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Age-Related Changes in the Phospholipase D-Dependent Signal Pathway of Insulin in the Rat Neocortex

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Neurophysiology Aims and scope

Insulin participates in stabilization of normal functioning of the CNS; phospholipase D (PLD) is an integral part of the signal cascade of this hormone. With age, the lipid spectrum of the cells is modified, which implicates dysfunction of different signal pathways, including that of insulin. In our study, we found that the contents of ceramides and free fatty acids in the neocortex of old (24 months) rats are appreciably higher than that in 3-month-old animals. Under such conditions, the ability of insulin to activate PLD sharply drops. Incubation of neocortical tissues obtained from young animals in the presence of exogenous С2 ceramide or palmitic acid (a precursor of sphingolipids) leads to an increase in the content of endogenous ceramides. This process is accompanied by suppression of the insulinstimulated formation of phosphatidylethanol (PET, a product of reaction of transphosphatidylation of ethanol by PLD). Thus, the obtained data indicate that the activity of a PLD-dependent link of the signal cascade of insulin in the neocortex is significantly weakened with aging; ceramide plays an important role in this process.

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References

  1. K. H. Lee, A. S. Calikoglu, P. Ye, and A. J. D’Ercole, “Insulin-like growth factor-I (IGF-I) ameliorates and IGF binding protein-1 (IGFBP-1) exacerbates the effects of undernutrition on brain growth during early postnatal life: studies in IGF-I and IGFBP-1 transgenic mice,” Pediat. Res., 45, No. 3, 331–336 (1999).

    Article  PubMed  CAS  Google Scholar 

  2. C. R. Plata-Salamán, “Insulin in the cerebrospinal fluid,” Neurosci. Biobehav. Rev., 15, No. 2, 243–258 (1991).

    Article  PubMed  Google Scholar 

  3. Y. Yu, A. Kastin, and W. Pan, “Reciprocal interactions of insulin and insulin-like growth factor I in receptormediated transport across the blood-brain barrier,” Endocrinology, 147, 2611–2615 (2006).

    Article  PubMed  CAS  Google Scholar 

  4. Z. Laron, “Insulin and the brain,” Arch. Physiol. Biochem., 115, No. 2, 112–116 (2009).

    Article  PubMed  CAS  Google Scholar 

  5. W. Zhao, H. Chen, H. Xu, et al., “Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats,” J. Biol. Chem., 274, No. 49, 34893–34902 (1999).

    Article  PubMed  CAS  Google Scholar 

  6. R. Schechter, T. Yanovitch, M. Abboud, et al., “Effects of brain endogenous insulin on neurofilament and MAPK in fetal rat neuron cell cultures,” Brain Res., 808, No. 2, 270–278 (1998).

    Article  PubMed  CAS  Google Scholar 

  7. J. Havrankova, J. Roth, and M. Brownstein, “Insulin receptors are widely distributed in the central nervous system of the rat,” Nature, 272, No. 5656, 827–829 (1978).

    Article  PubMed  CAS  Google Scholar 

  8. M. Salkovic-Petrisic and S. Hoyer, “Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach,” J. Neural. Transm., Suppl., No. 72, 217–233 (2007).

    Google Scholar 

  9. S. M. de la Monte and J. R. Wands, “Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease,” J. Alzheimers Dis., 7, No. 1, 45–61 (2005).

    PubMed  Google Scholar 

  10. S. M. de la Monte, “Insulin resistance and Alzheimer’s disease,” Biochem. Mol. Biol. Rep., 42, No. 8, 475–481 (2009).

    Google Scholar 

  11. S. Cockcroft, “Signalling roles of mammalian phospholipase D1 and D2,” Cell. Mol. Life Sci., 58, No. 11, 1674–1687 (2001).

    Article  PubMed  CAS  Google Scholar 

  12. J. H. Exton, “Phospholipase D – structure, regulation and function,” Rev. Physiol. Biochem. Pharmacol., 144, 1–94 (2002).

    Article  PubMed  CAS  Google Scholar 

  13. G. M. Jenkins and M. A. Frohman, “Phospholipase D: a lipid centric review,” Cell. Mol. Life Sci., 62, Nos. 19/20, 2305–2316 (2005).

