Hormone-sensitive lipase explained

Hormone-sensitive lipase (HSL), also previously known as cholesteryl ester hydrolase (CEH),^[1] sometimes referred to as triacylglycerol lipase, is an enzyme that, in humans, is encoded by the LIPE gene,^[2] and catalyzes the following reaction:

(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.^[3] 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.^[4]

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".^[5] 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 adrenocorticotropic hormone (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. ^[6]

Activation of partially purified HSL requires Mg²⁺, ATP, and cyclic AMP.^[7] 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.

Hormone stimulation of lipolysis in humans is similar to rats.^[7]

Function

The main function of hormone-sensitive lipase is to mobilize stored fats.^[8] 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.^[9] Although 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.^{[10] [11]}

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

Another important role is the release of cholesterol from cholesteryl esters for use in the production of steroids^[12] and cholesterol efflux.^[13] Activity of HSL is important in preventing or ameliorating the generation of foam cells in atherosclerosis.^[13]

References

Further reading

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

Notes and References

1. Aten RF, Kolodecik TR, Macdonald GJ, Behrman HR . 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 . November 1995 . 8527515 . 10.1095/biolreprod53.5.1110 . free .
2. Langin D, Laurell H, Holst LS, 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 . Proceedings of the National Academy of Sciences of the United States of America . 90 . 11 . 4897–901 . June 1993 . 8506334 . 46620 . 10.1073/pnas.90.11.4897 . 1993PNAS...90.4897L . free .
3. Kraemer FB, Shen WJ . Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis . Journal of Lipid Research . 43 . 10 . 1585–94 . October 2002 . 12364542 . 10.1194/jlr.R200009-JLR200 . free .
4. Web site: Entrez Gene: LIPE lipase, hormone-sensitive.
5. Kraemer FB, Shen WJ . Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis . Journal of Lipid Research . 43 . 10 . 1585–94 . October 2002 . 12364542 . 10.1194/jlr.R200009-JLR200 . free .
6. Book: Cox M, Nelson DR, Lehninger AL . Lehninger principles of biochemistry . W.H. Freeman . San Francisco . 2005 . 0-7167-4339-6 . registration .
7. Khoo JC, Aquino AA, Steinberg D . The mechanism of activation of hormone-sensitive lipase in human adipose tissue . The Journal of Clinical Investigation . 53 . 4 . 1124–31 . April 1974 . 4360857 . 333098 . 10.1172/JCI107650 .
8. Web site: Mehta S . Mobilization and Cellular Uptake of Stored Fats (Triacylglycerols) with Animation . Animations, Biochemistry Animations, Biochemistry Notes . PharmaXChange.info . October 2013 . 2020-04-02 .
9. Book: 10.1016/B978-0-08-091283-7.00110-7 . Ester Hydrolysis . Comprehensive Natural Products Chemistry . 1999 . Quinn DM, Medhekar R, Baker NR . 101–137 . 978-0-08-091283-7 .
10. Crabtree B, Newsholme EA . The activities of lipases and carnitine palmitoyltransferase in muscles from vertebrates and invertebrates . The Biochemical Journal . 130 . 3 . 697–705 . December 1972 . 4664927 . 1174508 . 10.1042/bj1300697 .
11. de Meijer J . Hormone sensitive lipase: structure, function and regulation . demeijer.com . 1998-05-01 . 2009-02-04 .
12. Kraemer FB . Adrenal cholesterol utilization . Molecular and Cellular Endocrinology . 265-266 . 42–5 . February 2007 . 17208360 . 10.1016/j.mce.2006.12.001 . 35354595 .
13. Ouimet M, Marcel YL . Regulation of lipid droplet cholesterol efflux from macrophage foam cells . Arteriosclerosis, Thrombosis, and Vascular Biology . 32 . 3 . 575–81 . March 2012 . 22207731 . 10.1161/ATVBAHA.111.240705 . free .