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A Role for Phosphatidic Acid in the Formation of “Supersized” Lipid Droplets


Lipid droplets (LDs) are important cellular organelles that govern the storage and turnover of lipids. Little is known about how the size of LDs is controlled, although LDs of diverse sizes have been observed in different tissues and under different (patho)physiological conditions. Recent studies have indicated that the size of LDs may influence adipogenesis, the rate of lipolysis and the oxidation of fatty acids. Here, a genome-wide screen identifies ten yeast mutants producing “supersized” LDs that are up to 50 times the volume of those in wild-type cells. The mutated genes include: FLD1, which encodes a homologue of mammalian seipin; five genes (CDS1, INO2, INO4, CHO2, and OPI3) that are known to regulate phospholipid metabolism; two genes (CKB1 and CKB2) encoding subunits of the casein kinase 2; and two genes (MRPS35 and RTC2) of unknown function. Biochemical and genetic analyses reveal that a common feature of these mutants is an increase in the level of cellular phosphatidic acid (PA). Results from in vivo and in vitro analyses indicate that PA may facilitate the coalescence of contacting LDs, resulting in the formation of “supersized” LDs. In summary, our results provide important insights into how the size of LDs is determined and identify novel gene products that regulate phospholipid metabolism.


Vyšlo v časopise: A Role for Phosphatidic Acid in the Formation of “Supersized” Lipid Droplets. PLoS Genet 7(7): e32767. doi:10.1371/journal.pgen.1002201
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002201

Souhrn

Lipid droplets (LDs) are important cellular organelles that govern the storage and turnover of lipids. Little is known about how the size of LDs is controlled, although LDs of diverse sizes have been observed in different tissues and under different (patho)physiological conditions. Recent studies have indicated that the size of LDs may influence adipogenesis, the rate of lipolysis and the oxidation of fatty acids. Here, a genome-wide screen identifies ten yeast mutants producing “supersized” LDs that are up to 50 times the volume of those in wild-type cells. The mutated genes include: FLD1, which encodes a homologue of mammalian seipin; five genes (CDS1, INO2, INO4, CHO2, and OPI3) that are known to regulate phospholipid metabolism; two genes (CKB1 and CKB2) encoding subunits of the casein kinase 2; and two genes (MRPS35 and RTC2) of unknown function. Biochemical and genetic analyses reveal that a common feature of these mutants is an increase in the level of cellular phosphatidic acid (PA). Results from in vivo and in vitro analyses indicate that PA may facilitate the coalescence of contacting LDs, resulting in the formation of “supersized” LDs. In summary, our results provide important insights into how the size of LDs is determined and identify novel gene products that regulate phospholipid metabolism.


Zdroje

1. FareseRVJrWaltherTC 2009 Lipid droplets finally get a little R-E-S-P-E-C-T. Cell 139 855 860

2. MartinSPartonRG 2006 Lipid droplets: a unified view of a dynamic organelle. Nat Rev Mol Cell Biol 7 373 378

3. WelteMA 2007 Proteins under new management: lipid droplets deliver. Trends Cell Biol 17 363 369

4. MiyanariYAtsuzawaKUsudaNWatashiKHishikiT 2007 The lipid droplet is an important organelle for hepatitis C virus production. Nat Cell Biol 9 1089 1097

5. SamsaMMMondotteJAIglesiasNGAssuncao-MirandaIBarbosa-LimaG 2009 Dengue virus capsid protein usurps lipid droplets for viral particle formation. PLoS Pathog 5 e1000632 doi:10.1371/journal.ppat.1000632

6. PloeghHL 2007 A lipid-based model for the creation of an escape hatch from the endoplasmic reticulum. Nature 448 435 438

7. ZweytickDAthenstaedtKDaumG 2000 Intracellular lipid particles of eukaryotic cells. Biochim Biophys Acta 1469 101 120

8. NishinoNTamoriYTateyaSKawaguchiTShibakusaT 2008 FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets. J Clin Invest 118 2808 2821

9. StraubBKStoeffelPHeidHZimbelmannRSchirmacherP 2008 Differential pattern of lipid droplet-associated proteins and de novo perilipin expression in hepatocyte steatogenesis. Hepatology 47 1936 1946

10. TohSYGongJDuGLiJZYangS 2008 Up-regulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of fsp27 deficient mice. PLoS ONE 3 e2890 doi:10.1371/journal.pone.0002890

11. GuoYWaltherTCRaoMStuurmanNGoshimaG 2008 Functional genomic screen reveals genes involved in lipid-droplet formation and utilization. Nature 453 657 661

12. FeiWShuiGGaetaBDuXKuerschnerL 2008 Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast. J Cell Biol 180 473 482

13. SzymanskiKMBinnsDBartzRGrishinNVLiWP 2007 The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proc Natl Acad Sci U S A 104 20890 20895

14. CuiXWangYTangYLiuYZhaoL 2011 Seipin ablation in mice results in severe generalized lipodystrophy. Hum Mol Genet

15. AgarwalAKGargA 2006 Genetic basis of lipodystrophies and management of metabolic complications. Annu Rev Med 57 297 311

