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Lipids

, Volume 51, Issue 4, pp 477–486 | Cite as

Dolichol: A Component of the Cellular Antioxidant Machinery

  • Gabriella CavalliniEmail author
  • Antonella Sgarbossa
  • Ilaria Parentini
  • Ranieri Bizzarri
  • Alessio Donati
  • Francesco Lenci
  • Ettore Bergamini
Original Article
  • 309 Downloads

Abstract

Dolichol, an end product of the mevalonate pathway, has been proposed as a biomarker of aging, but its biological role, not to mention its catabolism, has not been fully understood. UV-B radiation was used to induce oxidative stress in isolated rat hepatocytes by the collagenase method. Effects on dolichol, phospholipid-bound polyunsaturated fatty acids (PL-PUFA) and known lipid soluble antioxidants [coenzyme Q (CoQ) and α-tocopherol] were studied. The increase in oxidative stress was detected by a probe sensitive to reactive oxygen species (ROS). Peroxidation of lipids was assessed by measuring the release of thiobarbituric acid reactive substances (TBARS). Dolichol, CoQ, and α-tocopherol were assessed by high-pressure liquid chromatography (HPLC), PL-PUFA by gas–liquid chromatography (GC). UV-B radiation caused an immediate increase in ROS as well as lipid peroxidation and a simultaneous decrease in the levels of dolichol and lipid soluble antioxidants. Decrease in dolichol paralleled changes in CoQ levels and was smaller to that in α-tocopherol. The addition of mevinolin, a competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoAR), magnified the loss of dolichol and was associated with an increase in TBARS production. Changes in PL-PUFA were minor. These findings highlight that oxidative stress has very early and similar effects on dolichol and lipid soluble antioxidants. Lower levels of dolichol are associated with enhanced peroxidation of lipids, which suggest that dolichol may have a protective role in the antioxidant machinery of cell membranes and perhaps be a key to understanding some adverse effects of statin therapy.

Keywords

Dolichol Coenzyme Q α-Tocopherol Phospholipid-bound polyunsaturated fatty acids Rat hepatocytes Oxidative stress 

Abbreviations

CoQ

Coenzyme Q

DCFH-DA

2′,7′-dichlorodihydro-fuorescein diacetate

FA

Fatty acid(s)

FAME

Fatty acid methyl esters

GC

Gas–liquid chromatography

HMG-CoAR

3-hydroxy-3-methylglutaryl CoA reductase

HPLC

High-pressure liquid chromatography

MDA

Malondialdehyde

OS

Oxidative stress

PL

Phospholipid(s)

PL-PUFA

Phospholipid-bound polyunsaturated fatty acid(s)