    Article  PubMed  CAS  Google Scholar 

  14. J. Klein, V. Chalifa, M. Liscovitch, and K. Löffelholz, “Role of phospholipase D activation in nervous system physiology and pathophysiology,” J. Neurochem., 65, No. 4, 1445–1455 (1995).

    Article  PubMed  CAS  Google Scholar 

  15. G. A. Salvador, S. J. Pasquare, M. G. Ilincheta de Boschero, and N. M. Giusto, “Differential modulation of phospholipase D and phosphatidate phosphohydrolase during aging in rat cerebral cortex synaptosomes” Exp. Gerontol., 37, No. 4, 543–552 (2002).

    Article  PubMed  CAS  Google Scholar 

  16. T. G. Oliveira and G. Di Paolo, “Phospholipase D in brain function and Alzheimer’s disease,” Biochim. Biophys. Acta, 1801, No. 8, 799–805 (2010).

    Article  PubMed  CAS  Google Scholar 

  17. Y. Kanaho, Y. Funakoshi, and H. Hasegawa, “Phospholipase D signalling and its involvement in neurite outgrowth,” Biochim. Biophys. Acta, 1791, No. 9, 898–904 (2009).

    Article  PubMed  CAS  Google Scholar 

  18. D. Zhao, M. A. Frohman, and J. K. Blusztajn, “Generation of choline for acetylcholine synthesis by phospholipase D isoforms,” BMC (BioMed. Central) Neurosci., 2, 16 (2001).

    Article  CAS  Google Scholar 

  19. N. A. Babenko and V. S. Kharchenko, “Role of ceramides in dysfunction of insulin signaling in the rat diaphragm under in vivo and in vitro condiitons”, Probl. Endokrin. Pathol., No. 1, 37–43 (2009).

  20. N. A. Babenko and V. S. Kharchenko, “Ceramides inhibit phospholipase D-dependent insulin signaling in liver cells of old rats,” Biochemistry, 77, No. 2, 180–186 (2012).

    PubMed  CAS  Google Scholar 

  21. Y. A. Hannun and L. M. Obeid, “Principles of bioactive lipid signalling: lessons from sphingolipids,” Nat. Rev. Mol. Cell. Biol., 9, No. 2, 139–150 (2008).

    Article  PubMed  CAS  Google Scholar 

  22. N. A. Babenko and Y. A. Semenova, “Effects of long-term fish oil-enriched diet on the sphingolipid metabolism in brain of old rats,” Exp. Gerontol., 45, No. 5, 375–380 (2010).

    Article  PubMed  CAS  Google Scholar 

  23. S. M. de la Monte, M. Tong, V. Nguyen, et al., “Ceramide-mediated insulin resistance and impairment of cognitive-motor functions,” J. Alzheimers Dis., 21, No. 3, 967–984 (2010).

    PubMed  Google Scholar 

  24. S. M. de la Monte, E. Re, L. Longato, and M. Tong, “Dysfunctional pro-ceramide, ER stress, and insulin/IGF signaling networks with progression of Alzheimer’s disease,” J. Alzheimers Dis., 30, Suppl. 2, S217–S229 (2012).

    PubMed  Google Scholar 

  25. K. Lieb, B. L. Fiebich, M. Berger, et al., “The neuropeptide substance P activates transcription factor NF-kappa B and kappa B-dependent gene expression in human astrocytoma cells,” J. Immunol., 159, 4952–4958 (1997).

    PubMed  CAS  Google Scholar 

  26. K. Pahan, F. G. Sheikh, M. Khan, et al., “Sphingomyelinase and ceramide stimulate the expression of inducible nitric-oxide synthase in rat primary astrocytes,” J. Biol. Chem., 273, No. 5, 2591–2600 (1998).

    Article  PubMed  CAS  Google Scholar 

  27. T. Wei, C. Chen, J. Hou, et al., “Nitric oxide induces oxidative stress and apoptosis in neuronal cells,” Biochim. Biophys. Acta, 1498, No. 1, 72–79 (2000).

    Article  PubMed  CAS  Google Scholar 

  28. A. Szutowicz and W. Lysiak, “Regional and subcellular distribution of ATP-citrate lyase and other enzymes of acetyl-CoA metabolism in rat brain,” J Neurochem., 35, No. 4, 775–785 (1980).

