BMC Cell Biology | |
Two different pathways of phosphatidylcholine synthesis, the Kennedy Pathway and the Lands Cycle, differentially regulate cellular triacylglycerol storage | |
Christoph Thiele3  Christer S Ejsing1  Michael Hoch3  Andrej Shevchenko2  Julia Philippou-Massier2  Almut Steinhagen3  Kristina Klizaite3  Christine Moessinger2  | |
[1] Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, Odense, 5230, Denmark;Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, Dresden, D-01307, Germany;Life and Medical Sciences Institute, University of Bonn, Carl-Troll-Str. 31, Bonn, 53115, Germany | |
关键词: Drosophila melanogaster; Lipid droplets; Acyl transferase; Lysophosphatidylcholine; | |
Others : 1088697 DOI : 10.1186/s12860-014-0043-3 |
|
received in 2014-02-19, accepted in 2014-11-17, 发布年份 2014 | |
【 摘 要 】
Background
Lipids are stored within cells in lipid droplets (LDs). They consist of a core of neutral lipids surrounded by a monolayer of phospholipids, predominantly phosphatidylcholine (PC). LDs are very dynamic and can rapidly change in size upon lipid uptake or release. These dynamics require a fast adaptation of LD surface. We have recently shown that two Lands cycle PC synthesizing enyzmes, LPCAT1 and LPCAT2 can localize to the LD surface.
Results
Here, we show that knock-down of both enzymes leads to an increase in LD size without changes in the total amount of neutral lipids, while interference with the de-novo Kennedy pathway PC biosynthesis is associated with changes in triacylglyceride synthesis. We show that function of LPCAT1 and 2 is conserved in Drosophila melanogaster by the ortholog CG32699. Furthermore we demonstrate that modulation of the LD pool by LPCAT1 influences the release of lipoprotein from liver cells.
Conclusion
Activity of the Kennedy pathway regulates the balance between phospholipids and neutral lipids, while the Lands cycle regulates lipid droplet size by regulating surface availability and influencing surface to volume ratio. Differences in lipid droplet size may account for differences in lipid dynamics and be relevant to understand lipid overload diseases.
【 授权许可】
2014 Moessinger et al.; licensee BioMed Central.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
20150122010042670.pdf | 2486KB | download | |
Figure 6. | 112KB | Image | download |
Figure 5. | 52KB | Image | download |
Figure 4. | 133KB | Image | download |
Figure 3. | 83KB | Image | download |
Figure 2. | 104KB | Image | download |
Figure 1. | 95KB | Image | download |
【 图 表 】
Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.
Figure 6.
【 参考文献 】
- [1]Walther TC, Farese RV Jr: The life of lipid droplets. Biochim Biophys Acta 2009, 1791(6):459-466.
- [2]Bartz R, Li WH, Venables B, Zehmer JK, Roth MR, Welti R, Anderson RG, Liu P, Chapman KD: Lipidomics reveals that adiposomes store ether lipids and mediate phospholipid traffic. J Lipid Res 2007, 48(4):837-847.
- [3]Tauchi-Sato K, Ozeki S, Houjou T, Taguchi R, Fujimoto T: The surface of lipid droplets is a phospholipid monolayer with a unique Fatty Acid composition. J Biol Chem 2002, 277(46):44507-44512.
- [4]Brasaemle DL, Dolios G, Shapiro L, Wang R: Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3 T3-L1 adipocytes. J Biol Chem 2004, 279(45):46835-46842.
- [5]Fujimoto Y, Itabe H, Sakai J, Makita M, Noda J, Mori M, Higashi Y, Kojima S, Takano T: Identification of major proteins in the lipid droplet-enriched fraction isolated from the human hepatocyte cell line HuH7. Biochim Biophys Acta 2004, 1644(1):47-59.
