Release of exosomes and microvesicles harbouring specific RNAs and glycosylphosphatidylinositol-anchored proteins from rat and human adipocytes is controlled by histone methylation

Abstract

The transfer of proteins and nucleic acids from donor to acceptor cells via small membrane vesicles has been implicated with (patho)physiological consequences. Previously the upregulation of esterification and downregulation of lipolysis in small rat adipocytes upon incubation with exosomes and microvesicles (EMVs) released from large adipocytes and harbouring the glycosylphosphatidylinositol (GPI)-anchored proteins, Gce1 and CD73, transcripts specific for FSP27 and GPAT3, and microRNAs, miR-16 and miR-222 was demonstrated. Here the release of EMVs from large (but not small) primary and differentiated and human rat adipocytes in response to palmitate, H2O2 and the anti-diabetic sulfonylurea, glimepiride, is shown to be significantly reduced upon inhibition of histone H3 lysine9 methyltransferase G9a by trans-2-phenylcyclopropylamine (tPCPA) and histone H3 lysine4 demethylase LSD1 by BIX01294. Inhibition of EMV release by tPCPA and BIX01294 was not caused by apoptosis but accompanied by upregulation of the H2O2-induced stimulation of lipid synthesis and downregulation of lipolysis in large (but not small) primary and differentiated rat and human adipocytes. In contrast, the simultaneous presence of tPCPA and BIX-01294 had almost no effect on the induced release of EMVs and lipid metabolism. These findings argue for regulation of the release of EMVs harbouring specific GPI-anchored proteins, transcripts and microRNAs from rat and human adipocytes by histone H3 methylation at lysines 4 and 9 in interdependent fashion. Thus the EMV-mediated transfer of lipogenic and anti-lipolytic information between large and small adipocytes in response to certain physiological and pharmacological stimuli seems to be controlled by epigenetic mechanisms.

Share and Cite:

Müller, G. , Schneider, M. , Gassenhuber, J. and Wied, S. (2012) Release of exosomes and microvesicles harbouring specific RNAs and glycosylphosphatidylinositol-anchored proteins from rat and human adipocytes is controlled by histone methylation. American Journal of Molecular Biology, 2, 187-209. doi: 10.4236/ajmb.2012.23020.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Rosen, E.D. and Spiegelman, B.M. (2000) Molecular regulation of adipogenesis. Annual Review of Cell and Developmental Biology, 16, 145-171.
[2] Müller, G., Wied, S., Dearey, E.-A., Wetekam, E.-A. and Biemer-Daub, G. (2010) Lipid storage in large and small rat adipocytes by vesicle-associated glycosylphosphatidylinositol-anchored proteins. Results and Problems in Cell Differentiation – Sensory and Metabolic Control of Energy Balance, 52, 27-34.
[3] Aoki, N., Jinno, S., Nakagawa, Y., Asai, N., Arakawa, E., Tamura, N., Tamura T. and Matsuda, T. (2007) Identification and characterization of microvesicles secreted by 3T3-L1 adipocytes: redox-and hormone-dependent induction of milk fat globule-epidermal growth factor 8-associated microvesicles. Endocrinology, 148, 3850-3862.
[4] Ogawa, R., Tanaka, C., Stao, M., Nagasaki, H., Sugimura, K., Okumura, K., Nakagawa, Y. and Aoki N. (2010) Adipocyte-derived microvesicles contain RNA that is transported into macrophages and might be secreted into blood circulation. Biochemical and Biophysical Research Commununication, 398, 723-729.
[5] Müller, G., Jung, C., Straub, J. and Wied, S. (2009) Induced release of membrane vesicles and exosomes from rat adipocytes containing lipid droplet, lipid raft and glycosylphosphatidylinositol-anchored proteins. Cellular Signaling, 21, 324-338.
[6] Müller, G., Jung, C., Wied, S. and Biemer-Daub, G. (2009) Induced translocation of glycosylphosphatidylinositol-anchored proteins from lipid droplets to adiposomes in rat adipocytes. British Journal of Pharmacology, 158, 749-770.
[7] Müller, G. (2010) Control of lipid storage and cell size between adipocytes by vesicle-associated glycosylphosphatidylinositol-anchored proteins. Archives of Physiology and Biochemistry, 117, 23-43.
