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Specialized hepatocyte-like cells regulate Drosophila lipid metabolism

Abstract

Lipid metabolism is essential for growth and generates much of the energy needed during periods of starvation. In Drosophila, fasting larvae release large quantities of lipid from the fat body but it is unclear how and where this is processed. Here we identify the oenocyte as the principal cell type accumulating lipid droplets during starvation. Tissue-specific manipulations of the Slimfast amino-acid channel, the Lsd2 fat-storage regulator and the Brummer lipase indicate that oenocytes act downstream of the fat body. In turn, oenocytes are required for depleting stored lipid from the fat body during fasting. Hence, lipid-metabolic coupling between the fat body and oenocytes is bidirectional. When food is plentiful, oenocytes have critical roles in regulating growth, development and feeding behaviour. In addition, they specifically express many different lipid-metabolizing proteins, including Cyp4g1, an ω-hydroxylase regulating triacylglycerol composition. These findings provide evidence that some lipid-processing functions of the mammalian liver are performed in insects by oenocytes.

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Figure 1: Oenocytes accumulate lipids during starvation.
Figure 2: The fat body regulates lipid accumulation in oenocytes.
Figure 3: Oenocytes regulate growth and developmental progression.
Figure 4: Oenocytes are required for lipid depletion from the fat body during starvation.
Figure 5: Cyp4g1 is an essential oenocyte-specific gene regulating TAG composition.

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References

  1. Gibbons, G. F., Islam, K. & Pease, R. J. Mobilisation of triacylglycerol stores. Biochim. Biophys. Acta 1483, 37–57 (2000)

    Article  CAS  PubMed  Google Scholar 

  2. Lee, C. H., Olson, P. & Evans, R. M. Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 144, 2201–2207 (2003)

    Article  CAS  PubMed  Google Scholar 

  3. Yu, S., Rao, S. & Reddy, J. K. Peroxisome proliferator-activated receptors, fatty acid oxidation, steatohepatitis and hepatocarcinogenesis. Curr. Mol. Med. 3, 561–572 (2003)

    Article  CAS  PubMed  Google Scholar 

  4. Zechner, R., Strauss, J. G., Haemmerle, G., Lass, A. & Zimmermann, R. Lipolysis: pathway under construction. Curr. Opin. Lipidol. 16, 333–340 (2005)

    Article  CAS  PubMed  Google Scholar 

  5. Reddy, J. K. & Hashimoto, T. Peroxisomal β-oxidation and peroxisome proliferator-activated receptor-α: an adaptive metabolic system. Annu. Rev. Nutr. 21, 193–230 (2001)

    Article  CAS  PubMed  Google Scholar 

  6. Wanders, R. J. Peroxisomes, lipid metabolism, and peroxisomal disorders. Mol. Genet. Metab. 83, 16–27 (2004)

    Article  CAS  PubMed  Google Scholar 

  7. Ntambi, J. M. & Miyazaki, M. Regulation of stearoyl-CoA desaturases and role in metabolism. Prog. Lipid Res. 43, 91–104 (2004)

    Article  CAS  PubMed  Google Scholar 

  8. Wanders, R. J. et al. Peroxisomal fatty acid α- and β-oxidation in health and disease: new insights. Adv. Exp. Med. Biol. 544, 293–302 (2003)

    Article  CAS  PubMed  Google Scholar 

  9. Browning, J. D. & Horton, J. D. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Invest. 114, 147–152 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. McKay, R. M., McKay, J. P., Avery, L. & Graff, J. M. C. elegans: a model for exploring the genetics of fat storage. Dev. Cell 4, 131–142 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ashrafi, K. et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421, 268–272 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Butterworth, F. M., Bodenstein, D. & King, R. C. Adipose tissue of Drosophila melanogaster. I. An experimental study of larval fat body. J. Exp. Zool. 158, 141–153 (1965)

    Article  CAS  PubMed  Google Scholar 

  13. Keeley, L. L. in Comprehensive Insect Physiology, Biochemistry and Pharmacology (eds Kerkut, G. A. & Gilbert, L. I.) 211–248 (Pergamonn, New York, 1985)

    Google Scholar 

  14. Dean, R. L., Locke, M. & Collins, J. V. in Comprehensive Insect Physiology, Biochemistry and Pharmacology (eds Kerkut, G. A. & Gilbert, L. I.) 155–210 (Pergamonn, New York, 1985)

    Google Scholar 

  15. Canavoso, L. E., Jouni, Z. E., Karnas, K. J., Pennington, J. E. & Wells, M. A. Fat metabolism in insects. Annu. Rev. Nutr. 21, 23–46 (2001)

    Article  CAS  PubMed  Google Scholar 

  16. Dantuma, N. P. et al. An insect homolog of the vertebrate very low density lipoprotein receptor mediates endocytosis of lipophorins. J. Lipid Res. 40, 973–978 (1999)

