Adipose triglyceride lipase

PNPLA2
Identifiers
AliasesPNPLA2, 1110001C14Rik, ATGL, PEDF-R, TTS-2.2, TTS2, iPLA2zeta, FP17548, patatin like phospholipase domain containing 2
External IDsOMIM: 609059; MGI: 1914103; GeneCards: PNPLA2
Enzyme activity
EC #BRENDAExPASyKEGGMetaCyc
3.1.1.3↗↗↗↗
3.1.1.4↗↗↗↗
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
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 MbChr 7: 141.04 – 141.04 Mb
PubMed search
Wikidata
View/Edit HumanView/Edit Mouse

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. ATGL catalyses the first reaction of lipolysis, where triacylglycerols are hydrolysed to diacylglycerols.

Properties

ATGL has very high substrate specificity for triacylglycerols. 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.

Clinical significance

Defects in ATGL can cause problems in lipolysis, leading to neutral lipid storage disease. 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. 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.

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). Further, ATGL concentrations are regulated via the SACM1L—PtdIns4P—E3 ligase complex axis. Fasting and associated low glucose concentrations lead to translocation of SACM1L to the Golgi apparatus, where SACM1L dephosphorylates Golgi membrane lipids PtdIns4P to PtdIns. Since PtdIns4P stabilizes the E3 ligase complex, lower PtdIns4P levels lead to break down of the E3 ligase complex, and thus lower ubiquitination of ATGL for proteosomal degradation, ultimately increasing ATGL levels and ATGL-mediated lipolysis.

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

Therapeutic approaches

Upregulation of Adipose Triglyceride Lipase (ATGL) was successfully achieved by inhibiting phosphatidylinositol 4-kinase beta (PI4KB), an enzyme that phosphorylates Golgi membrane lipids PtdIns to PtdIns4P. Given that PtdIns4P stabilizes the E3 ligase complex, which in turn uniquitinates ATGL for proteosomal degradation, lower PtdIns4P levels lead to higher ATGL levels. ATGL upregulation was shown to increase lipolysis of tissue triglycerides and ameliorated non-alcoholic fatty liver disease and metabolic dysfunction associated steatohepatitis (MASH). Therefore, PI4KB inhibitors have been successfully administered as treatment for MASH.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000177666 – Ensembl, May 2017
  2. 1 2 3 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. 1 2 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. 1 2 3 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 978-0-12-803991-5. 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 978-0-12-408051-5. PMC 4529287. PMID 24099289.
  12. 1 2 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. 1 2 3 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. 1 2 3 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. 1 2 3 Ding L, Huwyler F, Long F, Yang W, Binz J, Wernlé K, et al. (April 2024). "Glucose controls lipolysis through Golgi PtdIns4P-mediated regulation of ATGL". Nature Cell Biology. 26 (4): 552–566. doi:10.1038/s41556-024-01386-y. PMC 11021197. PMID 38561547.
  18. ↑ 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.
  19. ↑ 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