Abstract
Alteration of lipid constituents of cellular membranes has been proposed as a possible mechanism for cancer promotion by fumonisin B1 (FB1). To further investigate this hypothesis a dietary dosage which initiates and promotes liver cancer (250 mg FB1/kg) was fed to male Fischer rats for 21 days and the lipid composition of plasma, microsomal, mitochondrial and nuclear subcellular fractions determined. The effect of FB1 on the cholesterol, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), as well as sphingomyelin (SM) and the phospholipids-associated fatty acid (FA) profiles, were unique for each subcellular membrane fraction. PE was significantly increased in the microsomal, mitochondrial and plasma membrane fractions, whereas cholesterol was increased in both the microsomal and nuclear fraction. In addition SM was decreased and increased in the mitochondrial and nuclear fractions, respectively. The decreased PC/PE and polyunsaturated/saturated (P/S) FA ratio in the different membrane fractions suggest a more rigid membrane structure. The decreased levels in polyunsaturated fatty acids in PC together with a pronounced increase in C18:1ω9 and C18:2ω6 were indicative of an impaired delta-6 desaturase. The increased ω6/ω3 ratio and decreased C20:4ω6 PC/PE ratio due to an increase in C20:4ω6 in PE relatively to PC in the different subcellular fractions suggests a shift towards prostanoid synthesis of the E2 series. Changes in the PE and C20:4ω6 parameters in the plasma membrane could alter key growth regulatory and/or other cell receptors in lipid rafts known to be altered by FB1. An interactive role between C20:4ω6 and ceramide in the mitochondria, is suggested to regulate the balance between proliferation and apoptosis in altered initiated hepatocytes resulting in their selective outgrowth during cancer promotion effected by FB1.
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Funari SS, Barceló F, Escribá PV (2003) Effects of oleic acid and its congeners, elaidic and stearic acids, on the structural properties of phosphatidylethanolamine membranes. J Lipid Res 44:567–575
Gudi S, Nolan JP, Frangos JA (1998) Modulation of GTPase activity of G proteins by fluid shear stress and phospholipid composition. Proc Natl Acad Sci 95:2515–2519
Fuller N, Rand RP (2001) The influence of lysolipids on the spontaneous curvature and bending elasticity of phospholipid membranes. Biophys J 81:243–254
Emoto K, Umeda M (2000) An essential role for a membrane lipid in cytokinesis: regulation of contractile ring disassembly by redistribution of phosphatidylethanolamine. J Cell Biol 149:1215–1224
Nyholm TKM, Nylund M, Slotte JP (2003) A calorimetric study of binary mixtures of dihydrosphingomyelin and sterols, sphingomeylin, or phosphatidylcholine. Biophys J 48:3138–3146
Brown RE (1998) Sphingolipid organization in biomembranes: what physical studies of model membranes reveal. J Cell Sci 111:1–9
Eriksson LC, Andersson GN (1992) Membrane biochemistry and chemical hepatocarcinogenesis. Crit Rev Biochem Mol Biol 27:1–55
Weisburger JH, Wynder EL (1984) The role of genotoxic carcinogens and of promoters in carcinogenesis and in human cancer causation. Acta Pharmacol Toxicol (Copenh) 55:53–68
Stern RG, Milestone BN, Gatenby RA (1999) Carcinogenesis and the plasma membrane. Med Hypotheses 52:367–372
Galeotti T, Borrello S, Minotti G, Masotti L (1986) Membrane alterations in cancer cells: the role of oxy radicals. Ann NY Acad Sci 488:468–480
Burns CP, Spector AA (1994) Biochemical effects of lipids on cancer therapy. J Nutr Biochem 5:114–123
