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Perilipin A and the control of triacylglycerol metabolism

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Abstract

Perilipin A is the most abundant protein associated with the lipid droplets of adipocytes and functions to control both basal and stimulated lipolysis. Under basal or fed conditions, perilipin A shields stored triacylglycerols from cytosolic lipases, thus promoting triacylglycerol storage. When catecholamines bind to cell surface receptors to initiate signals that activate cAMP-dependent protein kinase (PKA), phosphorylated perilipin A facilitates maximal lipolysis. Mutagenesis studies have revealed that central sequences of moderately hydrophobic amino acids are required to target nascent perilipin A to lipid droplets and provide an anchor into the hydrophobic environment of lipid droplets. Sequences of amino acids in the unique carboxyl terminus of perilipin A and those in amino terminal sequences flanking the first hydrophobic stretch are required for the barrier function of perilipin A in promoting triacylglycerol storage. Site-directed mutagenesis studies of serine residues within six PKA consensus sites of perilipin A reveal functions for phosphorylation of at least three of the sites. Phosphorylation of one or more of the serines within three amino terminal PKA sites is required to facilitate hormone-sensitive lipase access to lipid substrates. Phosphorylation of serines within two carboxyl terminal sites is also required for maximal lipolysis. Phosphorylation of serine 492 (site 5) triggers a massive remodeling of lipid droplets, whereby large peri-nuclear lipid droplets fragment into myriad lipid micro-droplets that scatter throughout the cytoplasm. We hypothesize that perilipin A binds accessory proteins to provide assistance in carrying out these functions.

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Abbreviations

ATGL:

Adipose triglyceride lipase

HSL:

Hormone-sensitive lipase

IBMX:

Isobutylmethylxanthine

PKA:

Protein kinase A (cAMP-dependent protein kinase)

References

  1. Greenberg AS, Egan JJ, Wek SA et al (1991) Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets. J Biol Chem 266:11341–11346

    PubMed  CAS  Google Scholar 

  2. Blanchette-Mackie EJ, Dwyer NK, Barber T et al (1995) Perilipin is located on the surface layer of intracellular lipid droplets in adipocytes. J Lipid Res 36:1211–1226

    PubMed  CAS  Google Scholar 

  3. Greenberg AS, Egan JJ, Wek SA et al (1993) Isolation of cDNAs for perilipins A and B: sequence and expression of lipid droplet-associated proteins of adipocytes. Proc Natl Acad Sci USA 90:12035–12039. doi:10.1073/pnas.90.24.12035

    Article  PubMed  CAS  Google Scholar 

  4. Lu E, Gruia-Gray J, Copeland NG et al (2001) The murine perilipin gene: the lipid droplet-associated perilipins derive from tissue-specific, mRNA splice variants and define a gene family of ancient origin. Mamm Genome 12:741–749

    Article  PubMed  CAS  Google Scholar 

  5. Brasaemle DL, Rubin B, Harten IA et al (2000) Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis. J Biol Chem 275:38486–38493. doi:10.1074/jbc.M007322200

    Article  PubMed  CAS  Google Scholar 

  6. Martinez-Botas J, Anderson JB, Tessier D et al (2000) Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice. Nat Genet 26:474–479. doi:10.1038/82630

    Article  PubMed  CAS  Google Scholar 

  7. Tansey JT, Sztalryd C, Gruia-Gray J et al (2001) Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity. Proc Natl Acad Sci USA 98:6494–6499. doi:10.1073/pnas.101042998

    Article  PubMed  CAS  Google Scholar 

  8. Miyoshi HS, Souza SC, Zang HH et al (2006) Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms. J Biol Chem 281:15837–15844. doi:10.1074/jbc.M601097200

    Article  PubMed  CAS  Google Scholar 

  9. Miyoshi H, Perfield JW, Souza SC et al (2007) Control of adipose triglyceride lipase action by serine 517 of perilipin A globally regulates protein kinase A-stimulated lipolysis in adipocytes. J Biol Chem 282:996–1002. doi:10.1074/jbc.M605770200

    Article  PubMed  CAS  Google Scholar 

  10. Souza SC, Muliro KV, Liscum L et al (2002) Modulation of hormone-sensitive lipase and protein kinase A-mediated lipolysis by perilipin A in an adenoviral reconstituted system. J Biol Chem 277:8267–8272. doi:10.1074/jbc.M108329200

