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Vitamin E prevents the age-dependent and palmitate-induced disturbances of sphingolipid turnover in liver cells

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Abstract

Sphingolipid turnover has been shown to be activated at old age and in response to various stress stimuli including oxidative stress. Reduction of vitamin E content in the liver under the pro-oxidant action is associated with enhanced sphingolipid turnover and ceramide accumulation in hepatocytes. In the present paper, the correction of sphingolipid metabolism in the liver cells of old rats and in the palmitate-treated young hepatocytes using α-tocopherol has been investigated. 3- and 24-month-old rats, [14 C]palmitic acid, [methyl−14 C-choline]sphingomyelin (SM), and [14 C]serine were used. α-Tocopherol administration to old rats or addition to the culture medium of old liver slices or hepatocytes prevented age-dependent increase of ceramide synthesis and lipid accumulation, and increased SM content in liver tissue and cells. α-Tocopherol treatment of old cells decreased the neutral and acid sphingomyelinase (SMase) activities in hepatocytes and serine palmitoyl transferase activity in the liver cell microsomes. Effect of α- or γ-tocopherol, but not of δ-tocopherol, on the newly synthesized ceramide content in old cells was correlated with the action of inhibitor of serine palmitoyl transferase (SPT) activity (myriocin) and SMase inhibitors (glutathione, imipramine). Addition of α-tocopherol as well as myriocin to the culture medium of young hepatocytes, treated by palmitate, abolished ceramide accumulation and synthesis. The data obtained demonstrate that α-tocopherol normalized elevated ceramide content in the old liver cells via inhibition of acid and neutral SMase activities and lipid synthesis de novo. α-Tocopherol, reducing ceramide synthesis, prevented palmitate-induced aging-like ceramide accumulation in young liver cells.

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References

  • Ayasolla K, Khan M, Singh AK, Singh I (2004) Inflammatory mediator and beta-amyloid (25–35)-induced ceramide generation and iNOS expression are inhibited by vitamin E. Free Radic Biol Med 37:325–338. doi:10.1016/j.freeradbiomed.2004.04.007

    Article  PubMed  CAS  Google Scholar 

  • Babenko NA, Semenova YA (2010) Effects of long-term fish oil-enriched diet on the sphingolipid metabolism in brain of old rats. Exp Gerontol 45:375–380. doi:10.1016/j.exger.2010.02.010

    Article  PubMed  CAS  Google Scholar 

  • Babenko N, Shakhova E (2006) Effects of Chamomilla recutita flavonoids on age-related liver sphingolipid turnover in rats. Exp Geront 41:32–39. doi:10.1016/j.exger.2005.08.008

    Article  CAS  Google Scholar 

  • Babenko N, Shakhova E (2008) Effects of flavonoids on sphingolipid turnover in the toxin-damaged liver and liver cells. Lipids Health Dis 7:1. doi:10.1186/1476-511X-7-1

    Article  PubMed  Google Scholar 

  • Bai Y, Wang J, Shan H, Lu Y, Zhang Y, Luo X, Yang B, Wang Z (2007) Sphingolipid metabolite ceramide causes metabolic perturbation contributing to HERG K + channel dysfunction. Cell Physiol Biochem 20:429–440. doi:10.1159/000107527

    Article  PubMed  CAS  Google Scholar 

  • Bansal AK, Bansal M, Soni G, Bhatnagar D (2005) Protective role of vitamin E pre-treatment on N-nitrosodiethylamine induced oxidative stress in rat liver. Chem Biol Interect 156:101–111. doi:10.1016/j.cbi.2005.08.001

    Article  CAS  Google Scholar 

  • Bartlett GR (1959) Phosphorus assay in column chromatography. J Biol Chem 234:466–468

    PubMed  CAS  Google Scholar 

  • Beutler E, Duron O, Kelly BM (1963) Improved method for the determination of blood glutathione. J Lab Clin Med 61:882–888

    PubMed  CAS  Google Scholar 

  • Blázquez C, Galve-Roperh I, Guzmán M (2000) De novo-synthesized ceramide signals apoptosis in astrocytes via extracellular signal-regulated kinase. FASEB J 14:2315–2322