Gelderblom WCA, Jaskiewicz K, Marasas WFO, Thiel PG, Horak MJ, Vleggaar R, Kriek NPJ (1988) Fumonisin—novel mycotoxin with cancer promoting activity produced by Fusarium moniliforme. Appl Environ Microb 54:1806–1811
Rheeder JP, Marasas WFO, Thiel PG, Sydenham EW, Shephard GS, Van Schalkwyk DJ (1992) Fusarium moniliforme and fumonisin in corn in relation to oesophageal cancer in Transkei. Phytopathology 82:353–357
Ueno Y, Iijima K, Wang SD, Sugiura Y, Sekijima M, Tanaka T, Chen C, Yu SZ (1997) Fumonisins as a possible contributory risk factor for primary liver cancer: a 3-year study of corn harvested in Haimen, China, by HPLC and ELISA. Food Chem Toxicol 35:1143–1150
Marasas WFO, Riley RT, Hendricks KA, Stevens VL, Sadler TW, Gelineau-van Waes J, Missmer SA, Cabrera J, Torres O, Gelderblom WCA, Allegood J, Martínez C, Maddox J, Miller JD, Starr L, Sullards MC, Roman AV, Voss KA, Wang E, Merrill AH (2004) Fumonisins disrupt sphingolipid metabolism, folate transport, and neural tube development in embryo culture and in vivo: a potential risk factor for human neural tube defects among populations consuming fumonisin-contaminated maize. J Nutr 134:711–716
Gelderblom WCA, Kriek NPJ, Marasas WFO, Thiel PG (1991) Toxicity and carcinogenicity of the Fusarium moniliforme metabolite, fumonisin B1, in rats. Carcinogenesis 12:1247–1251
Lemmer ER, Vessey CJ, Gelderblom WCA, Shephard EG, Van Schalkwyk DJ, Rochelle DJ, Van Wijk A, Marasas WFO, Kirsch RE, Hall P (2004) Fumonisin B1-induced hepatocellular and cholangiocellular tumors in male Fischer 344 rats: potentiating effects of 2-acetylaminofluorene on oval cell proliferation and neoplastic development in a discontinued feeding study. Carcinogenesis 25:1–8
Gelderblom WCA, Cawood ME, Snyman SD, Marasas WFO (1994) Fumonisin B1 dosimetry in relation to cancer initiation in rat liver. Carcinogenesis 15:209–214
Gelderblom WCA, Snyman SD, Lebepe-Mazur S, van der Westhuizen L, Kriek NPJ, Marasas WFO (1996) The cancer promoting potential of fumonisin B1 in rat liver using diethylnitrosamine as cancer initiator. Cancer Lett 109:101–108
Knasmueller S, Bresgen N, Kassie F, Merch-Sundermann V, Gelderblom WCA, Zohrer E, Eckl PM (1997) Genotoxic effects of three Fusarium mycotoxins, fumonisin B1, moniliformin and vomitoxin in bacteria and in primary rat hepatocytes. Mutat Res 391:39–48
Gelderblom WCA, Snyman SD (1991) Mutagenicity of potentially carcinogenic mycotoxins produced by Fusarium moniliforme. Mycol Res 7:46–52
Norred WP, Plattner RD, Vesonder RF, Bacon CW, Voss KA (1992) Effects of selected secondary metabolites of Fusarium moniliforme on unscheduled synthesis of DNA by rat primary hepatocytes. Food Chem Toxicol 30:233–237
Abel S, Gelderblom WCA (1998) Oxidative damage and fumonisin B1-induced toxicity in primary rat hepatocytes and rat liver in vivo. Toxicology 131:121–131
Ehrlich V, Darroudi F, Uhl M, Steinkellner H, Zsivkovits M, Knasmueller S (2002) Fumonisin B1 is genotoxic in human derived hepatoma (HepG2) cells. Mutagenesis 17:257–260
Gelderblom WCA, Abel S, Smuts CM, Marnewick J, Marasas WFO, Lemmer ER, Ramljak D (2001) Fumonisin-induced hepatocarcinogenesis: mechanisms related to cancer initiation and promotion. Environ Health Perspect 109:291–300
Gelderblom WCA, Snyman SD, Van der Westhuizen L, Marasas WFO (1995) Mitoinhibitory effect of fumonisin B1 on rat hepatocytes in primary culture. Carcinogenesis 16:625–631
Tsuda H, Lee G, Faber E (1981) Induction of resistant hepatocytes as a new principle for possible short-term in vivo test for carcinogens. Cancer Res 41:2096–2102
Faber E (1991) Clonal adaptation as an important phase of hepatocarcinogenesis. Cancer Biochem Biophys 12:157–165