    Article  PubMed  CAS  Google Scholar 

  11. Sztalryd C, Xu G, Dorward H et al (2003) Perilipin A is essential for the translocation of hormone-sensitive lipase during lipolytic activation. J Cell Biol 161:1093–1103. doi:10.1083/jcb.200210169

    Article  PubMed  CAS  Google Scholar 

  12. Tansey JT, Huml AM, Vogt R et al (2003) Functional studies on native and mutated forms of perilipins: a role in protein kinase A-mediated lipolysis of triacylglycerols. J Biol Chem 278:8401–8406. doi:10.1074/jbc.M211005200

    Article  PubMed  CAS  Google Scholar 

  13. Zhang HH, Souza SC, Muliro KV et al (2003) Lipase-selective functional domains of perilipin A differentially regulate constitutive and protein kinase A-stimulated lipolysis. J Biol Chem 278:51535–51542. doi:10.1074/jbc.M309591200

    Article  PubMed  CAS  Google Scholar 

  14. Brasaemle DL, Barber T, Wolins NE et al (1997) Adipose differentiation-related protein is an ubiquitously expressed lipid storage droplet-associated protein. J Lipid Res 38:2249–2263

    PubMed  CAS  Google Scholar 

  15. Heid HW, Moll R, Schwetlick I et al (1998) Adipophilin is a specific marker of lipid accumulation in diverse cell types and diseases. Cell Tissue Res 294:309–321. doi:10.1007/s004410051181

    Article  PubMed  CAS  Google Scholar 

  16. Miura S, Gan JW, Brzostowski J et al (2002) Functional conservation for lipid storage droplet association among Perilipin, ADRP, and TIP47 (PAT)-related proteins in mammals, Drosophila, and Dictyostelium. J Biol Chem 277:32253–32257. doi:10.1074/jbc.M204410200

    Article  PubMed  CAS  Google Scholar 

  17. Wolins NE, Rubin B, Brasaemle DL (2001) TIP47 associates with lipid droplets. J Biol Chem 276:5101–5108. doi:10.1074/jbc.M006775200

    Article  PubMed  CAS  Google Scholar 

  18. Dalen KT, Dahl T, Holter E et al (2007) LSDP5 is a PAT protein specifically expressed in fatty acid oxidizing tissues. Biochim Biophys Acta 1771:210–227

    PubMed  CAS  Google Scholar 

  19. Wolins NE, Quaynor BK, Skinner JR et al (2006) OXPAT/PAT-1 is a PPAR-induced lipid droplet protein that promotes fatty acid utilization. Diabetes 55:3418–3428. doi:10.2337/db06-0399

    Article  PubMed  CAS  Google Scholar 

  20. Yamaguchi TS, Matsushita S, Motojima K (2006) MLDP, a novel PAT family protein localized to lipid droplets and enriched in the heart, is regulated by peroxisome proliferator-activated receptor alpha. J Biol Chem 281:14232–14240. doi:10.1074/jbc.M601682200

    Article  PubMed  CAS  Google Scholar 

  21. Servetnick DA, Brasaemle DL, Gruia-Gray J et al (1995) Perilipins are associated with cholesteryl ester droplets in steroidogenic adrenal cortical and Leydig cells. J Biol Chem 270:16970–16973. doi:10.1074/jbc.270.28.16970

    Article  PubMed  CAS  Google Scholar 

  22. Scherer PE, Bickel PE, Kotler M et al (1998) Cloning of cell-specific secreted and surface proteins by subtractive antibody screening. Nat Biotechnol 16:581–586. doi:10.1038/nbt0698-581

    Article  PubMed  CAS  Google Scholar 

  23. Bussell R Jr, Eliezer D (2003) A structural and functional role for 11-mer repeats in alpha-synuclein and other exchangeable lipid binding proteins. J Mol Biol 329:763–778. doi:10.1016/S0022-2836(03)00520-5

    Article  PubMed  CAS  Google Scholar 

  24. Wolins NE, Skinner JR, Schoenfish MJ et al (2003) Adipocyte protein S3-12 coats nascent lipid droplets. J Biol Chem 278:37713–37721. doi:10.1074/jbc.M304025200

    Article  PubMed  CAS  Google Scholar 

  25. Gronke S, Beller M, Fellert S et al (2003) Control of fat storage by a Drosophila PAT domain protein. Curr Biol 13:603–606. doi:10.1016/S0960-9822(03)00175-1