    CAS  PubMed  Google Scholar 

  17. Lee, C. S. et al. Wax moth, Galleria mellonella, high density lipophorin receptor: alternative splicing, tissue-specific expression, and developmental regulation. Insect Biochem. Mol. Biol. 33, 761–771 (2003)

    Article  CAS  PubMed  Google Scholar 

  18. Zhang, H., Stallock, J. P., Ng, J. C., Reinhard, C. & Neufeld, T. P. Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev. 14, 2712–2724 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Colombani, J. et al. A nutrient sensor mechanism controls Drosophila growth. Cell 114, 739–749 (2003)

    Article  CAS  PubMed  Google Scholar 

  20. Gronke, S. et al. Brummer lipase is an evolutionary conserved fat storage regulator in Drosophila.. Cell Metab. 1, 323–330 (2005)

    Article  PubMed  Google Scholar 

  21. Gronke, S. et al. Control of fat storage by a Drosophila PAT domain protein. Curr. Biol. 13, 603–606 (2003)

    Article  CAS  PubMed  Google Scholar 

  22. Teixeira, L., Rabouille, C., Rorth, P., Ephrussi, A. & Vanzo, N. F. Drosophila Perilipin/ADRP homologue Lsd2 regulates lipid metabolism. Mech. Dev. 120, 1071–1081 (2003)

    Article  CAS  PubMed  Google Scholar 

  23. Britton, J. S. & Edgar, B. A. Environmental control of the cell cycle in Drosophila: nutrition activates mitotic and endoreplicative cells by distinct mechanisms. Development 125, 2149–2158 (1998)

    CAS  PubMed  Google Scholar 

  24. Martin, J. F., Hersperger, E., Simcox, A. & Shearn, A. minidiscs encodes a putative amino acid transporter subunit required non-autonomously for imaginal cell proliferation. Mech. Dev. 92, 155–167 (2000)

    Article  CAS  PubMed  Google Scholar 

  25. Britton, J. S., Lockwood, W. K., Li, L., Cohen, S. M. & Edgar, B. A. Drosophila's insulin/PI3-kinase pathway coordinates cellular metabolism with nutritional conditions. Dev. Cell 2, 239–249 (2002)

    Article  CAS  PubMed  Google Scholar 

  26. Lillie, R. D. Various oil soluble dyes as fat stains in the supersaturated isopropanol technic. Stain Technol. 19, 55–58 (1944)

    Article  Google Scholar 

  27. Lawrence, P. A. & Johnston, P. Observations on cell lineage of internal organs of Drosophila.. J. Embryol. Exp. Morphol. 91, 251–266 (1986)

    CAS  PubMed  Google Scholar 

  28. Elstob, P. R., Brodu, V. & Gould, A. P. spalt-dependent switching between two cell fates that are induced by the Drosophila EGF receptor. Development 128, 723–732 (2001)

    CAS  PubMed  Google Scholar 

  29. Rusten, T. E. et al. Spalt restricts EGFR mediated induction of chordotonal precursors in the embryonic PNS of Drosophila.. Development 128, 711–722 (2001)

    CAS  PubMed  Google Scholar 

  30. Brodu, V., Elstob, P. R. & Gould, A. P. EGF receptor signaling regulates pulses of cell delamination from the Drosophila ectoderm. Dev. Cell 7, 885–895 (2004)

    Article  CAS  PubMed  Google Scholar 

  31. Cherbas, L., Hu, X., Zhimulev, I., Belyaeva, E. & Cherbas, P. EcR isoforms in Drosophila: testing tissue-specific requirements by targeted blockade and rescue. Development 130, 271–284 (2003)

    Article  CAS  PubMed  Google Scholar 

  32. Wu, Q., Zhang, Y., Xu, J. & Shen, P. Regulation of hunger-driven behaviors by neural ribosomal S6 kinase in Drosophila. Proc. Natl Acad. Sci. USA 102, 13289–13294 (2005)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  33. Beadle, G. W., Tatum, E. L. & Clancy, C. W. Food level in relation to rate of development and eye pigmentation in Drosophila. Biol. Bull. 75, 447–462 (1938)

    Article  Google Scholar 

  34. Riddiford, L. M. in The Development of Drosophila melanogaster (eds Bate, M. & Martinez Arias, A.) 899–939 (Cold Spring Harbor Laboratory Press, New York, 1993)

  35. Gilbert, L. I. Halloween genes encode P450 enzymes that mediate steroid hormone biosynthesis in Drosophila melanogaster. Mol. Cell. Endocrinol. 215, 1–10 (2004)

