Abstract
Ceramides are a novel class of biologically active molecules involved in the regulation of different signaling pathways. Ceramide is involved in regulation of the phospholipase D (PLD) activity and development of cell resistance to insulin. In this work, we have studied age-related features of insulin regulation of PLD activity and glucose metabolism in intact cells and modeled their resistance to insulin by exogenous ceramide and palmitic acid. Contents of ceramides and of free fatty acids (FFA) are found to increase with age, as well as on incubation of liver cells of young rats in the presence of the ceramide precursor palmitic acid. Under these conditions, the ability of insulin to activate PLD, the cell uptake of glucose, and glycogen synthesis sharply decreased. On incubation of hepatocytes of young animals in the presence of exogenous C2-ceramide, the contents of endogenous ceramides increased but not the contents of FFAs and of neutral lipids. These events were accompanied by suppression of the insulin-induced production of phosphatidylethanol (a result of ethanol transphosphatidylation by PLD), glucose uptake, and glycogen synthesis. Incubation of insulin-resistant liver cells of young rats and also of hepatocytes of old rats in the presence of myriocin (an inhibitor of the de novo synthesis of ceramide) was associated with a decrease in ceramide content in the cells and an increase in the cell sensitivity to insulin. The findings indicate an important role of ceramide in disturbance of insulin signaling due to inhibition of the PLD-dependent link in the liver cells of old animals.
Similar content being viewed by others
Abbreviations
- DAG:
-
diacylglycerol
- FFA:
-
free fatty acids
- GLUT:
-
glucose transporter
- PC:
-
phosphatidylcholine
- PET:
-
phosphatidylethanol
- PI3K:
-
phosphatidylinositol-3 kinase
- PKC:
-
protein kinase C
- PLD:
-
phospholipase D
- 16:0:
-
palmitic acid
References
Lingtile, S. A., Oakley, J. I., and Nikolova-Karakashian, M. N. (2000) Mech. Ageing Dev., 120, 111–125.
Kavok, N. S., Krasilnikova, O. A., and Babenko, N. A. (2003) Exp. Gerontol., 38, 441–447.
Venable, M. E., Lee, J. Y., Smyth, M. J., Bielawska, A., and Obeid, L. M. (1995) J. Biol. Chem., 270, 30701–30708.
Babenko, N. A., and Shakhova, E. G. (2006) Exp. Gerontol., 41, 32–39.
Babenko, N. A., and Semenova, Y. A. (2010) Exp. Gerontol., 45, 375–380.
Cuttler, R. G., and Mattson, M. P. (2001) Mech. Ageing Dev., 122, 895–908.
Yang, G., Badeanlou, L., Bielawski, J., Roberts, A. J., Hannun, Y. A., and Samad, F. (2009) J. Physiol. Endocrinol. Metab., 297, E211–E224.
Turinsky, J., O’sullivan, D. M., and Bayly, B. P. (1990) J. Biol. Chem., 265, 16880–16885.
Hoffman, J. M., Standaert, M. L., Nair, G. P., and Farese, R. V. (1991) Biochemistry, 30, 3315–3322.
Slaaby, R., Du, G., Altshuller, Y. M., Frohman, M. A., and Seedorf, K. (2000) Biochem. J., 351, 613–619.
Donchenko, V., Zannetti, A., and Baldini, P. M. (1994) Biochim. Biophys. Acta, 1222, 492–500.
Karnam, P., Standaert, M. L., Galloway, L., and Farese, R. V. (1997) J. Biol. Chem., 272, 6136–6140.
Farese, R. V. (2002) Am. J. Physiol. Endocrinol. Metab., 283, E1–E11.
Kellett, G. L., and Brot-Laroche, E. (2005) Diabetes, 54, 3056–3062.
Zaid, H., Antonescu, C. N., Randhawa, V. K., and Klip, A. (2008) Biochem. J., 413, 201–215.
Hannun, Y. A., and Obeid, L. M. (2002) J. Biol. Chem., 277, 25847–25850.
Singh, I. N., Stromberg, L. M., Bourgoin, S. G., Sciorra, V. A., Morris, A. J., and Brindley, D. N. (2001) Biochemistry, 40, 11227–11233.
Abousalham, A., Liossis, C., O’Brien, L., and Brindley, D. N. (1997) J. Biol. Chem., 272, 1069–1075.
Gidwani, A., Brown, H. A., Holowka, D., and Baird, B. (2003) J. Cell. Sci., 116, 3177–3187.