    Article  PubMed  CAS  Google Scholar 

  26. Gronke S, Muller G, Hirsch J et al (2007) Dual lipolytic control of body fat storage and mobilization in Drosophila. PLoS Biol 5:1248–1256. doi:10.1371/journal.pbio.0050137

    Article  CAS  Google Scholar 

  27. Patel RT, Soulages JL, Hariharasundaram B et al (2005) Activation of the lipid droplet controls the rate of lipolysis of triglycerides in the insect fat body. J Biol Chem 280:22624–22631. doi:10.1074/jbc.M413128200

    Article  PubMed  CAS  Google Scholar 

  28. Teixeira L, Rabouille C, Rorth P et al (2003) Drosophila Perilipin/ADRP homologue Lsd2 regulates lipid metabolism. Mech Dev 120:1071–1081. doi:10.1016/S0925-4773(03)00158-8

    Article  PubMed  CAS  Google Scholar 

  29. Welte MA, Cermelli S, Griner J et al (2005) Regulation of lipid-droplet transport by the perilipin homolog LSD2. Curr Biol 15:1266–1275. doi:10.1016/j.cub.2005.06.062

    Article  PubMed  CAS  Google Scholar 

  30. Garcia A, Sekowski A, Subramanian V et al (2003) The central domain is required to target and anchor perilipin A to lipid droplets. J Biol Chem 278:625–635. doi:10.1074/jbc.M206602200

    Article  PubMed  CAS  Google Scholar 

  31. Subramanian V, Garcia A, Sekowski A et al (2004) Hydrophobic sequences target and anchor perilipin A to lipid droplets. J Lipid Res 45:1983–1991. doi:10.1194/jlr.M400291-JLR200

    Article  PubMed  CAS  Google Scholar 

  32. Hickenbottom SJ, Kimmel AR, Londos C et al (2004) Structure of a lipid droplet protein; the PAT family member TIP47. Structure 12:1199–1207. doi:10.1016/j.str.2004.04.021

    Article  PubMed  CAS  Google Scholar 

  33. Hatters DM, Peters-Libeu CA, Weisgraber KH (2006) Apolipoprotein E structure: insights into function. Trends Biochem Sci 31:445–454. doi:10.1016/j.tibs.2006.06.008

    Article  PubMed  CAS  Google Scholar 

  34. Saito HS, Lund-Katz S, Phillips MC (2004) Contributions of domain structure and lipid interaction to the functionality of exchangeable human apolipoproteins. Prog Lipid Res 43:350–380. doi:10.1016/j.plipres.2004.05.002

    Article  PubMed  CAS  Google Scholar 

  35. Wolins NE, Quaynor BK, Skinner JR et al (2005) S3-12, adipophilin, and TIP47 package lipid in adipocytes. J Biol Chem 280:19146–19155. doi:10.1074/jbc.M500978200

    Article  PubMed  CAS  Google Scholar 

  36. Gross DN, Miyoshi H, Hosaka T et al (2006) Dynamics of lipid droplet-associated proteins during hormonally stimulated lipolysis in engineered adipocytes: stabilization and lipid droplet binding of adipocyte differentiation-related protein/adipophilin. Mol Endocrinol 20:459–466. doi:10.1210/me.2005-0323

    Article  PubMed  CAS  Google Scholar 

  37. Masuda Y, Itabe H, Odaki M et al (2006) ADRP/adipophilin is degraded through the proteasome-dependent pathway during regression of lipid-storing cells. J Lipid Res 47:87–98. doi:10.1194/jlr.M500170-JLR200

    Article  PubMed  CAS  Google Scholar 

  38. Xu G, Sztalryd C, Lu X et al (2005) Post-translational regulation of adipose differentiation-related protein by the ubiquitin/proteasome pathway. J Biol Chem 280:42841–42847. doi:10.1074/jbc.M506569200

    Article  PubMed  CAS  Google Scholar 

  39. Brasaemle DL, Barber T, Kimmel AR et al (1997) Post-translational regulation of perilipin expression Stabilization by stored intracellular neutral lipids. J Biol Chem 272:9378–9387. doi:10.1074/jbc.272.14.9378