- [6]Liu P, Ying Y, Zhao Y, Mundy DI, Zhu M, Anderson RG: Chinese hamster ovary K2 cell lipid droplets appear to be metabolic organelles involved in membrane traffic. J Biol Chem 2004, 279(5):3787-3792.
- [7]Umlauf E, Csaszar E, Moertelmaier M, Schuetz GJ, Parton RG, Prohaska R: Association of stomatin with lipid bodies. J Biol Chem 2004, 279(22):23699-23709.
- [8]Ozeki S, Cheng J, Tauchi-Sato K, Hatano N, Taniguchi H, Fujimoto T: Rab18 localizes to lipid droplets and induces their close apposition to the endoplasmic reticulum-derived membrane. J Cell Sci 2005, 118(Pt 12):2601-2611.
- [9]Sato S, Fukasawa M, Yamakawa Y, Natsume T, Suzuki T, Shoji I, Aizaki H, Miyamura T, Nishijima M: Proteomic profiling of lipid droplet proteins in hepatoma cell lines expressing hepatitis C virus core protein. J Biochem 2006, 139(5):921-930.
- [10]Turro S, Ingelmo-Torres M, Estanyol JM, Tebar F, Fernandez MA, Albor CV, Gaus K, Grewal T, Enrich C, Pol A: Identification and characterization of associated with lipid droplet protein 1: a novel membrane-associated protein that resides on hepatic lipid droplets. Traffic 2006, 7(9):1254-1269.
- [11]Bartz R, Zehmer JK, Zhu M, Chen Y, Serrero G, Zhao Y, Liu P: Dynamic activity of lipid droplets: protein phosphorylation and GTP-mediated protein translocation. J Proteome Res 2007, 6(8):3256-3265.
- [12]Cermelli S, Guo Y, Gross SP, Welte MA: The lipid-droplet proteome reveals that droplets are a protein-storage depot. Curr Biol 2006, 16(18):1783-1795.
- [13]Beller M, Riedel D, Jansch L, Dieterich G, Wehland J, Jackle H, Kuhnlein RP: Characterization of the Drosophila lipid droplet subproteome. Mol Cell Proteomics 2006, 5(6):1082-1094.
- [14]Athenstaedt K, Zweytick D, Jandrositz A, Kohlwein SD, Daum G: Identification and characterization of major lipid particle proteins of the yeast Saccharomyces cerevisiae. J Bacteriol 1999, 181(20):6441-6448.
- [15]Krahmer N, Hilger M, Kory N, Wilfling F, Stoehr G, Mann M, Farese RV Jr, Walther TC: Protein correlation profiles identify lipid droplet proteins with high confidence. Mol Cell Proteomics 2013, 12(5):1115-1126.
- [16]Jeffcoat R: Obesity - a perspective based on the biochemical interrelationship of lipids and carbohydrates. Med Hypotheses 2007, 68(5):1159-1171.
- [17]Gesta S, Tseng YH, Kahn CR: Developmental origin of fat: tracking obesity to its source. Cell 2007, 131(2):242-256.
- [18]Le Lay S, Dugail I: Connecting lipid droplet biology and the metabolic syndrome. Prog Lipid Res 2009, 48(3–4):191-195.
- [19]Unger RH, Clark GO, Scherer PE, Orci L: Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 2010, 1801(3):209-214.
- [20]Jonas A, Phillips MC: Chapter 17 – Lipoprotein structure. In Biochemistry of Lipids, Lipoproteins and Membranes. 5th edition. Edited by Vance DE, Vance JE. Elsevier, UK; 2008.
- [21]Wettesten M, Bostrom K, Bondjers G, Jarfeldt M, Norfeldt PI, Carrella M, Wiklund O, Boren J, Olofsson SO: Pulse-chase studies of the synthesis of apolipoprotein B in a human hepatoma cell line, Hep G2. Eur J Biochem 1985, 149(3):461-466.