    Article  PubMed  CAS  Google Scholar 

  29. K. Ayasolla, M. Khan, A. K. Singh, and I. Singh, “Inflammatory mediator and beta-amyloid (25-35)-induced ceramide generation and iNOS expression are inhibited by vitamin E,” Free Radical. Biol. Med., 37, No. 3, 325–338 (2004).

    Article  CAS  Google Scholar 

  30. J. Klein, “Functions and pathophysiological roles of phospholipase D in the brain,” J. Neurochem., 94, No. 6, 1473–1487 (2005).

    Article  PubMed  CAS  Google Scholar 

  31. S. Yoshimura, H. Sakai, K. Ohguchi, et al., “Changes in the activity and mRNA levels of phospholipase D during ceramide-induced apoptosis in rat C6 glial cells,” J. Neurochem., 69, No. 2, 713–720 (1997).

    Article  PubMed  CAS  Google Scholar 

  32. B. Schatter, S. Jin, K. Löffelholz, and J. Klein, “Crosstalk between phosphatidic acid and ceramide during ethanol-induced apoptosis in astrocytes,” BMC (BioMed. Central) Pharmacol., 5, 3 (2005).

    Article  Google Scholar 

  33. J. A. Chavez, W. L. Holland, J. Bar, et al., “Acid ceramidase overexpression prevents the inhibitory effects of saturated fatty acids on insulin signaling,” J. Biol. Chem., 280, No. 20, 20148–20153 (2005).

    Article  PubMed  CAS  Google Scholar 

  34. G. L. Moehren, J. B. Gustavsson, and J. B. Hoek “Activation and desensitization of phospholipase D in intact rat hepatocytes,” J. Biol. Chem., 269, No. 2, 838–848 (1994).

    PubMed  CAS  Google Scholar 

  35. P. Huang, Y. M. Altshuller, J. C. Hou, et al., “Insulinstimulated plasma membrane fusion of Glut4 glucose transporter-containing vesicles is regulated by phospholipase D1,” Mol. Biol. Cell, 16, No. 6, 2614–2623 (2005).

    Article  PubMed  CAS  Google Scholar 

  36. E. G. Bligh and W. J. Dyer, “A rapid method of total lipid extraction and purification,” Can. J. Biochem. Physiol., 37, No. 8, 911–917 (1959).

    Article  PubMed  CAS  Google Scholar 

  37. J. B. March and D. B. Weinstein, “Simple charring method for determination of lipids,” J. Lipid Res., 7, No. 4, 574–580 (1966).

    Google Scholar 

  38. G. R. Bartlett, “Phosphorus assay in column chromatography,” J. Biol. Chem., 234, No. 3, 466–468 (1959).

    PubMed  CAS  Google Scholar 

  39. C. J. Lauter and E. G. Trams, “A spectrophotometric determination of sphingosine,” J. Lipid Res., 3, 136–138 (1962).

    CAS  Google Scholar 

  40. O. N. Lowry, N. J. Rosebrough, A. L. Farr, and R. J. Randal, “Protein measurement with the Folin phenol reagent,” J. Biol. Chem., 193, 365–375 (1951).

    Google Scholar 

  41. M. G. Roth, “Molecular mechanisms of PLD function in membrane traffic,” Traffic, 9, No. 8, 1233–1239 (2008).

    Article  PubMed  CAS  Google Scholar 

  42. Y. Humeau, N. Vitale, S. Chasserot-Golaz, et al., “A role for phospholipase D1 in neurotransmitter release,” Proc. Natl. Acad. Sci. USA, 98, No. 26, 15300–15305 (2001).

    Article  PubMed  CAS  Google Scholar 

  43. E. Sarri, I. Böckmann, U. Kempter, et al., “Regulation of phospholipase D activity in synaptosomes permeabilized with Staphylococcus aureus alpha-toxin,” FEBS Lett., 440, No. 3, 287–290 (1998).

    Article  PubMed  CAS  Google Scholar 

  44. M. Scarselli and J. G. Donaldson, “Constitutive internalization of G protein-coupled receptors and G proteins via clathrin-independent endocytosis,” J. Biol. Chem., 284, No. 6, 3577–3585 (2009).

