Adipose triglyceride lipase explained

Adipose triglyceride lipase, also known as patatin-like phospholipase domain-containing protein 2 and ATGL, is an enzyme that in humans is encoded by the PNPLA2 gene.^{[1] [2] [3]} ATGL catalyses the first reaction of lipolysis,^[4] where triacylglycerols are hydrolysed to diacylglycerols.^[5]

Properties

ATGL has very high substrate specificity for triacylglycerols.^[6] It contains a catalytic dyad using serine-aspartic acid.

Function

ATGL catalyses the first reaction of lipolysis. It hydrolysis triacylglycerols to diacylglycerols by attacking the fatty acid attached to carbon-3 of glycerol.

ATGL acts as a control mechanism of lipolysis, as variations in diacylglycerol concentration impact enzymes in later stages of lipolysis.^[7]

Clinical significance

Defects in ATGL can cause problems in lipolysis, leading to neutral lipid storage disease.^[8] As triacylglycerols are not hydrolysed to diacylglycerols, there is a build-up of triacylglycerol droplets in granulocytes.

ATGL is regulated by insulin, and is similar to structure with adiponutrin, a protein that is regulated by nutrition. When there is a lack of insulin, there is an increased expression of the ATGL protein. Because adipose tissue triglyceride is a major form of energy storage, the study of how ATGL regulation and dysregulation can lead to potential problems will increase understanding of the pathophysiology behind metabolic disorders.^[9] ATGL is also the key enzyme that would be able to maintain a balance between mobilization and lipid storage. Lipolytic breakdown performed by ATGL would impact regulatory functions including but not limited to cell death, growth, signaling, metabolism, and gene expression.^{[10] [11]}

Regulation

There must be mechanisms set to maintain the balance between energy storage, and energy release; a dysregulation in the equilibrium result in metabolic disorder, a prime one being diabetes. Adipose Triglyceride Lipase (ATGL) can undergo activation through two different pathways: transcriptionally and through post-translational modification. Through the transcriptional pathway, Beta-adrenergic, a receptor that can form a complex with agonist such as epinephrine, results in the signal transduction pathway activation of Adipose Triglyceride Lipase (ATGL). The alternative pathway is through a post-translational modification specifically phosphorylation of a serine 406 residue located on the enzyme by a kinase known as AMP activated protein kinase (AMPK). Both pathways facilitate the activation of the enzyme, resulting in the breakdown of triglyceride.^[12]

Insulin is a hormone that regulate the enzyme ATGL, it inhibits the enzyme by favoring lipid storage over lipolysis. One pathway of inhibition of ATGL when insulin is present is the activation of SIRT1, which inhibits FoxO1.^[13] Specifically, FoxO1 is repressed from localizing in the nucleus by deacetylation in adipocytes.^[14]

Further reading

• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA . Large-scale concatenation cDNA sequencing . Genome Research . 7 . 4 . 353–358 . April 1997 . 9110174 . 139146 . 10.1101/gr.7.4.353 .
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM . Functional proteomics mapping of a human signaling pathway . Genome Research . 14 . 7 . 1324–1332 . July 2004 . 15231748 . 442148 . 10.1101/gr.2334104 .
• Villena JA, Roy S, Sarkadi-Nagy E, Kim KH, Sul HS . Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis . The Journal of Biological Chemistry . 279 . 45 . 47066–47075 . November 2004 . 15337759 . 10.1074/jbc.M403855200 . free .
• Jenkins CM, Mancuso DJ, Yan W, Sims HF, Gibson B, Gross RW . Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities . The Journal of Biological Chemistry . 279 . 47 . 48968–48975 . November 2004 . 15364929 . 10.1074/jbc.M407841200 . free .
• Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A, Zechner R . Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase . Science . 306 . 5700 . 1383–1386 . November 2004 . 15550674 . 10.1126/science.1100747 . 33644973 . 2004Sci...306.1383Z .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–1178 . October 2005 . 16189514 . 10.1038/nature04209 . 4427026 . 2005Natur.437.1173R .
• Smirnova E, Goldberg EB, Makarova KS, Lin L, Brown WJ, Jackson CL . ATGL has a key role in lipid droplet/adiposome degradation in mammalian cells . EMBO Reports . 7 . 1 . 106–113 . January 2006 . 16239926 . 1369222 . 10.1038/sj.embor.7400559 .
• Schoenborn V, Heid IM, Vollmert C, Lingenhel A, Adams TD, Hopkins PN, Illig T, Zimmermann R, Zechner R, Hunt SC, Kronenberg F . The ATGL gene is associated with free fatty acids, triglycerides, and type 2 diabetes . Diabetes . 55 . 5 . 1270–1275 . May 2006 . 16644682 . 10.2337/db05-1498 . free .
• Lass A, Zimmermann R, Haemmerle G, Riederer M, Schoiswohl G, Schweiger M, Kienesberger P, Strauss JG, Gorkiewicz G, Zechner R . Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome . Cell Metabolism . 3 . 5 . 309–319 . May 2006 . 16679289 . 10.1016/j.cmet.2006.03.005 . free .
• Mairal A, Langin D, Arner P, Hoffstedt J . Human adipose triglyceride lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro triglyceride hydrolase activity . Diabetologia . 49 . 7 . 1629–1636 . July 2006 . 16752181 . 10.1007/s00125-006-0272-x . free .
• Notari L, Baladron V, Aroca-Aguilar JD, Balko N, Heredia R, Meyer C, Notario PM, Saravanamuthu S, Nueda ML, Sanchez-Sanchez F, Escribano J, Laborda J, Becerra SP . Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor . The Journal of Biological Chemistry . 281 . 49 . 38022–38037 . December 2006 . 17032652 . 10.1074/jbc.M600353200 . free .
• Fischer J, Lefèvre C, Morava E, Mussini JM, Laforêt P, Negre-Salvayre A, Lathrop M, Salvayre R . The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy . Nature Genetics . 39 . 1 . 28–30 . January 2007 . 17187067 . 10.1038/ng1951 . 23679419 .
• Rydén M, Jocken J, van Harmelen V, Dicker A, Hoffstedt J, Wirén M, Blomqvist L, Mairal A, Langin D, Blaak E, Arner P . Comparative studies of the role of hormone-sensitive lipase and adipose triglyceride lipase in human fat cell lipolysis . American Journal of Physiology. Endocrinology and Metabolism . 292 . 6 . E1847–E1855 . June 2007 . 17327373 . 10.1152/ajpendo.00040.2007 . 10.1.1.328.3523 .
• Jocken JW, Langin D, Smit E, Saris WH, Valle C, Hul GB, Holm C, Arner P, Blaak EE . Adipose triglyceride lipase and hormone-sensitive lipase protein expression is decreased in the obese insulin-resistant state . The Journal of Clinical Endocrinology and Metabolism . 92 . 6 . 2292–2299 . June 2007 . 17356053 . 10.1210/jc.2006-1318 . free .
• Steinberg GR, Kemp BE, Watt MJ . Adipocyte triglyceride lipase expression in human obesity . American Journal of Physiology. Endocrinology and Metabolism . 293 . 4 . E958–E964 . October 2007 . 17609260 . 10.1152/ajpendo.00235.2007 .
• Fischer J, Negre-Salvayre A, Salvayre R . [Neutral lipid storage diseases and ATGL (adipose triglyceride lipase) and CGI-58/ABHD5 (alpha-beta hydrolase domain-containing 5) deficiency: myopathy, ichthyosis, but no obesity] . Médecine/Sciences . 23 . 6–7 . 575–578 . 2007 . 17631826 . 10.1051/medsci/20072367575 . free .

Notes and References

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