- [22]Dixon JL, Furukawa S, Ginsberg HN: Oleate stimulates secretion of apolipoprotein B-containing lipoproteins from Hep G2 cells by inhibiting early intracellular degradation of apolipoprotein B. J Biol Chem 1991, 266(8):5080-5086.
- [23]Wiggins D, Gibbons GF: The lipolysis/esterification cycle of hepatic triacylglycerol. Its role in the secretion of very-low-density lipoprotein and its response to hormones and sulphonylureas. Biochem J 1992, 284(Pt 2):457-462.
- [24]Welte MA, Cermelli S, Griner J, Viera A, Guo Y, Kim DH, Gindhart JG, Gross SP: Regulation of lipid-droplet transport by the perilipin homolog LSD2. Curr Biol 2005, 15(14):1266-1275.
- [25]Kuerschner L, Moessinger C, Thiele C: Imaging of lipid biosynthesis: how a neutral lipid enters lipid droplets. Traffic 2008, 9(3):338-352.
- [26]Cheng J, Fujita A, Ohsaki Y, Suzuki M, Shinohara Y, Fujimoto T: Quantitative electron microscopy shows uniform incorporation of triglycerides into existing lipid droplets. Histochem Cell Biol 2009, 132(3):281-291.
- [27]Bostrom P, Rutberg M, Ericsson J, Holmdahl P, Andersson L, Frohman MA, Boren J, Olofsson SO: Cytosolic lipid droplets increase in size by microtubule-dependent complex formation. Arterioscler Thromb Vasc Biol 2005, 25(9):1945-1951.
- [28]Gong J, Sun Z, Wu L, Xu W, Schieber N, Xu D, Shui G, Yang H, Parton RG, Li P: Fsp27 promotes lipid droplet growth by lipid exchange and transfer at lipid droplet contact sites. J Cell Biol 2011, 195(6):953-963.
- [29]Ariotti N, Murphy S, Hamilton NA, Wu L, Green K, Schieber NL, Li P, Martin S, Parton RG: Postlipolytic insulin-dependent remodeling of micro lipid droplets in adipocytes. Mol Biol Cell 2012, 23(10):1826-1837.
- [30]Paar M, Jungst C, Steiner NA, Magnes C, Sinner F, Kolb D, Lass A, Zimmermann R, Zumbusch A, Kohlwein SD, Wolinski H: Remodeling of lipid droplets during lipolysis and growth in adipocytes. J Biol Chem 2012, 287(14):11164-11173.
- [31]Marcinkiewicz A, Gauthier D, Garcia A, Brasaemle DL: The phosphorylation of serine 492 of perilipin a directs lipid droplet fragmentation and dispersion. J Biol Chem 2006, 281(17):11901-11909.
- [32]Toh SY, Gong J, Du G, Li JZ, Yang S, Ye J, Yao H, Zhang Y, Xue B, Li Q, Yang H, Wen Z, Li P: Up-regulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of fsp27 deficient mice. PLoS One 2008, 3(8):e2890.
- [33]Nishino N, Tamori Y, Tateya S, Kawaguchi T, Shibakusa T, Mizunoya W, Inoue K, Kitazawa R, Kitazawa S, Matsuki Y, Hiramatsu R, Masubuchi S, Omachi A, Kimura K, Saito M, Amo T, Ohta S, Yamaguchi T, Osumi T, Cheng J, Fujimoto T, Nakao H, Nakao K, Aiba A, Okamura H, Fushiki T, Kasuga M: FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets. J Clin Invest 2008, 118(8):2808-2821.
- [34]Jacobs RL, Zhao Y, Koonen DP, Sletten T, Su B, Lingrell S, Cao G, Peake DA, Kuo MS, Proctor SD, Kennedy BP, Dyck JR, Vance DE: Impaired de novo choline synthesis explains why phosphatidylethanolamine N-methyltransferase-deficient mice are protected from diet-induced obesity. J Biol Chem 2010, 285(29):22403-22413.