    Article  PubMed  CAS  Google Scholar 

  40. Xu G, Sztalryd C, Londos C (2006) Degradation of perilipin is mediated through ubiquitination-proteasome pathway. Biochim Biophys Acta 1761:83–90

    PubMed  CAS  Google Scholar 

  41. Garcia A, Subramanian V, Sekowski A et al (2004) The amino and carboxyl termini of perilipin A facilitate the storage of triacylglycerols. J Biol Chem 279:8409–8416. doi:10.1074/jbc.M311198200

    Article  PubMed  CAS  Google Scholar 

  42. Brasaemle DL, Levin DM, Ader-Wailes DC et al (2000) The lipolytic stimulation of 3T3-L1 adipocytes promotes the translocation of hormone-sensitive lipase to the surfaces of lipid storage droplets. Biochim Biophys Acta 1483:251–262

    PubMed  CAS  Google Scholar 

  43. Egan JJ, Greenberg AS, Chang MK et al (1992) Mechanism of hormone-stimulated lipolysis in adipocytes: translocation of hormone-sensitive lipase to the lipid storage droplet. Proc Natl Acad Sci USA 89:8537–8541. doi:10.1073/pnas.89.18.8537

    Article  PubMed  CAS  Google Scholar 

  44. Su CL, Sztalryd C, Contreras JA et al (2003) Mutational analysis of the hormone-sensitive lipase translocation reaction in adipocytes. J Biol Chem 278:43615–43619. doi:10.1074/jbc.M301809200

    Article  PubMed  CAS  Google Scholar 

  45. Holm C, Kirchgessner TG, Svenson KL et al (1998) Hormone-sensitive lipase: sequence, expression, and chromosomal localization to 19 cent-q13.3. Science 241:1503–1506. doi:10.1126/science.3420405

    Article  Google Scholar 

  46. Cook KG, Lee FT, Yeaman SJ (1981) Hormone-sensitive cholesterol ester hydrolase of bovine adrenal cortex: identification of the enzyme protein. FEBS Lett 132:10–14. doi:10.1016/0014-5793(81)80416-4

    Article  PubMed  CAS  Google Scholar 

  47. Fredrikson GP, Stralfors P, Nilsson NO et al (1981) Hormone-sensitive lipase of rat adipose tissue. Purification and some properties. J Biol Chem 256:6311–6320

    PubMed  CAS  Google Scholar 

  48. Pittman RC, Khoo JC, Steinberg D (1975) Cholesterol esterase in rat adipose tissue and its activation by cyclic adenosine 3′:5′-monophosphate-dependent protein kinase. J Biol Chem 250:4505–4511

    PubMed  CAS  Google Scholar 

  49. Granneman JG, Moore HP, Granneman RL et al (2007) Analysis of lipolytic protein trafficking and interactions in adipocytes. J Biol Chem 282:5726–5735. doi:10.1074/jbc.M610580200

    Article  PubMed  CAS  Google Scholar 

  50. Jenkins CM, Mancuso DJ, Yan W et al (2004) Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J Biol Chem 279:48968–48975. doi:10.1074/jbc.M407841200

    Article  PubMed  CAS  Google Scholar 

  51. Lake AC, Sun Y, Li JL et al (2005) Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members. J Lipid Res 46:2477–2487. doi:10.1194/jlr.M500290-JLR200

    Article  PubMed  CAS  Google Scholar 

  52. Villena JA, Roy S, Sarkadi-Nagy E et al (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. J Biol Chem 279:47066–47075. doi:10.1074/jbc.M403855200

    Article  PubMed  CAS  Google Scholar 

  53. Zimmermann R, Strauss JG, Haemmerle G et al (2004) Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306:1383–1386. doi:10.1126/science.1100747

    Article  PubMed  CAS  Google Scholar 

  54. Haemmerle G, Lass A, Zimmermann R et al (2006) Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 312:734–737. doi:10.1126/science.1123965

    Article  PubMed  CAS  Google Scholar 

  55. Kershaw EE, Hamm JK, Verhagen LA et al (2006) Adipose triglyceride lipase: function, regulation by insulin, and comparison with adiponutrin. Diabetes 55:148–157. doi:10.2337/diabetes.55.01.06.db05-0982

    Article  PubMed  CAS  Google Scholar 

  56. Langin D, Dicker A, Tavernier G et al (2005) Adipocyte lipases and defect of lipolysis in human obesity. Diabetes 54:3190–3197. doi:10.2337/diabetes.54.11.3190