    Article  CAS  PubMed  Google Scholar 

  36. McGuire, S. E., Le, P. T., Osborn, A. J., Matsumoto, K. & Davis, R. L. Spatiotemporal rescue of memory dysfunction in Drosophila. Science 302, 1765–1768 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  37. Ueyama, M., Chertemps, T., Labeur, C. & Wicker-Thomas, C. Mutations in the desat1 gene reduces the production of courtship stimulatory pheromones through a marked effect on fatty acids in Drosophila melanogaster. Insect Biochem. Mol. Biol. 35, 911–920 (2005)

    Article  CAS  PubMed  Google Scholar 

  38. Sundseth, S. S., Nix, C. E. & Waters, L. C. Isolation of insecticide resistance-related forms of cytochrome P-450 from Drosophila melanogaster. Biochem. J. 265, 213–217 (1990)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Griswold, C. M., Matthews, A. L., Bewley, K. E. & Mahaffey, J. W. Molecular characterization and rescue of acatalasemic mutants of Drosophila melanogaster. Genetics 134, 781–788 (1993)

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Simpson, A. E. The cytochrome P450 4 (CYP4) family. Gen. Pharmacol. 28, 351–359 (1997)

    Article  CAS  PubMed  Google Scholar 

  41. Tomancak, P. et al. Systematic determination of patterns of gene expression during Drosophila embryogenesis. Genome Biol. 3, RESEARCH0088 (2002)

    Article  PubMed  PubMed Central  Google Scholar 

  42. Landois, L. Ueber die Funktion des Fettkörpers. Zeitschr. f. Wissensch. Zoologie 15, 371–372 (1865)

    Google Scholar 

  43. Koschevnikov, G. Ueber den Fettkörper und die Oenocyten der Honigbiene (Apis mellifera). Z. Anz. Bd. 23, 657–661 (1900)

    Google Scholar 

  44. Koller, G. Die innere Sekretion bei wirbellosen Tieren. Biol. Rev. 4, 269–306 (1928)

    Google Scholar 

  45. Wigglesworth, V. The physiology of the cuticle and of ecdysis in Rhodnius prolixus (Triatomidae, Hemiptera); with special reference to the function of the oenocytes and of the dermal glands. Quart. J. Micros. Sci. 76, 269–318 (1933)

    Google Scholar 

  46. Zinke, I., Kirchner, C., Chao, L. C., Tetzlaff, M. T. & Pankratz, M. J. Suppression of food intake and growth by amino acids in Drosophila: the role of pumpless, a fat body expressed gene with homology to vertebrate glycine cleavage system. Development 126, 5275–5284 (1999)

    CAS  PubMed  Google Scholar 

  47. Oike, Y., Akao, M., Kubota, Y. & Suda, T. Angiopoietin-like proteins: potential new targets for metabolic syndrome therapy. Trends Mol. Med. 11, 473–479 (2005)

    Article  CAS  PubMed  Google Scholar 

  48. Duerden, J. M. & Gibbons, G. F. Secretion and storage of newly synthesized hepatic triacylglycerol fatty acids in vivo in different nutritional states and in diabetes. Biochem. J. 255, 929–935 (1988)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Burdge, G. C., Wright, P., Jones, A. E. & Wootton, S. A. A method for separation of phosphatidylcholine, triacylglycerol, non-esterified fatty acids and cholesterol esters from plasma by solid-phase extraction. Br. J. Nutr. 84, 781–787 (2000)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank G. Gibbons and K. Frayn for providing advice and facilities for metabolic profiling, and P. Elstob, V. Brodu, S. Mahadevaiah and P. Sarchet for assistance with enhancer trap screening and sequencing. We also thank S. Celniker and BDGP for providing many of the panels used in Supplementary Fig. 4, and R. Barrio, B. Bello, L. Michaut, A. Brand, R. Carthew, W. Janning, S. Kennel, C. O’Kane, R. Kühnlein, P. Leopold, I. Miguel-Aliaga, I. Salecker, R. Schultz, N. Tapon, C. Thummel, J.-P. Vincent, T. Xu, Flyview, The NP consortium, the DGRC at Kyoto Institute of Technology, the Bloomington, Umeå, and Szeged stock centres and the DSHB at the University of Iowa for DNA constructs, flies and antibodies. We also thank I. Robinson for discussions and J. Briscoe, X. Franch-Marro, G. Gibbons, I. Miguel-Aliaga, E. Ober, E. Piddini, I. Salecker, P. Serpente and D. Wilkinson for critical reading of the manuscript. This work was supported by the Medical Research Council (E.G., D.W and A.P.G.), the Mexican National Council for Science and Technology (E.G.) and the Wellcome Trust (B.F.).

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Correspondence to Alex P. Gould.

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Gutierrez, E., Wiggins, D., Fielding, B. et al. Specialized hepatocyte-like cells regulate Drosophila lipid metabolism. Nature 445, 275–280 (2007). https://doi.org/10.1038/nature05382

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