    Article  PubMed  CAS  Google Scholar 

  45. M. S. Yoon, C. Yon, S. Y. Park, et al., “Role of phospholipase D1 in neurite outgrowth of neural stem cells,” Biochem. Biophys. Res. Commun., 329, No. 3, 804–811 (2005).

    Article  PubMed  CAS  Google Scholar 

  46. M. Czarny, Y. Lavie, G. Fiucci, and M. Liscovitch, “Localization of phospholipase D in detergent-insoluble, caveolin-rich membrane domains. Modulation by caveolin-1 expression and caveolin-182-101,” J. Biol. Chem., 274, No. 5, 2717–2724 (1999).

    Article  PubMed  CAS  Google Scholar 

  47. G. Du, Y. M. Altshuller, N. Vitale, et al., “Regulation of phospholipase D1 subcellular cycling through coordination of multiple membrane association motifs,” J. Cell Biol., 162, No. 2, 305–315 (2003).

    Article  PubMed  CAS  Google Scholar 

  48. L. J. Pike, “Growth factor receptors, lipid rafts and caveolae: an evolving story,” Biochim. Biophys. Acta, 1746, No. 3, 260–273 (2005).

    Article  PubMed  CAS  Google Scholar 

  49. X. Han, S. Rozen, S. H. Boyle, et al., “Metabolomics in early Alzheimer’s disease: identification of altered plasma sphingolipidome using shotgun lipidomics,” PLoS One, 6, No. 7, e21643 (2011).

    Article  PubMed  CAS  Google Scholar 

  50. L. Kh. M. Khassunekh, Ya. O. Semenova, O. A. Krasil’nikova, and N. A. Babenko, “Age-related peculiarities of the content of signal lipids in the liver and brain of rats,” Fiziol. Zh., 52, No. 6, 79–84 (2006).

    PubMed  CAS  Google Scholar 

  51. A. Abousalham, C. Liossis, L. O’Brien, and D. N. Brindley, “Cell-permeable ceramides prevent the activation of phospholipase D by ADP-ribosylation factor and RhoA,” J. Biol. Chem., 272, 1069–1075 (1997).

    Article  PubMed  CAS  Google Scholar 

  52. A. Gidwani, H. A. Brown, D. Holowka, and B. Baird, “Disruption of lipid order by short-chain ceramides correlates with inhibition of phospholipase D and downstream signaling by FcepsilonRI,” J. Cell Sci., 116, 3177–3187 (2003).

    Article  PubMed  CAS  Google Scholar 

  53. S. Mebarek, H. Komati, F. Naro, et al., “Inhibition of de novo ceramide synthesis upregulates phospholipase D and enhances myogenic differentiation,” J. Cell Sci., 120, Part 3, 407–416 (2007).

    Article  PubMed  CAS  Google Scholar 

  54. I. N. Singh, L. M. Stromberg, S. G. Bourgoin, et al., “Ceramide inhibition of mammalian phospholipase D1 and D2 activities is antagonized by phosphatidyl inositol 4,5-bisphosphate,” Biochemistry, 40, 11227–11233 (2001).

    Article  PubMed  CAS  Google Scholar 

  55. S. Patil, D. Balu, J. Melrose, and C. Chan, “Brain-regionspecificity of palmitic acid-induced abnormalities associated with Alzheimer’s disease,” BMC (BioMed Central) Res. Notes, 4, 1–20 (2008).

    Google Scholar 

  56. N. D. Ridgway and D. L. Merriam, “Metabolism of short-chain ceramide and dihydroceramide analogues in Chinese hamster ovary (CHO) cells,” Biochim. Biophys. Acta, 1256, No. 1, 57–70 (1995).

    Article  PubMed  Google Scholar 

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  1. Research Institute of Biology at the Karazin Khar’kov National University, Khar’kov, Ukraine

    N. A. Babenko & V. S. Kharchenko

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Babenko, N.A., Kharchenko, V.S. Age-Related Changes in the Phospholipase D-Dependent Signal Pathway of Insulin in the Rat Neocortex. Neurophysiology 45, 120–127 (2013). https://doi.org/10.1007/s11062-013-9346-9

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