16. AgarwalAKAriogluEDe AlmeidaSAkkocNTaylorSI 2002 AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet 31 21 23

17. MagreJDelepineMKhalloufEGedde-DahlTJrVan MaldergemL 2001 Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28 365 370

18. CortesVACurtisDESukumaranSShaoXParameswaraV 2009 Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy. Cell Metab 9 165 176

19. GaleSEFrolovAHanXBickelPECaoL 2006 A regulatory role for 1-acylglycerol-3-phosphate-O-acyltransferase 2 in adipocyte differentiation. J Biol Chem 281 11082 11089

20. HanGSWuWICarmanGM 2006 The Saccharomyces cerevisiae Lipin homolog is a Mg2+-dependent phosphatidate phosphatase enzyme. J Biol Chem 281 9210 9218

21. PeterfyMPhanJXuPReueK 2001 Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin. Nat Genet 27 121 124

22. FeiWDuXYangH 2011 Seipin, adipogenesis and lipid droplets. Trends Endocrinol Metab 22 204 210

23. CzabanyTWagnerAZweytickDLohnerKLeitnerE 2008 Structural and biochemical properties of lipid particles from the yeast Saccharomyces cerevisiae. J Biol Chem 283 17065 17074

24. MnaimnehSDavierwalaAPHaynesJMoffatJPengWT 2004 Exploration of essential gene functions via titratable promoter alleles. Cell 118 31 44

25. CarmanGMHenrySA 2007 Phosphatidic acid plays a central role in the transcriptional regulation of glycerophospholipid synthesis in Saccharomyces cerevisiae. J Biol Chem 282 37293 37297

26. KuratCFWolinskiHPetschniggJKaluarachchiSAndrewsB 2009 Cdk1/Cdc28-dependent activation of the major triacylglycerol lipase Tgl4 in yeast links lipolysis to cell-cycle progression. Mol Cell 33 53 63

27. ShenHHeacockPNClanceyCJDowhanW 1996 The CDS1 gene encoding CDP-diacylglycerol synthase in Saccharomyces cerevisiae is essential for cell growth. J Biol Chem 271 789 795

28. ChoiSYHuangPJenkinsGMChanDCSchillerJ 2006 A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis. Nat Cell Biol 8 1255 1262

29. VitaleNCaumontASChasserot-GolazSDuGWuS 2001 Phospholipase D1: a key factor for the exocytotic machinery in neuroendocrine cells. EMBO J 20 2424 2434

30. MarchesanDRutbergMAnderssonLAspLLarssonT 2003 A phospholipase D-dependent process forms lipid droplets containing caveolin, adipocyte differentiation-related protein, and vimentin in a cell-free system. J Biol Chem 278 27293 27300

31. MorlockKRLinYPCarmanGM 1988 Regulation of phosphatidate phosphatase activity by inositol in Saccharomyces cerevisiae. J Bacteriol 170 3561 3566

32. TokeDABennettWLDillonDAWuWIChenX 1998 Isolation and characterization of the Saccharomyces cerevisiae DPP1 gene encoding diacylglycerol pyrophosphate phosphatase. J Biol Chem 273 3278 3284

33. LoewenCJGasparMLJeschSADelonCKtistakisNT 2004 Phospholipid metabolism regulated by a transcription factor sensing phosphatidic acid. Science 304 1644 1647

34. TianYBiJShuiGLiuZXiangY 2011 Tissue-autonomous function of Drosophila seipin in preventing ectopic lipid droplet formation. PLoS Genet 7 e1001364 doi:10.1371/journal.pgen.1001364

35. OelkersPCromleyDPadamseeMBillheimerJTSturleySL 2002 The DGA1 gene determines a second triglyceride synthetic pathway in yeast. J Biol Chem 277 8877 8881

36. SandagerLGustavssonMHStahlUDahlqvistAWibergE 2002 Storage lipid synthesis is non-essential in yeast. J Biol Chem 277 6478 6482

37. SiniossoglouS 2009 Lipins, lipids and nuclear envelope structure. Traffic 10 1181 1187

38. AthenstaedtKDaumG 1999 Phosphatidic acid, a key intermediate in lipid metabolism. Eur J Biochem 266 1 16

39. ReindersJZahediRPPfannerNMeisingerCSickmannA 2006 Toward the complete yeast mitochondrial proteome: multidimensional separation techniques for mitochondrial proteomics. J Proteome Res 5 1543 1554

40. GanXKitakawaMYoshinoKOshiroNYonezawaK 2002 Tag-mediated isolation of yeast mitochondrial ribosome and mass spectrometric identification of its new components. Eur J Biochem 269 5203 5214

41. ChangYFCarmanGM 2006 Casein kinase II phosphorylation of the yeast phospholipid synthesis transcription factor Opi1p. J Biol Chem 281 4754 4761

42. RiederSEEmrSD 2001 Isolation of subcellular fractions from the yeast Saccharomyces cerevisiae. Curr Protoc Cell Biol Chapter 3 Unit 3 8

43. LowCPShuiGLiewLPButtnerSMadeoF 2008 Caspase-dependent and -independent lipotoxic cell-death pathways in fission yeast. J Cell Sci 121 2671 2684

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