ROS

Reactive oxygen species

TBARS

Thiobarbituric acid reactive substances

Trolox

6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid

UV-B

Ultraviolet-B

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Freidovich I (1999) Fundamental aspects of reactive oxygen species, or what’s the matter with oxygen? Ann NY Acad Sci 893:13–18CrossRefGoogle Scholar
  2. 2.
    Halliwell B, Gutteridge JMC (2007) Free radicals in biology and medicine, 4th edn. Oxford University Press, OxfordGoogle Scholar
  3. 3.
    Sies H (1993) Strategies of antioxidant defense. Eur J Biochem 215:213–219CrossRefPubMedGoogle Scholar
  4. 4.
    Chojnacki T, Dallner G (1988) The biological role of dolichol. Biochem J 251:1–9CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kalén A, Appelkvist EL, Dallner G (1989) Age-related changes in the lipid compositions of rat and human tissues. Lipids 24:579–584CrossRefPubMedGoogle Scholar
  6. 6.
    Daniels I, Hemming FW (1990) Changes in murine tissue concentrations of dolichol and dolichol derivatives associated with age. Lipids 25:586–593CrossRefPubMedGoogle Scholar
  7. 7.
    Marino M, Dolfi C, Paradiso C, Cavallini G, Masini M, Gori Z, Pollera M, Trentalance A, Bergamini E (1998) Age-dependent accumulation of dolichol in rat liver: is tissue dolichol a biomarker of aging? J Gerontol A Biol Sci Med Sci 53:B87–B93CrossRefPubMedGoogle Scholar
  8. 8.
    Cavallini G, Dolfi C, Donati A, Maccheroni M, Parentini I, Gori Z, Bergamini E (2003) Effect of increasing age on tissue dolichol levels in ad libitum and food restricted rats. Biogerontology 4:341–345CrossRefPubMedGoogle Scholar
  9. 9.
    Parentini I, Cavallini G, Donati A, Gori Z, Bergamini E (2005) Accumulation of dolichol in older tissues satisfies the criteria to be qualified a biomarker of aging. J Gerontol A Biol Sci Med Sci 60:39–43CrossRefPubMedGoogle Scholar
  10. 10.
    Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343:425–430CrossRefPubMedGoogle Scholar
  11. 11.
    Pallottini V, Montanari L, Cavallini G, Bergamini E, Gori Z, Trentalance A (2004) Mechanisms underlying the impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in aged rat liver. Mech Ageing Dev 125:633–639CrossRefPubMedGoogle Scholar
  12. 12.
    Pallottini V, Martini C, Cavallini G, Bergamini E, Mustard KJ, Hardie DG, Trentalance A (2007) Age-related HMG-CoA reductase deregulation depends on ROS-induced p38 activation. Mech Ageing Dev 128:688–695CrossRefPubMedGoogle Scholar
  13. 13.
    Pallottini V, Martini C, Pascolini A, Cavallini G, Gori Z, Bergamini E, Incerpi S, Trentalance A (2005) 3-Hydroxy-3-methylglutaryl coenzyme A reductase deregulation and age-related hypercholesterolemia: a new role for ROS. Mech Ageing Dev 126:845–851CrossRefPubMedGoogle Scholar
  14. 14.
    Surmacz L, Swiezewska E (2011) Polyisoprenoids—secondary metabolites or physiologically important superlipids? Biochem Biophys Res Commun 407:627–632CrossRefPubMedGoogle Scholar
  15. 15.
    Sanyal S, Menon AK (2010) Stereoselective transbilayer translocation of mannosyl phosphoryl dolichol by an endoplasmic reticulum flippase. Proc Natl Acad Sci USA 107:11289–11294CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Buczkowska A, Swiezewska E, Lefeber DJ (2015) Genetic defects in dolichol metabolism. J Inherit Metab Dis 38:157–169CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Van Houte HA, Van Veldhoven PP, Mannaerts GP, Baes MI, Declercq PE (1997) Metabolism of dolichol, dolichoic acid and nordolichoic acid in cultured cells. Biochim Biophys Acta 1347:93–100CrossRefPubMedGoogle Scholar
  18. 18.
    Carroll KK, Guthrie N, Ravi K (1992) Dolichol: function, metabolism, and accumulation in human tissues. Biochem Cell Biol 70:382–384CrossRefPubMedGoogle Scholar
  19. 19.
    Cavallini G, Parentini I, Di Stefano R, Maccheroni M, Masini M, Pollera M, Gori Z, Mosca F, Bergamini E (2002) Dolichol levels in younger and older rat hearts heterotopically transplanted in younger recipients. Lipids 37:913–916CrossRefPubMedGoogle Scholar
  20. 20.
    Bizzarri R, Cerbai B, Signori F, Solaro R, Bergamini E, Tamburini I, Chiellini E (2003) New perspectives for (S)-dolichol and (S)-nordolichol synthesis and biological functions. Biogerontology 4:353–363CrossRefPubMedGoogle Scholar
  21. 21.
    Parentini I, Bergamini E, Cecchi L, Cavallini G, Donati A, Maccheroni M, Tamburini I, Gori Z (2003) The effect of carbon tetrachloride and ultraviolet radiation on dolichol levels in liver cells isolated from 3- and 24-month-old male Sprague-Dawley rats. Biogerontology 4:365–370CrossRefPubMedGoogle Scholar
  22. 22.
    Sgarbossa A, Lenci F, Bergamini E, Bizzarri R, Cerbai B, Signori F, Gori Z, Maccheroni M (2003) Dolichol: a solar filter with UV-absorbing properties which can be photoenhanced. Biogerontology 4:379–386CrossRefPubMedGoogle Scholar
  23. 23.
    Bergamini E, Bizzarri R, Cavallini G, Cerbai B, Chiellini E, Donati A, Gori Z, Manfrini A, Parentini I, Signori F, