Group XVI phospholipase A2 also commonly known as adipocyte phospholipase A2 (AdPLA) is an enzyme that in humans is encoded by the PLA2G16gene.[1][2][3] This enzyme has also been identified as PLA2G16, HRASLS3, HREV107, HREV107-3, MGC118754 or H-REV107-1 from studies on class II tumor suppression but not on its enzymatic properties.[4] AdPLA is encoded by a 1.3 kilobase AdPLA messenger RNA and is an 18 kDa protein. It belongs to a superfamily of phospholipase A2 (PLA2) enzymes and is found primarily in adipose tissue. AdPLA regulates adipocyte lipolysis and release of fatty acids through a G-protein coupled pathway involving prostaglandin and EP3. It has also been reported to play a crucial role in the development of obesity in mouse models.[5]
AdPLA has been characterized in Group XVI as a separate subgroup of the PLA2 family for its distinct properties from other known PLA2s. It bears similarity to its PLA2 family in phospholipase activity and calcium dependence. Unlike other PLA2 enzymes, AdPLA is expressed predominantly in adipose tissue at higher levels than in the rest of the body, more so in white adipose tissue (WAT) than brown adipose tissue (BAT). Its primary enzymatic function is to catalyze the preferential hydrolysis of phosphatidylcholines at the sn-2 position, generating free fatty acids.
AdPLA contains a membrane-spanning domain on the C-terminus, which localizes intracellularly for phospholipase activity in proximity to cyclooxygenase 1 (COX-1). His-23 and Cys-113 residues have been shown to be essential in AdPLA activity, which differs from the known His/Asp catalytic dyad or Ser/His/Asp catalytic triad of other PLA2 enzymes. Gln-129 and Asn-112 have also been shown to be necessary in catalysis but their role is not known.[2]
AdPLA activity is calcium and pH dependent. Calcium binds to AdPLA and forms a positively charged oxyanion hole to stabilize a negatively charged transition state, similar to other PLA2 active sites. Whereas asparagine binds to calcium in other PLA2 enzymes,[6] the residue that participates in the creation of oxyanion hole in AdPLA has not yet been verified. Optimum AdPLA activity occurs in relatively basic conditions, between pH 7 and 9, to facilitate formation of a histidine-water complex and subsequent fatty acid hydrolysis.[2]
Studies on AdPLA have shown lipolysis regulation following a G-protein coupled pathway in WAT.[5] WAT is responsible for releasing fatty acids from stored triacylglycerol as energy sources for other tissues which is regulated predominately by AdPLA over other phospholipase A2 enzymes. Lipolysis is inversely related to AdPLA activity. AdPLA catalyzes the rate-limiting step, production of arachidonic acid, for the production of prostaglandins, specifically prostaglandin E2 (PGE2). PGE2 enters the signaling pathway binding to G protein-coupled receptor (EP3) which inhibits adenylyl cyclase. Inhibition of adenylyl cyclase decreases the conversion of cyclic AMP (cAMP) from ATP. Lower levels of cAMP decrease the activity of protein kinase A to phosphorylate, thereby activating, hormone-sensitive lipase.[7] The opposite effect can be reached with inactivated AdPLA, decreasing PGE2 concentration and EP3 activity, leading to an increase in cAMP and lipase activity. This mechanism was postulated on the basis that the predominant signaling protein and receptor present in WAT are PGE2 and EP3. These results were based on a mouse model and although they are mammalian cells, it has not been shown to apply to human cells.