Petrenko, A. Y., Sukach, A. N., and Roslyakov, A. D. (1991) Biokhimiya, 56, 1647–1651.
Chavez, J. A., Holland, W. L., Bar, J., Sandhoff, K., and Summers, S. A. (2005) J. Biol. Chem., 280, 20148–20153.
Blair, A. S., Hajduc, J. E., Litherland, G. J., and Hundal, H. S. (1999) J. Biol. Chem., 274, 36293–36299.
Billah, M. M., and Anthes, J. C. (1990) Biochem. J., 269, 281–291.
Moehren, G., Gustavsson, L., and Hoek, J. B. (1994) J. Biol. Chem., 269, 838–848.
Exton, J. H. (2002) FEBS Lett., 531, 58–61.
Huang, D. P., Altshuller, Y. M., Hou, J. C., Pessin, J. E., and Frohman, M. A. (2005) Mol. Biol. Cell, 16, 2614–2623.
Bligh, E. G., and Dyer, W. J. (1959) Can. J. Biochem. Physiol., 37, 911–917.
March, J. B., and Weinstein, D. B. (1966) J. Lipid Res., 7, 574–580.
Kates, M. (1975) Techniques of Lipidology [Russian translation], Mir, Moscow.
Lauter, C. J., and Trams, E. G. (1962) J. Lipid Res., 3, 136–138.
Holland, W. L., and Summers, S. A. (2008) Endocr. Rev., 29, 381–402.
Lyn-Cook, L. E., Jr., Lawton, M., Tong, M., Silbermann, E., Longato, L., Jiao, P., Mark, P., Wands, J. R., Xu, H., and de la Monte, S. M. (2009) J. Alzheimer’s Dis., 16, 715–729.
Holland, W. L., Brozinick, J. T., Wang, L. P., Hawkins, E. D., Sargent, K. M., Liu, Y., Narra, K., Hoehn, K. L., Knotts, T. A., Siesky, A., Nelson, D. H., Rathanasis, S. K., Fontenot, G. K., Birnbaum, M. J., and Summers, S. A. (2007) Cell. Metab., 5, 167–179.
Farese, R. V. (2001) Exp. Biol. Med., 226, 283–295.
Venable, M. E., Blobe, G. C., and Obeid, L. M. (1994) J. Biol. Chem., 269, 26040–26044.
Webb, L. M., Arnholt, A. T., and Venable, M. E. (2010) Mol. Cell. Biochem., 337, 153–158.
Gomez-Munoz, A., Martin, A., O’Brien, L., and Brindley, D. N. (1994) J. Biol. Chem., 269, 8937–8943.
Kooijman, E. E., Chupin, V., de Kruijff, B., and Burger, K. N. (2003) Traffic, 4, 162–174.
Mizutani, T., Nakashima, S., and Nozawa, Y. (1998) Mech. Ageing Dev., 105, 151–172.
Mebarek, S., Komati, H., Naro, F., Zeiller, C., Alvisi, M., Lagarde, M., Prigent, A.-F., and Nemoz, G. (2007) J. Cell Sci., 120, 407–416.
Chavez, J. A., Knotts, T. A., Wang, L. P., Li, G., Dobrowsky, R. T., Florant, G. L., and Summers, S. A. (2003) J. Biol. Chem., 278, 10297–10303.
Kotronen, A., Seppunen-Laakso, T., Westerbacka, J., Kiviluoto, T., Arola, J., Rusk, A. L., Yki-Jrvinen, H., and Oresic, M. (2010) Obesity (Silver Spring), 18, 937–944.
Ogretmen, B., Pettus, B. J., Rossi, M. J., Wood, R., Usta, J., Szulc, Z., Bielawska, A., Obeid, L. M., and Hannun, Y. A. (2002) J. Biol. Chem., 277, 12960–12969.
Grether-Beck, S., Timmer, A., Felsner, I., Brenden, H., Brammertz, D., and Krutmann, J. (2005) J. Invest. Dermatol., 125, 545–553.
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © N. A. Babenko, V. S. Kharchenko, 2012, published in Biokhimiya, 2012, Vol. 77, No. 2, pp. 223–230.
Rights and permissions
About this article
Cite this article
Babenko, N.A., Kharchenko, V.S. Ceramides inhibit phospholipase D-dependent insulin signaling in liver cells of old rats. Biochemistry Moscow 77, 180–186 (2012). https://doi.org/10.1134/S0006297912020095
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S0006297912020095