[8] Goichot, B., Grunebaum, L., Desprez, D., Vinzio, S., Meyer, L., Schlienger, J.L., Lessard, G. and Simon, C. (2006) Circulating procoagulant microparticles in obesity. Diabetes and Metabolism, 32, 82-85.
[9] Leroyer, A.S., Tedgui, A. and Boulanger, C.M. (2008) Microparticles and type 2 diabetes. Diabetes and Metabolism, 34, S27-S31.
[10] Cocucci, E., Racchetti, G. and Meldolesi, J. (2008) Shedding microvesicles: artefacts no more. Trends in Cell Biology, 19, 43-51.
[11] Piccin, A., Murphy, W.G. and Smith, O.P. (2007) Circulating microparticles: pathophysiology and clinical implications. Blood Reviews, 21, 157-171.
[12] Simons, M. and Raposo, G. (2009) Exosomes-vesicular carriers for intercellular communication. Current Opinion in Cell Biology, 21, 575-581.
[13] Shen, B., Wu, N., Yang, Jr.M. and Gould, S.J. (2011) Protein targeting to exosomes/microvesicles by plasma membrane anchors. Journal of Biological Chemistry, 286, 14383-14395.
[14] Valadi, H., Ekstrom, K., Bossios, A., Sjostrand, M., Lee, J.J. and Lotvall, J.O. (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology, 9, 654-659.
[15] Camussi, G., Deregibus, M.C., Bruno, S., Cantaluppi, V. and Biancone, L. (2010) Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney International, 78, 838-848.
[16] Al-Nedawi, K., Meehan, B., Kerbel, R.S., Allison, A.C. and Rak, J. Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proceedings of the National Academy of Sciences USA, 106, 3794-3789.
[17] Castellana, D., Toti, F. and Freyssinet, J.M. (2010) Membrane microvesicles: Macromessengers in cancer disease and progression. Thrombosis Research, 125, S84-S88.
[18] Yuan, A., Farber, E.L. and Rapoport, A.L. (2009) Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One, 4, e4722.
[19] Heneghan, H.M., Miller, N. and Kerin, M.J. (2009) Role of microRNAs in obesity and the metabolic syndrome. Obesity Reviews, 11, 354-361.
[20] Lin, Q., Gao, Z., Alarcon, R.M., Ye, J. and Yun, Z. (2009) A role of miR-27 in the regulation of adipogenesis. FEBS Journal, 276, 2348-2358.
[21] Esau, C., Kang, X., Peralta, E., Hanson, E., Marcusson, E.G., Ravichandran, L.V., Sun, Y., Koo, S., Perera, R.J., Jain, R., Dean, N.M., Freier, S.M., Bennet, C.F., Lollo, B. and Griffey, R. (2004) MicroRNA-143 regulates adipocyte differentiation. Journal of Biological Chemistry, 279, 52361-52365.
[22] Xie, H., Lim, B. and Lodish, H.F. (2009) MicroRNAs induced during adipogenesis that accelerate fat cell development are downregulated in obesity. Diabetes, 58, 1050-1057.
[23] Ortega, F.J., Moreno-Navarrete, J.M., Pardo, G., Sabater, M., Hummel, M.; Ferrer, A., Rodriguez-Hermosa, J.I., Ruiz, B., Ricart, W., Pera, B. and Fernandez-Real, J.M. (2010) miRNA expression profile of human subcutaneous adipose and during adipocyte differentiation. PLoS One, 5, e9022.
[24] Müller, G., Schneider, M., Biemer-Daub, G. and Wied, S. (2011) Microvesicles released from rat adipocytes and harboring glycosylphosphatidylinositol-anchored proteins transfer RNA stimulating lipid synthesis. Cellular Signaling, 23, 1207-1223.
[25] Müller, G., Wied, S., Jung, C., Biemer-Daub, G. and Frick, W. (2010) Transfer of glycosylphosphatidylinositol-anchored 5’-nucleotidase CD73 from adiposomes into rat adipocytes stimulates lipid synthesis. British Journal of Pharmacology, 160, 878-891.
[26] Müller, G., Wied, S., Jung, C., Frick, W. and Biemer-Daub, G. (2010) Inhibition of lipolysis by adiposomes containing glycosylphosphatidylinositol-anchored Gce1 protein in rat adipocytes. Archives of Physiology and Biochemistry, 116, 28-41.
[27] Müller, G., Wied, S., Dearey, E.-A. and Biemer-Daub, G. (2011) Glycosylphosphatidylinositol-anchored proteins coordinate lipolysis inhibition between large and small adipocytes. Metabolism, 60, 1021-1037.
