Adipose_triglyceride_lipase

Adipose triglyceride lipase

Adipose triglyceride lipase

Mammalian protein found in Homo sapiens

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]

Quick Facts PNPLA2, Identifiers ...

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

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    GRCh38: Ensembl release 89: ENSG00000177666 – Ensembl, May 2017
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    "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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    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.
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    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.
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    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.
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    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.
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    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.
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    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.
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    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.
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    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.
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    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.
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    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.
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    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.

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