    Article  PubMed  Google Scholar 

  • Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37:911–917

    Article  PubMed  CAS  Google Scholar 

  • Charruyer A, Grazide S, Bezombes C, Muller S, Laurent G, Jaffrezou JP (2005) UV-C light induces raft-associated acid sphingomyelinase and JNK activation and translocation independently on a nuclear signal. J Biol Chem 280:19196–19204. doi:10.1074/jbc.M412867200

    Article  PubMed  CAS  Google Scholar 

  • Crivello NA, Rosenberg IH, Dallal GE, Bielinski D, Joseph JA (2005) Age-related changes in neutral sphingomyelin-specific phospholipase C activity in striatum, hippocampus, and frontal cortex: implication for sensitivity to stress and inflammation. Neurochem Int 47:573–579. doi:10.1016/j.neuint.2005.06.011

    Article  PubMed  CAS  Google Scholar 

  • Cutler RG, Mattson MP (2001) Sphingomyelin and ceramide as regulators of development and lifespan. Mech Ageing Dev 122:895–908. doi:10.1016/S0047-6374(01)00246-9

    Article  PubMed  CAS  Google Scholar 

  • Denis U, Lecomte M, Paget C, Ruggiero D, Wiernsperger N, Lagarde M (2002) Advanced glycation end-products induce apoptosis of bovine retinal pericytes in culture: involvement of diacylglycerol/ceramide production and oxidative stress induction. Free Radic Biol Med 33:236–247. doi:10.1016/S0891-5849(02)00879-1

    Article  PubMed  CAS  Google Scholar 

  • Dumitru CA, Gulbins E (2006) TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis. Oncogene 25:5612–5625. doi:10.1038/sj.onc.1209568

    Article  PubMed  CAS  Google Scholar 

  • Freisleben H-Y, Mentrup E (1992) Preparation and properties of liposomes containing vitamin E. In: Packes L, Fuchs J (eds) Vitamin E in Health and Disease. Marsel Dekker, New York, pp 193–206

    Google Scholar 

  • Garcia-Ruiz C, Mari M, Morales A, Colell A, Ardite E, Fernandez-Checa JC (2000) Human placenta sphingomyelinase, induces oxidative stress, glutathione depletion, and apoptosis in rat hepatocytes. Hepatology 32:56–65. doi:10.1053/jhep.2000.8267

    Article  PubMed  CAS  Google Scholar 

  • Grether-Beck S, Bonizzi G, Schmitt-Brenden H, Felsner I, Timmer A, Sies H, Johnson JP, Piette J, Krutmann J (2000) Non-enzymatic triggering of the ceramide signaling cascade by solar UVA radiation. EMBO J 19:5793–5800. doi:10.1093/emboj/19.21.5793

    Article  PubMed  CAS  Google Scholar 

  • Grether-Beck S, Timmer A, Felsner I, Brenden H, Brammertz D, Krutmann J (2005) Ultraviolet A-induced signaling involves a ceramide-mediated autocrine loop leading to ceramide de novo synthesis. J Invest Dermatol 125:545–553. doi:10.1111/j.0022-202X.2005.23782.x

    Article  PubMed  CAS  Google Scholar 

  • Hatanaka Y, Fujii J, Fukutomi T, Watanabe T, Che W, Sanada Y, Igarashi Y, Taniguchi N (1998) Reactive oxygen species enhances the induction of inducible nitric oxide synthase by sphingomyelinase in RAW264.7 cells. Biochim Biophys Acta 1393:203–210. doi:10.1016/S0005-2760(98)00066-6

    Article  PubMed  CAS  Google Scholar 

  • Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y, Narra K, Hoehn KL, Knotts TA, Siesky A, Nelson DH, Karathanasis SK, Fontenot GK, Birnbaum MJ, Summers SA (2007) Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 5:167–179. doi:10.1016/j.cmet.2007.01.002

    Article  PubMed  CAS  Google Scholar 

  • Ichi I, Kamikawa C, Nakagawa T, Kobayashi K, Kataoka R, Nagata E, Kitamura Y, Nakazaki C, Matsura T, Kojo S (2009) Neutral sphingomyelinase-induced ceramide accumulation by oxidative stress during carbon tetrachloride intoxication. Toxicology 261:33–40. doi:10.1016/j.tox.2009.04.040

