus musculus
Shen, W.J.; Yu, Z.; Patel, S.; Jue, D.; Liu, L.F.; Kraemer, F.B.
Hormone-sensitive lipase modulates adipose metabolism through PPARgamma
Biochim. Biophys. Acta
1811
9-16
2011
Mus musculus, Mus musculus C57/BL6J
Kawasaki, M.; Miura, Y.; Yagasaki, K.
Effects of sulfur amino acids, L-methionine, L-cystine and L-cysteine on lipoprotein lipase and hormone-sensitive lipase in differentiated mouse 3T3-L1 adipocytes
Cytotechnology
62
225-233
2010
Mus musculus
Pinent, M.; Prokesch, A.; Hackl, H.; Voshol, P.J.; Klatzer, A.; Walenta, E.; Panzenboeck, U.; Kenner, L.; Trajanoski, Z.; Hoefler, G.; Bogner-Strauss, J.G.
Adipose triglyceride lipase and hormone-sensitive lipase are involved in fat loss in JunB-deficient mice
Endocrinology
152
2678-2689
2011
Mus musculus
Wang, S.P.; Wu, J.W.; Bourdages, H.; Lefebvre, J.F.; Casavant, S.; Leavitt, B.R.; Labuda, D.; Trasler, J.; Smith, C.E.; Hermo, L.; Mitchell, G.A.
The catalytic function of hormone-sensitive lipase is essential for fertility in male mice
Endocrinology
155
3047-3053
2014
Mus musculus
Eichmann, T.O.; Kumari, M.; Haas, J.T.; Farese, R.V.; Zimmermann, R.; Lass, A.; Zechner, R.
Studies on the substrate and stereo/regioselectivity of adipose triglyceride lipase, hormone-sensitive lipase, and diacylglycerol-O-acyltransferases
J. Biol. Chem.
287
41446-41457
2012
Mus musculus, Mus musculus C57BL/6
Manna, P.R.; Cohen-Tannoudji, J.; Counis, R.; Garner, C.W.; Huhtaniemi, I.; Kraemer, F.B.; Stocco, D.M.
Mechanisms of action of hormone-sensitive lipase in mouse Leydig cells: its role in the regulation of the steroidogenic acute regulatory protein
J. Biol. Chem.
288
8505-8518
2013
Mus musculus, Mus musculus MA-10
Marvyn, P.M.; Bradley, R.M.; Button, E.B.; Mardian, E.B.; Duncan, R.E.
Fasting upregulates adipose triglyceride lipase and hormone-sensitive lipase levels and phosphorylation in mouse kidney
Biochem. Cell Biol.
93
262-267
2015
Mus musculus
Takanashi, M.; Taira, Y.; Okazaki, S.; Takase, S.; Kimura, T.; Li, C.C.; Xu, P.F.; Noda, A.; Sakata, I.; Kumagai, H.; Ikeda, Y.; Iizuka, Y.; Yahagi, N.; Shimano, H.; Osuga, J.I.; Ishibashi, S.; Kadowaki, T.; Okazaki, H.
Role of hormone-sensitive lipase in leptin-promoted fat loss and glucose lowering
J. Artheroscler. Thromb.
24
110-1116
2017
Mus musculus (P54310)
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