Gelderblom WCA, Smuts CM, Abel S, Snyman SD, Van der Westhuizen L, Huber WW, Swanevelder S (1997) The effect of fumonisin B1 on the levels and fatty acid composition of selected lipids in rat liver in vivo. Food Chem Toxicol 35:647–656
Gelderblom WCA, Moritz W, Swanevelder S, Smuts CM, Abel S (2002) Lipids and delta 6-desaturase activity alterations in rat liver microsomal membranes induced by fumonisin B1. Lipids 37:869–877
Cawood ME, Gelderblom WCA, Vleggaar R, Behrend Y, Thiel PG, Marasas WFO (1991) Isolation of the fumonisin mycotoxins: a quantitative approach. J Agric Food Chem 39:1958–1962
Bartoli GM, Bartoli S, Galeotti T, Bertoli E (1980) Superoxide dismutase content and microsomal lipid composition of tumours with different growth rates. Biochim Biophys Acta 620:205–211
Loten EG, Redshaw-Loten JC (1986) Preparation of rat liver plasma membranes in a high yield. Anal Biochem 154:183–185
Kaushal V, Barnes LD (1986) Effect of zwitterionic buffers on measurement of small masses of protein with bicinchoninic acid. Anal Biochem 157:291–294
Folch J, Lees M, Stanley GHS (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226:497–509
Smuts CM, Weich HFH, Weight MJ, Faber M, Kruger M, Lombard CJ, Benadé AJS (1994) Free cholesterol concentrations in the high-density Lipoprotein subfraction-3 as a risk indicator in patients with angiographically documented coronary artery disease. Coron Artery Dis 5:331–338
Gilfillan AM, Chu AJ, Smart DA, Rooney SA (1983) Single plate separation of lung phospholipids including disaturated phosphatidylcholine. J Lipid Res 24:1651–1656
Itaya K, Ui M (1966) A new micromethod for the colorimetric determination of inorganic phosphate. Clin Chim Acta 14:361–366
Richmond W (1973) Preparation and properties of a cholesterol oxidase from Nocardia sp. and its application to the enzymatic assay of total cholesterol in serum. Clin Chem 19:1350–1356
Tichelaar HY, Benadé AJS, Daubitzer AK, Kotze TJ (1989) An improved rapid thin-layer chromatographic–gas-liquid chromatographic procedure for the determination of free fatty acids in plasma. Clin Chim Acta 183:207–216
Riley RT, Enongene E, Voss KA, Norred WP, Meredith FI, Sharma RP, Williams DE, Carlson DB, Spitsbergen J, Merrill AH Jr (2001) Sphingolipid perturbations as mechanisms for fumonisin carcinogenesis. Environ Health Perspect 109:301–308
Mahler SM, Wilce A, Shanley BC (1988) Studies on regenerating liver and hepatoma plasma membranes—I. Lipid and protein composition. Int J Biochem 20:605–611
Mahler SM, Wilce A, Shanley BC (1988) Studies on regenerating liver and hepatoma plasma membranes—II. Membrane fluidity and enzyme activity. Int J Biochem 20:613–619
Abel S, Smuts CM, De Villiers C, Gelderblom WCA (2001) Changes in essential fatty acid patterns associated with normal liver regeneration and the progression of hepatocyte nodules in rat hepatocarcinogenesis. Carcinogenesis 22:795–804
Ohvo-Rekila H, Ramstedt B, Leppimaki P, Slotte JP (2002) Cholesterol interaction with phospholipids in membranes. Prog Lipid Res 41:66–97
Sehgal PB, Guo GG, Shah M, Kumar V, Patel K (2002) Cytokine Signaling: STATS in plasma membrane rafts. J Biol Chem 277:12067–12074
Pike LJ (2003) Lipid rafts: bringing order to chaos. J Lipid Res 44:655–667
Huo H, Guo X, Hong S, Jiang M, Liu X, Liao K (2003) Lipid rafts/caveolae are essential for insulin-like growth factor-1 receptor signaling during 3T3-L1 preadipocyte differentiation induction. J Biol Chem 278:11561–11569
Pike LJ (2005) Growth factor receptors, lipid rafts and caveolae: an evolving story. Biochim Biophys Acta 1746:260–273