- [35]Kennedy EP, Weiss SB: The function of cytidine coenzymes in the biosynthesis of phospholipides. J Biol Chem 1956, 222(1):193-214.
- [36]Lands WE: Metabolism of glycerolipides; a comparison of lecithin and triglyceride synthesis. J Biol Chem 1958, 231(2):883-888.
- [37]Nakanishi H, Shindou H, Hishikawa D, Harayama T, Ogasawara R, Suwabe A, Taguchi R, Shimizu T: Cloning and characterization of mouse lung-type acyl-CoA:lysophosphatidylcholine acyltransferase 1 (LPCAT1). Expression in alveolar type II cells and possible involvement in surfactant production. J Biol Chem 2006, 281(29):20140-20147.
- [38]Chen X, Hyatt BA, Mucenski ML, Mason RJ, Shannon JM: Identification and characterization of a lysophosphatidylcholine acyltransferase in alveolar type II cells. Proc Natl Acad Sci U S A 2006, 103(31):11724-11729.
- [39]Shindou H, Hishikawa D, Nakanishi H, Harayama T, Ishii S, Taguchi R, Shimizu T: A single enzyme catalyzes both platelet-activating factor production and membrane biogenesis of inflammatory cells. Cloning and characterization of acetyl-CoA:LYSO-PAF acetyltransferase. J Biol Chem 2007, 282(9):6532-6539.
- [40]Soupene E, Fyrst H, Kuypers FA: Mammalian acyl-CoA:lysophosphatidylcholine acyltransferase enzymes. Proc Natl Acad Sci U S A 2008, 105(1):88-93.
- [41]Zhao Y, Chen Y, Bonacci TM, Bredt DS, Li S, Bensch WR, Moller DE, Kowala M, Konrad RJ, Cao G: Identification and characterization of a lysophosphatidylcholine acyltransferase that is primarily expressed in metabolic tissues. J Biol Chem 2008, 283(13):8258-8265.
- [42]Soupene E, Kuypers FA: Phosphatidylcholine formation by LPCAT1 is regulated by Ca2+ and the redox status of the cell. BMC Biochem 2012, 13(1):8. BioMed Central Full Text
- [43]Moessinger C, Kuerschner L, Spandl J, Shevchenko A, Thiele C: Human lysophosphatidylcholine acyltransferases 1 and 2 are located in lipid droplets where they catalyze the formation of phosphatidylcholine. J Biol Chem 2011, 286(24):21330-21339.
- [44]Ohsaki Y, Cheng J, Fujita A, Tokumoto T, Fujimoto T: Cytoplasmic lipid droplets are sites of convergence of proteasomal and autophagic degradation of apolipoprotein B. Mol Biol Cell 2006, 17(6):2674-2683.
- [45]Yao H, Ye J: Long chain acyl-CoA synthetase 3-mediated phosphatidylcholine synthesis is required for assembly of very low density lipoproteins in human hepatoma Huh7 cells. J Biol Chem 2008, 283(2):849-854.
- [46]Fujimoto Y, Itabe H, Kinoshita T, Homma KJ, Onoduka J, Mori M, Yamaguchi S, Makita M, Higashi Y, Yamashita A, Takano T: Involvement of ACSL in local synthesis of neutral lipids in cytoplasmic lipid droplets in human hepatocyte HuH7. J Lipid Res 2007, 48(6):1280-1292.
- [47]Guo Y, Walther TC, Rao M, Stuurman N, Goshima G, Terayama K, Wong JS, Vale RD, Walter P, Farese RV Jr: Functional genomic screen reveals genes involved in lipid-droplet formation and utilization. Nature 2008, 453(7195):657-661.
- [48]Krahmer N, Guo Y, Wilfling F, Hilger M, Lingrell S, Heger K, Newman HW, Schmidt-Supprian M, Vance DE, Mann M, Farese RV, Walther TC: Phosphatidylcholine synthesis for lipid droplet expansion is mediated by localized activation of CTP:phosphocholine cytidylyltransferase. Cell Metab 2011, 14(4):504-515.
