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
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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 regulates the enzyme ATGL, it inhibits the enzyme, 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 to the nucleus by deacetylation in adipocytes.^[16][18]