[28] Müller, G., Wied, S. and Schneider, M. (2011) Regulation of lipid synthesis between large and small rat adipocytes by glycosylphosphatidylinositol-anchored CD73. Obesity, 19, 1531-1544.
[29] Müller, G., Over, S., Wied, S. and Frick, W. (2008) Association of (c)AMP-degrading glycosylphosphatidylinositol-anchored proteins with lipid droplets is induced by palmitate, H2O2 and the sulfonylurea drug, glimepiride, in rat adipocytes. Biochemistry, 47, 12774-12787.
[30] Müller, G., Wied, S., Jung, C. and Over, S. (2008) Translocation of glycosylphosphatidylinositol-anchored proteins to lipid droplets and inhibition of lipolysis in rat adipocytes is mediated by reactive oxygen species. British Journal of Pharmacology, 154, 901-913.
[31] Müller, G., Wied, S., Jung, C. and Straub, J. (2008) Coordinated regulation of esterification and lipolysis by palmitate, H2O2 and the anti-diabetic sulfonylurea drug, glimepiride, in rat adipocytes. European Journal of Pharmacology, 597, 6-18.
[32] Cao, J., Li, J.L., Li, D., Tobin, J.F. and Gimeno, R.E. (2006) Molecular identification of microsomal acyl-CoA:glycerol-3-phosphate acyltransferase, a key enzyme in de novo triacylglycerol synthesis. Proceedings of the National Academy of Sciences USA, 103, 19695-19700.
[33] Nishino, N., Tamori, Y., Tateya, S., Kawaguchi, T. and Shibakusa, T. (2008) FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets. Journal of Clinical Investigation, 118, 2808-2821.
[34] Puri, V., Ranjit, S., Konda, S., Nicoloro, S.M., Straubhaar, J., Chawla, A., Chouinard, M., Lin, C., Burkart, A., Corvera, S., Perugini, R.A. and Czech, M.P. (2008) Cidea is associated with lipid droplets and insulin sensitivity in humans. Proceedings of the National Academy of Sciences USA, 105, 7833-7838.
[35] Heerwagen, M.J.R., Miller, M.R., Barbour, L.A. and Friedman, J.E. (2010) Maternal obesity and fetal metabolic programming: a fertile epigenetic soil. American Journal of Physiology Regulatory, Integrative and Comparative Physiology, 299, R711-R722.
[36] Stoger, R. (2008) Epigenetics and obesity. Pharmacogenomics, 9, 1851-1860.
[37] Jenuwein, T. and Allis, C.D. (2001) Translating the histone code. Science, 293, 1074-1080.
[38] Schreiber, S.L. and Bernstein, B.E. (2002) Signaling network model of chromatin. Cell, 111, 771-778.
[39] Martin, C. and Zhang, Y. (2005) The diverse functions of histone lysine modification. Nature Reviews Molecular Cell Biology, 6, 838-849.
[40] Campion, J., Milagro, F.I. and Martinez, J.A. (2009) Individuality and epigenetics in obesity. Obesity Reviews, 10, 383-392.
[41] Parra, P., Serra, F. and Palou, A. (2010) Expression of adipose microRNAs is sensitive to dietary conjugated linoleic acid treatment in mice. PLoS One, 5, e13005.
[42] Sommerfeld, M., Müller, G., Tschank, G., Seipke, G., Habermann, P., Kurrle, R. and Tennagels, N. (2010) In vitro metabolic and mitogenic signaling of insulin glargine and its metabolites. PLoS One, 5, e9540.
[43] Geisen, K. (1988) Special pharmacology of the new sulfonylurea glimepiride. Drug Research, 38, 1120-1130.
[44] Müller, G., Ertl, J., Gerl, M. and Preibisch, G. (1997) Leptin impairs metabolic actions of insulin in isolated rat adipocytes. Journal of Biological Chemistry, 272, 10585-10593.
[45] Frick, W., Bauer, A., Bauer, J., Wied, S. and Müller, G. (1998) Structure-activity relationship of synthetic phosphoinositolglycans mimicking metabolic insulin action. Biochemistry, 37, 13421-13436.
[46] Müller, G., Wied, S., Over, S. and Frick, W. (2008) Inhibition of lipolysis by palmitate, H2O2 and the sulfonylurea drug, glimepiride, in rat adipocytes depends on cAMP degradation by lipid droplets. Biochemistry, 47, 1259-1273.