Cottin V, Doan JES, Riches DWH (2002) Restricted localization of the TNF receptor CD120a to lipid rafts: a novel role for the death domain. J Immunol 168:4095–4102
Kamen BA, Smith AK (2004) A review of folate receptor alpha cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro. Adv Drug Deliv Rev 56:1085–1097
Stevens VL, Tang J (1997) Fumonisin B1-induced sphingolipid depletion inhibits vitamin uptake via the glycosylphosphatidylinositol-anchored folate receptor. J Biol Chem 272:18020–18025
He Q, Kim J, Sharma RP (2005) Fumonisin B1 hepatotoxicity in mice is attenuated by depletion of Kupffer cells by gadolinium chloride. Toxicology 207:137–147
Gelderblom WC, Abel S, Smuts CM, Swanevelder S, Snyman SD (1999) Regulation of fatty acid biosynthesis as a possible mechanism for the mitoinhibitory effect of fumonisin B1 in primary rat hepatocytes. Prostaglandins Leukot Essent Fatty Acids 61:225–234
Bagga D, Wang L, Farias-Eisner R, Glaspy JA, Reddy ST (2003) Differential effects of prostaglandin derived from w6 and w3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion. Proc Natl Acad Sci USA 100:1751–1756
Pahl HL (1999) Signal transduction from the endoplasmic reticulum to the cell nucleus. Physiol Rev 79:683–701
Spotti M, Maas RFM, De Nijs CM, Fink-Gremmels J (2000) Effect of fumonisin B1 on rat hepatic P450 system. Environ Toxicol Pharmacol 8:197–204
Wang E, Norred WP, Bacon CW, Riley RT, Merill AH Jr (1991) Inhibition of sphingolipid biosynthesis by fumonisins: implications for disease associated with Fusarium Moniliforme. J Biol Chem 266:14486–14490
Bevers EM, Comfurius P, Dekkers DWC, Zwaal RFE (1999) Lipid translocation across the plasma membrane of mammalian cells. Biochem Biophys Acta 1439:317–330
Ardail D, Popa I, Alcantara K, Pons A, Zanetta JP, Louisot P, Thomas L, Portoukalian J (2001) Occurrence of ceramides and neutral glycolipids with unusual long-chain base composition in purified rat liver mitochondria. FEBS Lett, 488:160–164
Bionda C, Portoukalian J, Schmitt D, Rodriguez-Lafrasse C, Ardail D (2004) Subcellular compartmentalization of ceramide metabolism: MAM (mitochondria-associated membrane) and/or mitochondria? Biochem J 382:527–533
Won JS, Singh I (2006) Sphingolipid signaling and redox regulation. Free Rad Biol Med 40:1875–1888
Klöhn PC, Soriano ME, Irwin W, Penzo D, Scorrano L, Bitsch A, Neumann H-G, Bernardi P (2003) Early resistance to cell death and to onset of the mitochondrial permeability transition during hepatocarcinogenesis with 2-acetylaminofluorene. Proc Natl Acad Sci 100:10014–10019
Dragan YP, Bidlack WR, Cohen SM, Goldsworthy TL, Hard GC, Howard PC, Riley RT, Voss KA (2001) Implications of apoptosis for toxicity, carcinogenicity, and risk assessment: fumonisin B1 as an example. Toxicol Sci 61:6–17
Lemmer ER, Hall PDM, Gelderblom WCA, Marasas WFO (1998) Poor reporting of oocyte apoptosis. Nat Med 4:373
Van der Westhuizen L, Gelderblom WCA, Shephard GS, Swanevelder S (2004) Disruption of sphingolipid biosynthesis in hepatocyte nodules: selective proliferative stimulus induced by fumonisin B1. Toxicology 200:69–75
Ledeen RW, Wu G (2004) Nuclear lipids: key signaling effectors in the nervous system and other tissues. J Lipid Res 45:1–8
Sahu AC, Epply RM, Page SW, Gray GG, Barton CN, O’Donnell MW (1998) Peroxidation of membrane lipids and oxidative DNA damage by fumonisin B1 in isolated rat liver nuclei. Cancer Lett 125:117–121
Pala V, Krogh V, Muti P, Chajès V, Riboli E, Micheli A, Saadatian M, Sieri S, Berrino F (2001) Erythrocyte membrane fatty acids and subsequent breast cancer: a prospective Italian study. J Natl Cancer Inst 93:1088–1095