Effects on obesity
Obesity has been attributed to adipocyte hypertrophy, where triacylglycerol synthesis exceeds lipolysis, resulting in elevated triacylglycerol storage.[8] Previous studies have associated obesity with endocrine factors and have led pharmacological work toward hormone regulation.[9] Studies on AdPLA deficient mice have shown that the enzyme increased lipolysis in WAT as a result of decreased lipolysis regulation. AdPLA deficiency was shown to reduce adipose tissue mass for mice in both standard and high fat diets. Adipocyte hypotrophy was attributed primarily to reduced triacylglyceride content in WAT from lipolysis, while adipocyte differentiation did not play a role in reduced adipose tissue despite the effects of prostaglandins on adipogenesis.[10] AdPLA defieciency also led to higher oxygen consumption due to the upreguation of genes involved in oxidative metabolism, increasing fatty acid oxidation. One upregulated gene in particular, uncoupling protein-1 (UCP1), has been shown to reduce diet-induced obesity.[11]
Studies on AdPLA deficient and genetically obese mice (leptin deficiency) have also shown similar effects, reduced adipose tissue mass and increased lipolysis by reduction in PGE2 and EP3 activity. Fatty acid oxidation was also found to increase to levels of wild-type mice that were deficient in non-AdPLA deficient obese mice. Body composition also showed a higher percentage of water and lean tissue mass compared to non-AdPLA deficient obese mice.[5]
AdPLA deficiency also demonstrated adverse effects, increasing ectopic triglyceride storage and insulin resistance. Liver enlargement was attributed to higher fatty acid uptake and triacylglycerol content. Insulin stimulated glucose uptake and metabolism were also blunted in AdPLA deficiency, decreasing glycolysis and glycogen synthesis.[5] Despite these side effects, AdPLA is a novel breakthrough in studying autocrine and paracrine action of AdPLA in regulating obesity and fat metabolism. These side effects have triggered new studies to be performed on reduction of AdPLA function as opposed to complete ablation.[12]
References
↑Husmann K, Sers C, Fietze E, Mincheva A, Lichter P, Schäfer R (Oct 1998). "Transcriptional and translational downregulation of H-REV107, a class II tumour suppressor gene located on human chromosome 11q11-12". Oncogene. 17 (10): 1305–12. doi:10.1038/sj.onc.1202060. PMID9771974.
↑Six DA, Dennis EA (October 2000). "The expanding superfamily of phospholipase A(2) enzymes: classification and characterization". Biochim. Biophys. Acta. 1488 (1–2): 1–19. doi:10.1016/S1388-1981(00)00105-0. PMID11080672.
↑Richelsen B (November 1992). "Release and effects of prostaglandins in adipose tissue". Prostaglandins Leukot. Essent. Fatty Acids. 47 (3): 171–82. doi:10.1016/0952-3278(92)90235-B. PMID1475271.
Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, Gure AO, Jäger D, Jäger E, Knuth A, Chen YT, Old LJ (1999). "Antigens recognized by autologous antibody in patients with renal-cell carcinoma". Int. J. Cancer. 83 (4): 456–64. doi:10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5. PMID10508479.
Sers C, Husmann K, Nazarenko I, Reich S, Wiechen K, Zhumabayeva B, Adhikari P, Schröder K, Gontarewicz A, Schäfer R (2002). "The class II tumour suppressor gene H-REV107-1 is a target of interferon-regulatory factor-1 and is involved in IFNgamma-induced cell death in human ovarian carcinoma cells". Oncogene. 21 (18): 2829–39. doi:10.1038/sj.onc.1205377. PMID11973642.
Roder K, Kim KH, Sul HS (2002). "Induction of murine H-rev107 gene expression by growth arrest and histone acetylation: involvement of an Sp1/Sp3-binding GC-box". Biochem. Biophys. Res. Commun. 294 (1): 63–70. doi:10.1016/S0006-291X(02)00440-0. PMID12054741.
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 (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID16189514.
Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY (2006). "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration". Cell. 125 (4): 801–14. doi:10.1016/j.cell.2006.03.032. PMID16713569.
Nazarenko I, Schäfer R, Sers C (2007). "Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells". J. Cell Sci. 120 (Pt 8): 1393–404. doi:10.1242/jcs.000018. PMID17374643.
