Hormone-sensitive lipase

Hormone-sensitive lipase (EC 3.1.1.79, HSL), also previously known as cholesteryl ester hydrolase (CEH),^[5] sometimes referred to as triacylglycerol lipase, is an enzyme that, in humans, is encoded by the LIPE gene,^[6] and catalyzes the following reaction:

LIPE
Identifiers
Aliases	LIPE, AOMS4, FPLD6, HSL, LHS, lipase E, hormone sensitive type, REH
External IDs	OMIM: 151750 MGI: 96790 HomoloGene: 3912 GeneCards: LIPE
Gene location (Human) Chr. Chromosome 19 (human)^[1] Band 19q13.2 Start 42,401,514 bp^[1] End 42,427,388 bp^[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)^[2] Band 7 A3|7 13.78 cM Start 25,078,952 bp^[2] End 25,098,135 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in subcutaneous adipose tissue pericardium inferior ganglion of vagus nerve middle frontal gyrus inferior olivary nucleus subthalamic nucleus substantia nigra corpus callosum left ventricle pons Top expressed in brown adipose tissue white adipose tissue subcutaneous adipose tissue seminiferous tubule intercostal muscle ankle joint adrenal gland ankle spermatid lip More reference expression data BioGPS More reference expression data
Gene ontology Molecular function lipase activity triglyceride lipase activity hormone-sensitive lipase activity protein binding hydrolase activity protein kinase binding serine hydrolase activity Cellular component cytoplasm membrane lipid droplet plasma membrane caveola cytosol Biological process diacylglycerol catabolic process steroid metabolic process lipid metabolism cholesterol metabolic process lipid catabolic process protein phosphorylation long-chain fatty acid catabolic process metabolism triglyceride catabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3991 16890 Ensembl ENSG00000079435 ENSMUSG00000003123 UniProt Q05469 P54310 RefSeq (mRNA) NM_005357 NM_001039507 NM_010719 RefSeq (protein) NP_005348 NP_001034596 NP_034849 Location (UCSC) Chr 19: 42.4 – 42.43 Mb Chr 7: 25.08 – 25.1 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Hormone-sensitive lipase (HSL) N-terminus
Identifiers
Symbol	HSL_N
Pfam	PF06350
InterPro	IPR010468
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

(1) diacylglycerol + H₂O = monoacylglycerol + a carboxylate

(2) triacylglycerol + H₂O = diacylglycerol + a carboxylate

(3) monoacylglycerol + -H₂O = glycerol + a carboxylate

HSL is an intracellular neutral lipase capable of hydrolyzing a variety of esters.^[7] The enzyme has a long and a short form. The long form is expressed in steroidogenic tissues such as testis, where it converts cholesteryl esters to free cholesterol for steroid hormone production. The short form is expressed in adipose tissue, among others, where it hydrolyzes stored triglycerides to free fatty acids.^[8]

Nomenclature

During fasting-state the increased free fatty acid secretion by adipocyte cells was attributed to the hormone epinephrine, hence the name "hormone-sensitive lipase".^[9] Other catecholamines and adrenocorticotropic hormone (ACTH) can also stimulate such responses. Such enzymatic action plays a key role in providing major source of energy for most cells.

Activation

Extracellular hormones, such as glucagon, epinephrine, Thyroid-Stimulating Hormone, or ACTH, bind to their respective G protein–coupled receptors (GPCR). When a GPCR is activated by its extracellular ligand, a conformational change is induced in the receptor that is transmitted to an attached intracellular heterotrimeric G protein complex by protein domain dynamics. The Gs alpha subunit of the stimulated G protein complex exchanges GDP for GTP in a reaction catalyzed by the GPCR and is released from the complex. The activated Gs alpha subunit binds to and activates an enzyme called adenylyl cyclase, which, in turn, catalyzes the conversion of ATP into cyclic AMP (cAMP). cAMP binds to and activates Protein Kinase A (PKA). It is PKA, activated by a hormone-induced signal transduction cascade, that phosphorylates and activates Hormone Sensitive Lipase (HSL), hence the name. In addition to phosphorylating HSL, PKA phosphorylates perilipins on the surface of lipid droplets within adipose cells. This triggers them to "spread out" and allow for HSL to enter the lipid droplet. ^[10]

Activation of partially purified HSL requires Mg²⁺, ATP, and cyclic AMP.^[11] Activation can be blocked when Ser552 is not phosphorylated because Ser554 is phosphorylated and when the dephosphorylation of Ser552 causes insulin to the insulin receptor, causing inhibition of lipolysis and stimulation of glucose transport.^[12]

Hormone stimulation of lipolysis in humans is similar to rats.^[11]

Function

The main function of hormone-sensitive lipase is to mobilize stored fats.^[13] HSL functions to hydrolyze either a fatty acid from a triacylglycerol molecule, freeing a fatty acid and diglyceride, or a fatty acid from a diacylglycerol molecule, freeing a fatty acid and monoglyceride. This process allows energy metabolism in mammals.^[12] Although Hormone-Sensitive Lipase (HSL) is able to catalyze hydrolysis of triglycerides and diglycerides, another enzyme found in adipose tissue, Adipose triglyceride lipase (ATGL), has a higher affinity for triglycerides than HSL, and ATGL predominantly acts as the enzyme for triglyceride-specific hydrolysis in the adipocyte. Hormone-sensitive lipase, which has 11-fold greater affinity for diglycerides than triglycerides, predominantly cleaves these diglycerides, forming 2-monoglyceride and a free fatty acid.^[14][15]

HSL is activated when the body needs to mobilize energy stores, and so responds positively to catecholamines, ACTH. It is inhibited by insulin.