- [49]Jackowski S, Wang J, Baburina I: Activity of the phosphatidylcholine biosynthetic pathway modulates the distribution of fatty acids into glycerolipids in proliferating cells. Biochim Biophys Acta 2000, 1483(3):301-315.
- [50]Cao J, Shan D, Revett T, Li D, Wu L, Liu W, Tobin JF, Gimeno RE: Molecular identification of a novel mammalian brain isoform of acyl-CoA:lysophospholipid acyltransferase with prominent ethanolamine lysophospholipid acylating activity, LPEAT2. J Biol Chem 2008, 283(27):19049-19057.
- [51]Teixeira L, Rabouille C, Rorth P, Ephrussi A, Vanzo NF: Drosophila Perilipin/ADRP homologue Lsd2 regulates lipid metabolism. Mech Dev 2003, 120(9):1071-1081.
- [52]Gronke S, Mildner A, Fellert S, Tennagels N, Petry S, Muller G, Jackle H, Kuhnlein RP: Brummer lipase is an evolutionary conserved fat storage regulator in Drosophila. Cell Metab 2005, 1(5):323-330.
- [53]Arrese EL, Rivera L, Hamada M, Mirza S, Hartson SD, Weintraub S, Soulages JL: Function and structure of lipid storage droplet protein 1 studied in lipoprotein complexes. Arch Biochem Biophys 2008, 473(1):42-47.
- [54]Beller M, Bulankina AV, Hsiao HH, Urlaub H, Jackle H, Kuhnlein RP: PERILIPIN-dependent control of lipid droplet structure and fat storage in Drosophila. Cell Metab 2010, 12(5):521-532.
- [55]Fuss B, Becker T, Zinke I, Hoch M: The cytohesin Steppke is essential for insulin signalling in Drosophila. Nature 2006, 444(7121):945-948.
- [56]Bauer R, Voelzmann A, Breiden B, Schepers U, Farwanah H, Hahn I, Eckardt F, Sandhoff K, Hoch M: Schlank, a member of the ceramide synthase family controls growth and body fat in Drosophila. EMBO J 2009, 28(23):3706-3716.
- [57]Becker T, Loch G, Beyer M, Zinke I, Aschenbrenner AC, Carrera P, Inhester T, Schultze JL, Hoch M: FOXO-dependent regulation of innate immune homeostasis. Nature 2010, 463(7279):369-373.
- [58]Arrese EL, Soulages JL: Insect fat body: energy, metabolism, and regulation. Annu Rev Entomol 2010, 55:207-225.
- [59]Cases S, Smith SJ, Zheng YW, Myers HM, Lear SR, Sande E, Novak S, Collins C, Welch CB, Lusis AJ, Erickson SK, Farese RV Jr: Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc Natl Acad Sci U S A 1998, 95(22):13018-13023.
- [60]Stone SJ, Levin MC, Farese RV Jr: Membrane topology and identification of key functional amino acid residues of murine acyl-CoA:diacylglycerol acyltransferase-2. J Biol Chem 2006, 281(52):40273-40282.
- [61]Stone SJ, Levin MC, Zhou P, Han J, Walther TC, Farese RV Jr: The endoplasmic reticulum enzyme DGAT2 is found in mitochondria-associated membranes and has a mitochondrial targeting signal that promotes its association with mitochondria. J Biol Chem 2009, 284(8):5352-5361.
- [62]Henneberry AL, Wright MM, McMaster CR: The major sites of cellular phospholipid synthesis and molecular determinants of Fatty Acid and lipid head group specificity. Mol Biol Cell 2002, 13(9):3148-3161.
- [63]Hishikawa D, Shindou H, Kobayashi S, Nakanishi H, Taguchi R, Shimizu T: Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity. Proc Natl Acad Sci U S A 2008, 105(8):2830-2835.