    Article  PubMed  CAS  Google Scholar 

  • Kavok NS, Krasilnikova OA, Babenko NA (2003) Increase in diacylglycerol production by liver and liver nuclei at old age. Exp Gerontol 38:441–447. doi:10.1016/j.exger.2005.08.008

    Article  PubMed  CAS  Google Scholar 

  • Lauter CJ, Trams EG (1962) A spectrophotometric determination of sphingosine. J Lipid Res 3:135–138

    Google Scholar 

  • Lightle SA, Oakley JI, Nikolova-Karakashian MN (2000) Activation of sphingolipid turnover and chronic generation of ceramide and sphingosine in liver during aging. Mech Ageing Dev 120:111–125

    Article  PubMed  CAS  Google Scholar 

  • Listenberger LL, Han X, Lewis SE, Cases S, Farese RV Jr, Ory DS, Schaffer JE (2003) Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci USA 100:3077–3082. doi:10.1073/pnas.0630588100

    Article  PubMed  CAS  Google Scholar 

  • Liu B, Hannun YA (1997) Inhibition of the neutral magnesium-dependent sphingomyelinase by glutathione. J Biol Chem 272:16281–16287. doi:10.1074/jbc.272.26.16281

    Article  PubMed  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin–phenol reagents. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  • Martín SF, Navarro F, Forthoffer N, Navas P, Villalba JM (2001) Neutral magnesium-dependent sphingomyelinase from liver plasma membrane: purification and inhibition by ubiquinol. J Bioenerg Biomembr 33:143–153

    Article  PubMed  Google Scholar 

  • Massip L, Garand C, Paquet ER, Cogger VC, O’Reilly JN, Tworek L, Hatherell A, Taylor CG, Thorin E, Zahradka P, Le Couteur DG, Lebel M (2010) Vitamin C restores healthy aging in a mouse model for Werner syndrome. FASEB J 24:158–172. doi:10.1096/fj.09-137133

    Article  PubMed  Google Scholar 

  • Mazière C, Conte MA, Leborgne L, Levade T, Hornebeck W, Santus R, Mazière JC (2001) UVA radiation stimulates ceramide production: relationship to oxidative stress and potential role in ERK, JNK, and p38 activation. Biochem Biophys Res Commun 281:289–294. doi:10.1006/bbrc.2001.4348

    Article  PubMed  Google Scholar 

  • Merrill AH Jr, Nixon DW, Williams RD (1985) Activities of serine palmitoyltransferase (3-ketosphinganine synthase) in microsomes from different rat tissues. J Lipid Res 26:617–622

    PubMed  CAS  Google Scholar 

  • Merrill AH Jr, Lingrell S, Wang E, Nikolova-Karakashian M, Vales TR, Vance DE (1995) Sphingolipid biosynthesis de novo by rat hepatocytes in culture. J Biol Chem 270:13834–13841. doi:10.1074/jbc.270.23.13834

    Article  PubMed  CAS  Google Scholar 

  • Nagle CA, Klett EL, Coleman RA (2009) Hepatic triacylglycerol accumulation and insulin resistance. J Lipid Res 50:S74–S79. doi:10.1194/jlr.R800053-JLR200

    Article  PubMed  Google Scholar 

  • Nakamura S, Takamura T, Matsuzawa-Nagata N, Takayama H, Misu H, Noda H, Nabemoto S, Kurita S, Ota T, Ando H, Miyamoto K, Kaneko S (2009) Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria. J Biol Chem 284:14809–14818. doi:10.1074/jbc.M901488200

    Article  PubMed  CAS  Google Scholar 

  • Nakata K, Kawase M, Ogino S, Kinoshita C, Murata H, Sakaue T, Ogata T, Ohmori S (1996) Effects of age on levels of cysteine, glutathione and related enzyme activities in livers of mice and rats and an attempt to replenish hepatic glutathione level of mouse with cysteine derivatives. Mech Ageing Dev 90:195–207. doi:10.1016/0047-6374(96)01771-X