Lu J, Pei H, Kaeck M, Thompson HJ (1997) Gene expression changes associated with chemically induced rat mammary carcinogenesis. Mol Carcinog 20:204–215
De Alaniz MJ, Marra CA (1994) Role of delta 9-desaturase activity in the maintenance of high levels of monoenoic fatty acids in hepatoma cultured cells. Mol Cell Biochem 137:85–90
Marzo I, Martinez-Lorenzo MJ, Anel A, Desportes P, Alava MA, Naval J, Pineiro A (1995) Biosynthesis of unsaturated fatty acids in the main cell lineages of human leukemia and lymphoma. Biochim Biophys Acta 1257:140–148
Khoo DE, Fermor B, Miller J, Wood CB, Apostolov K, Barker W, Williamson RC, Habib NA (1991) Manipulation of body fat composition with sterculic acid can inhibit mammary carcinomas in vivo. Br J Cancer 63:97–101
Diplock AT, Balasubramanian KA, Manohar M, Mathan VI, Ashton D (1988) Purification and chemical characterization of the inhibitor of lipid peroxidation from intestinal mucosa, Biochim Biophys Acta 926:42–50
Abel S, De Kock M, Smuts CM, De Villiers C, Swanevelder S, Gelderblom WCA (2004) Dietary modulation of fatty acid profiles and oxidative status of rat hepatocyte nodules: effect of different n − 6/n − 3 fatty acid ratios. Lipids 39:963–976
Seegers JC, Joubert AM, Panzer A, Lottering ML, Jordan CA, Joubert F, Maree JL, Bianchi P, De Kock M, Gelderblom WCA (2000) Fumonisin B1 influenced the effects of arachidonic acid, prostaglandins E2 and A2 on cell cycle progression, apoptosis induction, tyrosine- and CDC2-kinase activity in oesophageal cancer cells. Prostaglandins Leukot Essent Fatty Acids 62:75–84
Tapiero H, Ba GN, Couvreur P, Tew KD (2002) Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies. Biomed Pharmacother 56:215–222
Cao Y, Pearman AT, Zimmerman GA, McUntyre TM, Prescott SM (2000) Intracellular unestrified arachidonic acid signals apoptosis. Proc Natl Acad Sci USA 97:11280–11285
Zhao S, Du XY, Chai MQ, Chen JS, Zhou YC, Song JG (2002) Secretory phospholipase A2 induces apoptosis via a mechanism involving ceramide generation. Biochem Biophys Acta 1581:75–88
Liou JY, Aleksic N, Chen SF, Han TJ, Shyue SK, Wu KK (2005) Mitochondrial localization of cyclooxygenase-2 and calcium-independent phospholipase A2 in human cancer cells: implication in apoptosis resistance. Exp Cell Res 306:75–84
Pinelli E, Poux N, Garren L, Pipy B, Castegnaro M, Miller DJ, Pfohl-Leszkowicz A (1999) Activation of mitogen-activated protein kinase by fumonisin B1 stimulates cPLA2 phophorylation, the arachidonic acid cascade and cAMP production. Carcinogenesis 20:1683–1688
Shibata M, Kodani I, Osaki M, Araki K, Adachi H, Ryoke K, Ito H (2005) Cyclo-oxygenase-1 and -2 expression in human oral mucosa, dysplasias and squamous cell carcinomas and their pathological significance. Oral Oncol 41:304–312
Acknowledgments
The authors wish to thank the Nutritional Intervention Research Unit for the use of their laboratory and gas-chromatography equipment. With thanks also to Johanna van Wyk for conducting the gas-chromatography analysis as well as Amelia Damons and John Moketary for washing and cleaning all the glassware. This project was funded by the Medical Research Council of South Africa and the National Research Foundation. Grant no FA2005032200026.
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Burger, HM., Abel, S., Snijman, P. et al. Altered Lipid Parameters in Hepatic Subcellular Membrane Fractions Induced by Fumonisin B1 . Lipids 42, 249–261 (2007). https://doi.org/10.1007/s11745-007-3025-9
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DOI: https://doi.org/10.1007/s11745-007-3025-9