Adipose triglyceride lipase

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.^[5][6][7] ATGL catalyses the first reaction of lipolysis,^[8] where triacylglycerols are hydrolysed to diacylglycerols.^[9]

PNPLA2
Identifiers
Aliases	PNPLA2, 1110001C14Rik, ATGL, PEDF-R, TTS-2.2, TTS2, iPLA2zeta, FP17548, patatin like phospholipase domain containing 2
External IDs	OMIM: 609059; MGI: 1914103; HomoloGene: 10687; GeneCards: PNPLA2; OMA:PNPLA2 - orthologs
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11p15.5 Start 818,914 bp[1] End 825,573 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 F5 Start 141,035,111 bp[2] End 141,040,656 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in apex of heart subcutaneous adipose tissue left coronary artery gastric mucosa right lung mucosa of transverse colon minor salivary glands body of stomach right coronary artery gastrocnemius muscle Top expressed in lactiferous gland brown adipose tissue white adipose tissue muscle of thigh subcutaneous adipose tissue tunica adventitia of aorta intercostal muscle interventricular septum cardiac muscles myocardium of ventricle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function hydrolase activity lipoprotein lipase activity acylglycerol O-acyltransferase activity triglyceride lipase activity Cellular component integral component of membrane cytosol lipid droplet plasma membrane endoplasmic reticulum membrane cytoplasm membrane nucleoplasm endoplasmic reticulum lumen Biological process lipid catabolic process lipid storage metabolism negative regulation of sequestering of triglyceride positive regulation of triglyceride catabolic process acylglycerol acyl-chain remodeling lipid droplet organization lipid metabolism triglyceride catabolic process lipid homeostasis post-translational protein modification cellular lipid catabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 57104 66853 Ensembl ENSG00000177666 ENSMUSG00000025509 UniProt Q96AD5 Q8BJ56 RefSeq (mRNA) NM_020376 NM_001163689 NM_025802 RefSeq (protein) NP_065109 NP_001157161 NP_080078 Location (UCSC) Chr 11: 0.82 – 0.83 Mb Chr 7: 141.04 – 141.04 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Properties

ATGL has very high substrate specificity for triacylglycerols.^[10] It contains a catalytic dyad using serine-aspartic acid.^[9]

Function

ATGL catalyses the first reaction of lipolysis.^[8] It hydrolysis triacylglycerols to diacylglycerols^[9] 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.^[11]

Clinical significance

Defects in ATGL can cause problems in lipolysis, leading to neutral lipid storage disease.^[12] As triacylglycerols are not hydrolysed to diacylglycerols, there is a build-up of triacylglycerol droplets in granulocytes.^[12]

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.^[13] 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.^[14][15]

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.^[13] 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.^[16]

Insulin is a hormone that regulate the enzyme ATGL, it inhibits the enzyme by favoring lipid storage over lipolysis.^[13] One pathway of inhibition of ATGL when insulin is present is the activation of SIRT1, which inhibits FoxO1.^[16][17] Specifically, FoxO1 is repressed from localizing in the nucleus by deacetylation in adipocytes.^[16][18]

References

1. GRCh38: Ensembl release 89: ENSG00000177666 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000025509 – 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. Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (April 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–113. doi:10.1006/abio.1996.0138. PMID 8619474.
6. Wilson PA, Gardner SD, Lambie NM, Commans SA, Crowther DJ (September 2006). "Characterization of the human patatin-like phospholipase family". Journal of Lipid Research. 47 (9): 1940–1949. doi:10.1194/jlr.M600185-JLR200. PMID 16799181.
7. Kienesberger PC, Oberer M, Lass A, Zechner R (April 2009). "Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions". Journal of Lipid Research. 50 (Suppl): S63–S68. doi:10.1194/jlr.R800082-JLR200. PMC 2674697. PMID 19029121.
8. Ojha S, Budge H, Symonds ME (2014). "Adipocytes in Normal Tissue Biology". In McManus LM, Mitchell RN (eds.). Pathobiology of Human Disease. San Diego: Academic Press. pp. 2003–2013. doi:10.1016/b978-0-12-386456-7.04408-7. ISBN 978-0-12-386457-4.
9. Lehner R, Quiroga AD (2016). "Chapter 5 - Fatty Acid Handling in Mammalian Cells". In Ridgway ND, McLeod RS (eds.). Biochemistry of Lipids, Lipoproteins and Membranes (Sixth ed.). Boston: Elsevier. pp. 149–184. doi:10.1016/b978-0-444-63438-2.00005-5. ISBN 978-0-444-63438-2.
10. Tsiloulis T, Watt MJ (2015). "Chapter Eight - Exercise and the Regulation of Adipose Tissue Metabolism". In Bouchard C (ed.). Progress in Molecular Biology and Translational Science. Molecular and Cellular Regulation of Adaptation to Exercise. Vol. 135. Academic Press. pp. 175–201. doi:10.1016/bs.pmbts.2015.06.016. ISBN 9780128039915. PMID 26477915.
11. Zhang X, Heckmann BL, Liu J (2013-01-01). "Studying lipolysis in adipocytes by combining siRNA knockdown and adenovirus-mediated overexpression approaches". In Yang P, Li H (eds.). Lipid Droplets. Methods in Cell Biology. Vol. 116. Academic Press. pp. 83–105. doi:10.1016/b978-0-12-408051-5.00006-1. ISBN 9780124080515. PMC 4529287. PMID 24099289.
12. Bongarzone ER, Givogri MI, Darryl C, DiMauro S (January 2012). "Inborn Metabolic Defects of Lysosomes, Peroxisomes, Carbohydrates, Fatty Acids and Mitochondria.". In Brady ST, Siegel GJ, Albers RW, Price DL (eds.). Basic Neurochemistry (Eighth ed.). New York: Academic Press. pp. 755–782. doi:10.1016/b978-0-12-374947-5.00043-2. ISBN 978-0-12-374947-5.
13. Kershaw EE, Hamm JK, Verhagen LA, Peroni O, Katic M, Flier JS (January 2006). "Adipose triglyceride lipase: function, regulation by insulin, and comparison with adiponutrin". Diabetes. 55 (1): 148–157. doi:10.2337/diabetes.55.01.06.db05-0982. PMC 2819178. PMID 16380488.
14. Cerk IK, Wechselberger L, Oberer M (2017-12-18). "Adipose Triglyceride Lipase Regulation: An Overview". Current Protein & Peptide Science. 19 (2): 221–233. doi:10.2174/1389203718666170918160110. PMC 7613786. PMID 28925902.
15. Liu S, Promes JA, Harata M, Mishra A, Stephens SB, Taylor EB, et al. (June 2020). "Adipose Triglyceride Lipase Is a Key Lipase for the Mobilization of Lipid Droplets in Human β-Cells and Critical for the Maintenance of Syntaxin 1a Levels in β-Cells". Diabetes. 69 (6): 1178–1192. doi:10.2337/db19-0951. PMC 7243295. PMID 32312867.
16. Li T, Guo W, Zhou Z (December 2021). "Adipose Triglyceride Lipase in Hepatic Physiology and Pathophysiology". Biomolecules. 12 (1): 57. doi:10.3390/biom12010057. PMC 8773762. PMID 35053204.
17. Chakrabarti P, English T, Karki S, Qiang L, Tao R, Kim J, et al. (September 2011). "SIRT1 controls lipolysis in adipocytes via FOXO1-mediated expression of ATGL". Journal of Lipid Research. 52 (9): 1693–1701. doi:10.1194/jlr.M014647. PMC 3151689. PMID 21743036.
18. Chakrabarti P, Kandror KV (May 2009). "FoxO1 controls insulin-dependent adipose triglyceride lipase (ATGL) expression and lipolysis in adipocytes". The Journal of Biological Chemistry. 284 (20): 13296–13300. doi:10.1074/jbc.C800241200. PMC 2679428. PMID 19297333.