    Article  PubMed  CAS  Google Scholar 

  • Perry DK, Carton J, Shah AK, Meredith F, Uhlinger DJ, Hannun YA (2000) Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J Biol Chem 275:9078–9084. doi:10.1074/jbc.275.12.9078

    Article  PubMed  CAS  Google Scholar 

  • Post A, Holsboer F, Behl C (1998) Induction of NF-kappaB activity during haloperidol-induced oxidative toxicity in clonal hippocampal cells: suppression of NF-kappaB and neuroprotection by antioxidants. J Neurosci 18:8236–8246

    PubMed  CAS  Google Scholar 

  • Rutkute K, Asmis RH, Nikolova-Karakashian MN (2007) Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation. J Lipid Res 48:2443–2452. doi:10.1194/jlr.M700227-JLR200

    Article  PubMed  CAS  Google Scholar 

  • Sanvicens N, Cotter TG (2006) Ceramide is the key mediator of oxidative stress-induced apoptosis in retinal photoreceptors. J Neurochem 98:1432–1444. doi:10.1111/j.1471-4159.2006.03977.x

    Article  PubMed  CAS  Google Scholar 

  • Sathishkumar S, Boyanovsky B, Karakashian AA, Rozenova K, Giltiay NV, Kudrimoti M, Mohiuddin M, Ahmed MM, Nikolova-Karakashian M (2005) Elevated sphingomyelinase activity and ceramide concentration in serum of patients undergoing high dose spatially fractionated radiation treatment: implications for endothelial apoptosis. Cancer Biol Ther 4:979–986. doi:10.4161/cbt.4.9.1915

    Article  PubMed  CAS  Google Scholar 

  • Scheel-Toellner D, Wang K, Craddock R, Webb PR, McGettrick HM, Assi LK, Parkes N, Clough LE, Gulbins E, Salmon M, Lord JM (2004) Reactive oxygen species limit neutrophil life span by activating death receptor signaling. Blood 104:2557–2564. doi:10.1182/blood-2004-01-0191

    Article  PubMed  CAS  Google Scholar 

  • Strivastava S, Chan C (2007) Hydrogen peroxide and hydroxyl radicals mediate palmitate-induced cytotoxicity to hepatoma cells: relation to mitochondrial permeability transition. Free Radical Res 41:38–49. doi:10.1080/10715760600943900

    Article  Google Scholar 

  • Su JF, Guo CJ, Wei JY, Yang JJ, Jiang YG, Li YF (2003) Protection against hepatic ischemia-reperfusion injury in rats by oral pretreatment with guercetin. Biomed Environ Sci 16:1–8

    PubMed  Google Scholar 

  • Watson ML, Coghlan M, Hundal HS (2009) Modulating serine palmitoyl transferase (SPT) expression and activity unveils a critical role in lipid-induced insulin resistance in rat skeletal muscle cells. Biochem J 417:791–801. doi:10.1042/BJ20081149

    Article  PubMed  CAS  Google Scholar 

  • Wei Y, Wang D, Topczewski F, Pagliassotti MJ (2006) Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab 291:E275–E281. doi:10.1152/ajpendo.00644.2005

    Article  PubMed  CAS  Google Scholar 

  • Yamagata K, Ichinose S, Tagawa C, Tagami M (2009) Vitamin E regulates SMase activity, GSH levels, and inhibits neuronal death in stroke-prone spontaneously hypertensive rats during hypoxia and reoxygenation. J Exp Stroke Transl Med 2:2. doi:10.1016/j.neuroscience.2010.07.013

    Article  Google Scholar 

  • Zeidan YH, Hannun YA (2007) Activation of acid sphingomyelinase by protein kinase Cδ-mediated phosphorylation. J Biol Chem 282:11549–11561. doi:10.1074/jbc.M609424200

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Nataliya A. Babenko.

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Babenko, N.A., Hassouneh, L.K.M., Kharchenko, V.S. et al. Vitamin E prevents the age-dependent and palmitate-induced disturbances of sphingolipid turnover in liver cells. AGE 34, 905–915 (2012). https://doi.org/10.1007/s11357-011-9288-3

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