[47] Müller, G., Wied, S., Walz, N. and Jung, C. (2008) Translocation of glycosylphosphatidylinositol-anchored proteins from plasma membrane microdomains to lipid droplets in rat adipocytes is induced by palmitate, H2O2 and the sulfonylurea drug, glimepiride. Molecular Pharmacology, 73, 1513-1529.
[48] Miranville, A., Herling, A.W., Biemer-Daub, G. and Voss, M.D. (2010) Reversal of inflammation-induced impairment of glucose uptake in adipocytes by direct effect of CB1 antagonism on adipose tissue macrophages. Obesity, 18, 2247-2254.
[49] Rodbell, M. (1964) Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis. Journal of Biological Chemistry, 239, 375-380.
[50] Sugihara, H., Yonemitsu, N., Miyabara, S. and Yun, K. (1986) Primary culture of unilocular fat cells: characteristics of growth in vitro and changes in differentiation properties. Differentiation, 31, 42-49.
[51] Zhang, H.H., Kumar, S., Barnett, A.H. and Eggo, M.C. (2000) Ceiling culture of mature human adipocytes: use in studies of adipocyte functions. Journal of Endocrinology, 164, 119-128.
[52] Linscheid, P., Seboek, D., Zulewski, H., Keller, U. and Müller, B. (2000) Autocrine/Paracrine role of inflammation-mediated calcitonin gene-related peptide and adrenomedullin expression in human adipose tissue. Endocrinology, 146, 2699-2708.
[53] Tchkonia, T., Giorgadze, N., Pirtskhalava, T., Tchoukalova, Y., Karagiannides, I., Forse, R.A., Deponte, M., Stevenson, M., Guo, W., Han, J., Waloga, G., Lash, T.L., Jensen, M.D. and Kirkland, J.K. (2002) Fat depot origin affects adipogenesis in primary cultured and cloned human preadipocytes. Americal Journal of Physiology Regulatory, Integrative and Comparative Physiology, 282, R1286-R1296.
[54] Müller, G. and Wied, S. (1993) The sulfonylurea drug, glimepiride, stimulates glucose transport, glucose transporter translocation, and dephosphorylation In insulin-resistant rat adipocytes in vitro. Diabetes, 42, 1852-1867.
[55] Müller, G., Jordan, H., Petry, S., Wetekam, E.-M. and Schindler, P. (1997) Analysis of lipid metabolism in adipocytes using fluorescent fatty acids. I. Insulin stimulation of lipogenesis. Biochimica et Biophysica Acta, 1347, 23-39.
[56] Jenuwein, T. (2006) The epigenetic magic of histone lysine methylation. FEBS Journal, 273, 3121-3135.
[57] Cole, P.A. (2008) Chemical probes for histone-modifying enzymes. Nature Chemical Biology, 4, 590-597.
[58] Spannhoff, A., Hauser, A.T., Heinke, R., Sippl, W. and Jung, M. (2009) The emerging therapeutic potential of histone methyltransferase and demethylase inhibitors. ChemMedChem, 4, 1568-1582.
[59] Shi, Y., Lan, F., Matson, C., Mulligan, P., Whetstine, J.R., Cole, P.A., Casero, R.A. and Shi, Y. (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 119, 941-953.
[60] Huang, Y., Greene, E., Stewart, T.M., Goodwin, A.C., Baylin, S.B., Woster, P.M. and Casero, R.A. (2007) Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proceeding of the National Academy of Sciences USA, 104, 8023-8028.
[61] Kubicek, S., O’Sullivan, R.J., August, E.M., Hickey, E.R., Zhang, Q., Teodoro, M.L., Rea, S., Mechtler, K., Kowalski, J.A., Homon, C.A., Kelly, T.A. and Jenuwein, T. (2007) Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Molecular Cell, 25, 473-481.
[62] Chang, Y., Zhang, X., Horton, J.R., Upadhyay, A.K., Spannhoff, A., Liu, J., Snyder, J.P., Bedford, M.T. and Cheng, X. (2009) Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nature Structural Molecular Biology, 16, 312-317.
[63] Yang, M., Culhane, J.C., Szewczuk, L.M., Gocke, C.B., Brautigam, C.A., Tomchick, D.R., Machius, M., Cole, P.A. and Yu, H. (2007) Structural basis of histone demethylation by LSD1 revealed by suicide inactivation. Nature Structural Molecular Biology, 14, 535-539.