Further reading

• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, et al. (April 1997). "Large-scale concatenation cDNA sequencing". Genome Research. 7 (4): 353–358. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, et al. (July 2004). "Functional proteomics mapping of a human signaling pathway". Genome Research. 14 (7): 1324–1332. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.
• Villena JA, Roy S, Sarkadi-Nagy E, Kim KH, Sul HS (November 2004). "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. doi:10.1074/jbc.M403855200. PMID 15337759.
• Jenkins CM, Mancuso DJ, Yan W, Sims HF, Gibson B, Gross RW (November 2004). "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. doi:10.1074/jbc.M407841200. PMID 15364929.
• Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, et al. (November 2004). "Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase". Science. 306 (5700): 1383–1386. Bibcode:2004Sci...306.1383Z. doi:10.1126/science.1100747. PMID 15550674. S2CID 33644973.
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–1178. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
• Smirnova E, Goldberg EB, Makarova KS, Lin L, Brown WJ, Jackson CL (January 2006). "ATGL has a key role in lipid droplet/adiposome degradation in mammalian cells". EMBO Reports. 7 (1): 106–113. doi:10.1038/sj.embor.7400559. PMC 1369222. PMID 16239926.
• Schoenborn V, Heid IM, Vollmert C, Lingenhel A, Adams TD, Hopkins PN, et al. (May 2006). "The ATGL gene is associated with free fatty acids, triglycerides, and type 2 diabetes". Diabetes. 55 (5): 1270–1275. doi:10.2337/db05-1498. PMID 16644682.
• Lass A, Zimmermann R, Haemmerle G, Riederer M, Schoiswohl G, Schweiger M, et al. (May 2006). "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. doi:10.1016/j.cmet.2006.03.005. PMID 16679289.
• Mairal A, Langin D, Arner P, Hoffstedt J (July 2006). "Human adipose triglyceride lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro triglyceride hydrolase activity". Diabetologia. 49 (7): 1629–1636. doi:10.1007/s00125-006-0272-x. PMID 16752181.
• Notari L, Baladron V, Aroca-Aguilar JD, Balko N, Heredia R, Meyer C, et al. (December 2006). "Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor". The Journal of Biological Chemistry. 281 (49): 38022–38037. doi:10.1074/jbc.M600353200. PMID 17032652.
• Fischer J, Lefèvre C, Morava E, Mussini JM, Laforêt P, Negre-Salvayre A, et al. (January 2007). "The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy". Nature Genetics. 39 (1): 28–30. doi:10.1038/ng1951. PMID 17187067. S2CID 23679419.
• Rydén M, Jocken J, van Harmelen V, Dicker A, Hoffstedt J, Wirén M, et al. (June 2007). "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. CiteSeerX 10.1.1.328.3523. doi:10.1152/ajpendo.00040.2007. PMID 17327373.
• Jocken JW, Langin D, Smit E, Saris WH, Valle C, Hul GB, et al. (June 2007). "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. doi:10.1210/jc.2006-1318. PMID 17356053.
• Steinberg GR, Kemp BE, Watt MJ (October 2007). "Adipocyte triglyceride lipase expression in human obesity". American Journal of Physiology. Endocrinology and Metabolism. 293 (4): E958–E964. doi:10.1152/ajpendo.00235.2007. PMID 17609260.
• Fischer J, Negre-Salvayre A, Salvayre R (2007). "[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. doi:10.1051/medsci/20072367575. PMID 17631826.

External links

• Human PNPLA2 genome location and PNPLA2 gene details page in the UCSC Genome Browser.