Another important role is the release of cholesterol from cholesteryl esters for use in the production of steroids^[16] and cholesterol efflux.^[17] Activity of HSL is important in preventing or ameliorating the generation of foam cells in atherosclerosis.^[17]

References

1. GRCh38: Ensembl release 89: ENSG00000079435 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000003123 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Aten RF, Kolodecik TR, Macdonald GJ, Behrman HR (November 1995). "Modulation of cholesteryl ester hydrolase messenger ribonucleic acid levels, protein levels, and activity in the rat corpus luteum". Biology of Reproduction. 53 (5): 1110–7. doi:10.1095/biolreprod53.5.1110. PMID 8527515.
6. Langin D, Laurell H, Holst LS, Belfrage P, Holm C (June 1993). "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". Proceedings of the National Academy of Sciences of the United States of America. 90 (11): 4897–901. Bibcode:1993PNAS...90.4897L. doi:10.1073/pnas.90.11.4897. PMC 46620. PMID 8506334.
7. Kraemer FB, Shen WJ (October 2002). "Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis". Journal of Lipid Research. 43 (10): 1585–94. doi:10.1194/jlr.R200009-JLR200. PMID 12364542.
8. "Entrez Gene: LIPE lipase, hormone-sensitive".
9. Kraemer FB, Shen WJ (October 2002). "Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis". Journal of Lipid Research. 43 (10): 1585–94. doi:10.1194/jlr.R200009-JLR200. PMID 12364542.
10. Cox M, Nelson DR, Lehninger AL (2005). Lehninger principles of biochemistry. San Francisco: W.H. Freeman. ISBN 0-7167-4339-6.
11. Khoo JC, Aquino AA, Steinberg D (April 1974). "The mechanism of activation of hormone-sensitive lipase in human adipose tissue". The Journal of Clinical Investigation. 53 (4): 1124–31. doi:10.1172/JCI107650. PMC 333098. PMID 4360857.
12. Quinn DM, Medhekar R, Baker NR (1999). "Ester Hydrolysis". Comprehensive Natural Products Chemistry. pp. 101–137. doi:10.1016/B978-0-08-091283-7.00110-7. ISBN 978-0-08-091283-7.
13. Mehta S (October 2013). "Mobilization and Cellular Uptake of Stored Fats (Triacylglycerols) with Animation". Animations, Biochemistry Animations, Biochemistry Notes. PharmaXChange.info. Retrieved 2020-04-02.
14. Crabtree B, Newsholme EA (December 1972). "The activities of lipases and carnitine palmitoyltransferase in muscles from vertebrates and invertebrates". The Biochemical Journal. 130 (3): 697–705. doi:10.1042/bj1300697. PMC 1174508. PMID 4664927.
15. de Meijer J (1998-05-01). "Hormone sensitive lipase: structure, function and regulation" (PDF). demeijer.com. Retrieved 2009-02-04. {{cite journal}}: Cite journal requires |journal= (help)
16. Kraemer FB (February 2007). "Adrenal cholesterol utilization". Molecular and Cellular Endocrinology. 265–266: 42–5. doi:10.1016/j.mce.2006.12.001. PMID 17208360. S2CID 35354595.
17. Ouimet M, Marcel YL (March 2012). "Regulation of lipid droplet cholesterol efflux from macrophage foam cells". Arteriosclerosis, Thrombosis, and Vascular Biology. 32 (3): 575–81. doi:10.1161/ATVBAHA.111.240705. PMID 22207731.