- [64]Bouchoux J, Beilstein F, Pauquai T, Guerrera IC, Chateau D, Ly N, Alqub M, Klein C, Chambaz J, Rousset M, Rousset M, Lacorte JM, Morel E, Demignot S: The proteome of cytosolic lipid droplets isolated from differentiated Caco-2/TC7 enterocytes reveals cell-specific characteristics. Biol Cell 2011, 103(11):499-517.
- [65]Butler PL, Mallampalli RK: Cross-talk between remodeling and de novo pathways maintains phospholipid balance through ubiquitination. J Biol Chem 2010, 285(9):6246-6258.
- [66]Li Z, Vance DE: Phosphatidylcholine and choline homeostasis. J Lipid Res 2008, 49(6):1187-1194.
- [67]Walker AK, Jacobs RL, Watts JL, Rottiers V, Jiang K, Finnegan DM, Shioda T, Hansen M, Yang F, Niebergall LJ, Vance DE, Tzoneva M, Hart AC, Näär AM: A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell 2011, 147(4):840-852.
- [68]Penno A, Hackenbroich G, Thiele C: Phospholipids and lipid droplets. Biochim Biophys Acta 2013, 1831(3):589-594.
- [69]Ridgway ND: The role of phosphatidylcholine and choline metabolites to cell proliferation and survival. Crit Rev Biochem Mol Biol 2013, 48(1):20-38.
- [70]Fagone P, Jackowski S: Phosphatidylcholine and the CDP-choline cycle. Biochim Biophys Acta 2013, 1831(3):523-532.
- [71]Wang H, Gilham D, Lehner R: Proteomic and lipid characterization of apolipoprotein B-free luminal lipid droplets from mouse liver microsomes: implications for very low density lipoprotein assembly. J Biol Chem 2007, 282(45):33218-33226.
- [72]Kuhnlein RP: Lipid droplet-based storage fat metabolism in Drosophila: thematic review series: lipid droplet synthesis and metabolism: from yeast to man. J Lipid Res 2012, 53(8):1430-1436.
- [73]Spandl J, White DJ, Peychl J, Thiele C: Live cell multicolor imaging of lipid droplets with a new dye, LD540. Traffic 2009, 10(11):1579-1584.
- [74]Ejsing CS, Sampaio JL, Surendranath V, Duchoslav E, Ekroos K, Klemm RW, Simons K, Shevchenko A: Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry. Proc Natl Acad Sci U S A 2009, 106(7):2136-2141.
- [75]Ejsing CS, Duchoslav E, Sampaio J, Simons K, Bonner R, Thiele C, Ekroos K, Shevchenko A: Automated identification and quantification of glycerophospholipid molecular species by multiple precursor ion scanning. Anal Chem 2006, 78(17):6202-6214.
- [76]Zech T, Ejsing CS, Gaus K, de Wet B, Shevchenko A, Simons K, Harder T: Accumulation of raft lipids in T-cell plasma membrane domains engaged in TCR signalling. EMBO J 2009, 28(5):466-476.
- [77]Schwudke D, Hannich JT, Surendranath V, Grimard V, Moehring T, Burton L, Kurzchalia T, Shevchenko A: Top-down lipidomic screens by multivariate analysis of high-resolution survey mass spectra. Anal Chem 2007, 79(11):4083-4093.
- [78]Gaebler A, Milan R, Straub L, Hoelper D, Kuerschner L, Thiele C: Alkyne lipids as substrates for click chemistry-based in vitro enzymatic assays. J Lipid Res 2013, 54(8):2282-2290.
- [79]Thiele C, Papan C, Hoelper D, Kusserow K, Gaebler A, Schoene M, Piotrowitz K, Lohmann D, Spandl J, Stevanovic A, Shevchenko A, Kuerschner L: Tracing fatty acid metabolism by click chemistry. ACS Chem Biol 2012, 7(12):2004-2011.