[64] Kang, J., Heart, E. and Sung, C.K. (2001) Effects of cellular ATP depletion on glucose transport and insulin signaling in 3T3-L1 adipocytes. American Journal of Physiology, Endocrinology and Metabolism, 280, E428-435.
[65] Stimson, L., Rowlands, M.G., Newblatt, Y.M., Smith, N.F., Raynaud, F.I., Rogers, P., Bavetsias, V., Gorsuch, S., Jarman, M., Bannister, A., Kouzarides, T., McDonald, E., Workman, P. and Aherne, G.W. (2005) Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity. Molecular Cancer Therapy, 4, 1521-1532.
[66] [Kijima, M., Yoshida, M., Sugita, K., Horinouchi, S. and Beppu, T. (1993) Trapoxin, an antitumor cyclic tetrapeptide, is an inhibitor of mammalian histone deacetylase. Journal of Biological Chemistry, 268, 22429-22435.
[67] Cheng, X. and Blumenthal, R.M. (2010) Coordinated chromatin control: Structural and functional linkage of DNA and histone methylation. Biochemistry, 49, 2999-3008.
[68] Müller, G. (2011) Let’s shift lipid burden – from large to small adipocytes. European Journal of Pharmacology, 656, 1-4.
[69] Cho, Y.-W., Hong, S.H., Jin, Q., Wang, L., Lee, J.E., Gavrilova, O. and Ge, K. (2009) Histone methylation regulator PTIP is required for PPARγ and C/EBPα expression and adipogenesis. Cell Metabolism, 10, 27-39.
[70] Musri, M.M., Carmona, M.C., Hanzu, F.A., Kaliman, P., Gomis, R. and Parrizas, M. (2010) Histone demethylase LSD1 regulates adipogenesis. Journal of Biological Chemistry, 285, 30034-30041.
[71] Booth, A.M., Fang, Y., Fallon, J.K., Yang, Y.M., Hildreth, J.E. and Gould, S.J. (2006) Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. Journal of Cell Biology, 172, 923-935.
[72] Saksena, S., Sun, J., Chu, T. and Emr, S.D. (2007) ESCRTing proteins in the endocytic pathway. Trends in Biochemical Sciences, 32, 561-573.
[73] Welsch, S., Keppler, O.T., Habermann, A., Allespach, I., Krijnse-Locker, J. and Krausslich, H.G. HIV-1 buds predominantly at the plasma membrane of primary human macrophages. PLoS pathogens, 3, e36.
[74] Zacharias, D.A., Violon, J.D., Newton, A.C. and Tsien, R.Y. (2002) Partitioning of lipid-modified monomeric GFPs into membrane microdomains of live cells. Science, 296, 913-916.
[75] Leventhal, I., Grzybek, M. and Simons, K. (2010) Greasing their way: lipid modifications determine protein association with membrane rafts. Biochemistry, 49, 6305-6316.
[76] Toh, S.Y., Gong, J., Du, G., Li, J.Z., Yang, S., Ye, J., Yao, H., Zhang, Y., Xue, B. and Li, Q. (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.
[77] Kuypers, F.A., Larkin, S.K., Emeis, J.J. and Allison, A.C. (2007) Interaction of an annexin V homodimer (Diannexin) with phosphatidylserine on cell surfaces and consequent anti-thrombotic activity. Thrombosis and Haemostasis, 97, 478-486.
[78] Salti, I. and the Diabetes and Ramadan Study Group. Efficacy and safety of insulin glargine and glimepiride in subjects with type 2 diabetes before, during and after the period of fasting in Ramadan. (2009) Diabetes Medicine, 26, 1255-1261.
[79] Gottschalk, M., Danne, T., Vlajnic, A. and Cara, J.F. (2007) Glimepiride versus metformin as monotherapy in pediatric patients with type 2 diabetes: a randomized, single-blind comparative study. Diabetes Care, 30, 790-794.
[80] Gesta, S., Tseng, Y.H. and Kahn, C.R. (2007) Developmental origin of fat: tracking obesity to its source. Cell, 131, 242-256.
[81] Cinti, S. (2011) Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metabolism, 11, 352-256.
[82] Cinti, S. (2002) Adipocyte differentiation and transdifferentation: plasticity of the adipose organ. Journal of Endocrinological Investigations, 25, 823-835.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.