Further reading

• Kraemer FB, Shen WJ (October 2002). "Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis". Journal of Lipid Research. 43 (10): 1585–94. doi:10.1194/jlr.R200009-JLR200. PMID 12364542.
• Langfort J, Donsmark M, Ploug T, Holm C, Galbo H (August 2003). "Hormone-sensitive lipase in skeletal muscle: regulatory mechanisms". Acta Physiologica Scandinavica. 178 (4): 397–403. doi:10.1046/j.1365-201X.2003.01155.x. PMID 12864745.
• Holm C (December 2003). "Molecular mechanisms regulating hormone-sensitive lipase and lipolysis". Biochemical Society Transactions. 31 (Pt 6): 1120–4. doi:10.1042/BST0311120. PMID 14641008.
• Holm C, Kirchgessner TG, Svenson KL, Fredrikson G, Nilsson S, Miller CG, et al. (September 1988). "Hormone-sensitive lipase: sequence, expression, and chromosomal localization to 19 cent-q13.3". Science. 241 (4872): 1503–6. Bibcode:1988Sci...241.1503H. doi:10.1126/science.3420405. PMID 3420405.
• Levitt RC, Liu Z, Nouri N, Meyers DA, Brandriff B, Mohrenweiser HM (1995). "Mapping of the gene for hormone sensitive lipase (LIPE) to chromosome 19q13.1-->q13.2". Cytogenetics and Cell Genetics. 69 (3–4): 211–4. doi:10.1159/000133966. PMID 7698015.
• Langin D, Laurell H, Holst LS, Belfrage P, Holm C (June 1993). "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". Proceedings of the National Academy of Sciences of the United States of America. 90 (11): 4897–901. Bibcode:1993PNAS...90.4897L. doi:10.1073/pnas.90.11.4897. PMC 46620. PMID 8506334.
• Holst LS, Langin D, Mulder H, Laurell H, Grober J, Bergh A, et al. (August 1996). "Molecular cloning, genomic organization, and expression of a testicular isoform of hormone-sensitive lipase". Genomics. 35 (3): 441–7. doi:10.1006/geno.1996.0383. PMID 8812477.
• Anthonsen MW, Rönnstrand L, Wernstedt C, Degerman E, Holm C (January 1998). "Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro". The Journal of Biological Chemistry. 273 (1): 215–21. doi:10.1074/jbc.273.1.215. PMID 9417067.
• Shen WJ, Sridhar K, Bernlohr DA, Kraemer FB (May 1999). "Interaction of rat hormone-sensitive lipase with adipocyte lipid-binding protein". Proceedings of the National Academy of Sciences of the United States of America. 96 (10): 5528–32. Bibcode:1999PNAS...96.5528S. doi:10.1073/pnas.96.10.5528. PMC 21893. PMID 10318917.
• Syu LJ, Saltiel AR (July 1999). "Lipotransin: a novel docking protein for hormone-sensitive lipase". Molecular Cell. 4 (1): 109–15. doi:10.1016/S1097-2765(00)80192-6. PMID 10445032.
• Shen WJ, Patel S, Hong R, Kraemer FB (March 2000). "Hormone-sensitive lipase functions as an oligomer". Biochemistry. 39 (9): 2392–8. doi:10.1021/bi992283h. PMID 10694408.
• Johnson WJ, Jang SY, Bernard DW (August 2000). "Hormone sensitive lipase mRNA in both monocyte and macrophage forms of the human THP-1 cell line". Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology. 126 (4): 543–52. doi:10.1016/S0305-0491(00)00220-0. PMID 11026666.
• Laurin NN, Wang SP, Mitchell GA (November 2000). "The hormone-sensitive lipase gene is transcribed from at least five alternative first exons in mouse adipose tissue". Mammalian Genome. 11 (11): 972–8. doi:10.1007/s003350010185. PMID 11063252. S2CID 25295956.
• Greenberg AS, Shen WJ, Muliro K, Patel S, Souza SC, Roth RA, Kraemer FB (November 2001). "Stimulation of lipolysis and hormone-sensitive lipase via the extracellular signal-regulated kinase pathway". The Journal of Biological Chemistry. 276 (48): 45456–61. doi:10.1074/jbc.M104436200. PMID 11581251.
• Talmud PJ, Palmen J, Luan J, Flavell D, Byrne CD, Waterworth DM, Wareham NJ (November 2001). "Variation in the promoter of the human hormone sensitive lipase gene shows gender specific effects on insulin and lipid levels: results from the Ely study". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1537 (3): 239–44. doi:10.1016/s0925-4439(01)00076-x. PMID 11731226.
• Kolehmainen M, Vidal H, Ohisalo JJ, Pirinen E, Alhava E, Uusitupa MI (January 2002). "Hormone sensitive lipase expression and adipose tissue metabolism show gender difference in obese subjects after weight loss". International Journal of Obesity and Related Metabolic Disorders. 26 (1): 6–16. doi:10.1038/sj.ijo.0801858. PMID 11791141.
• Smih F, Rouet P, Lucas S, Mairal A, Sengenes C, Lafontan M, et al. (February 2002). "Transcriptional regulation of adipocyte hormone-sensitive lipase by glucose". Diabetes. 51 (2): 293–300. doi:10.2337/diabetes.51.2.293. PMID 11812735.
• Mairal A, Melaine N, Laurell H, Grober J, Holst LS, Guillaudeux T, et al. (February 2002). "Characterization of a novel testicular form of human hormone-sensitive lipase". Biochemical and Biophysical Research Communications. 291 (2): 286–90. doi:10.1006/bbrc.2002.6427. PMID 11846402.
• Ylitalo K, Nuotio I, Viikari J, Auwerx J, Vidal H, Taskinen MR (May 2002). "C3, hormone-sensitive lipase, and peroxisome proliferator-activated receptor gamma expression in adipose tissue of familial combined hyperlipidemia patients". Metabolism. 51 (5): 664–70. doi:10.1053/meta.2002.32032. PMID 11979403.

External links

• Hormone-Sensitive+Lipase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)