    Article  PubMed  CAS  Google Scholar 

  57. Mairal A, Langin D, Arner P et al (2006) Human adipose triglyceride lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro triglyceride hydrolase activity. Diabetologia 49:1629–1636. doi:10.1007/s00125-006-0272-x

    Article  PubMed  CAS  Google Scholar 

  58. Ryden M, Jocken J, van Harmelen V et al (2007) Comparative studies of the role of hormone-sensitive lipase and adipose triglyceride lipase in human fat cell lipolysis. Am J Physiol Endocrinol Metab 292:E1847–E1855. doi:10.1152/ajpendo.00040.2007

    Article  PubMed  CAS  Google Scholar 

  59. Smirnova E, Goldberg EB, Makarova KS et al (2006) ATGL has a key role in lipid droplet/adiposome degradation in mammalian cells. EMBO Rep 7:106–113. doi:10.1038/sj.embor.7400559

    Article  PubMed  CAS  Google Scholar 

  60. Brasaemle DL, Dolios G, Shapiro L et al (2004) Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3T3–L1 adipocytes. J Biol Chem 279:46835–46842. doi:10.1074/jbc.M409340200

    Article  PubMed  CAS  Google Scholar 

  61. Londos C, Brasaemle DL, Schultz CJ et al (1999) Perilipins, ADRP, and other proteins that associate with intracellular neutral lipid droplets in animal cells. Semin Cell Dev Biol 10:51–58. doi:10.1006/scdb.1998.0275

    Article  PubMed  CAS  Google Scholar 

  62. Marcinkiewicz A, Gauthier D, Garcia A et al (2006) The phosphorylation of serine 492 of perilipin A directs lipid droplet fragmentation and dispersion. J Biol Chem 281:11901–11909. doi:10.1074/jbc.M600171200

    Article  PubMed  CAS  Google Scholar 

  63. Brasaemle DL (2007) Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis. J Lipid Res 48:2547–2559. doi:10.1194/jlr.R700014-JLR200

    Article  PubMed  CAS  Google Scholar 

  64. Subramanian V, Rothenberg A, Gomez C et al (2004) Perilipin A mediates the reversible binding of CGI–58 to lipid droplets in 3T3–L1 adipocytes. J Biol Chem 279:42062–42071. doi:10.1074/jbc.M407462200

    Article  PubMed  CAS  Google Scholar 

  65. Yamaguchi T, Omatsu N, Morimoto E et al (2007) CGI-58 facilitates lipolysis on lipid droplets but is not involved in the vesiculation of lipid droplets caused by hormonal stimulation. J Lipid Res 48:1078–1089. doi:10.1194/jlr.M600493-JLR200

    Article  PubMed  CAS  Google Scholar 

  66. Lefevre C, Jobard F, Caux F et al (2001) Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome. Am J Hum Genet 69:1002–1012. doi:10.1086/324121

    Article  PubMed  CAS  Google Scholar 

  67. Lass A, Zimmermann R, Haemmerle G et al (2006) Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome. Cell Metab 3:309–319. doi:10.1016/j.cmet.2006.03.005

    Article  PubMed  CAS  Google Scholar 

  68. Schweiger M, Scheriber R, Haemmerle G et al (2006) Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism. J Biol Chem 281:40236–40241. doi:10.1074/jbc.M608048200

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Research has been supported by NIH R01 DK54797, an Established Investigator Award from the American Heart Association, a Research Award from the American Diabetes Association, and Johnson & Johnson Discovery Awards administered through Rutgers University.

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  1. Department of Nutritional Sciences, Rutgers, The State University of New Jersey, 96 Lipman Drive, New Brunswick, NJ, 08901, USA

    Dawn L. Brasaemle, Vidya Subramanian, Anne Garcia, Amy Marcinkiewicz & Alexis Rothenberg

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  1. Dawn L. Brasaemle
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  2. Vidya Subramanian
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  3. Anne Garcia
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Correspondence to Dawn L. Brasaemle.

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Brasaemle, D.L., Subramanian, V., Garcia, A. et al. Perilipin A and the control of triacylglycerol metabolism. Mol Cell Biochem 326, 15–21 (2009). https://doi.org/10.1007/s11010-008-9998-8

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  • DOI: https://doi.org/10.1007/s11010-008-9998-8

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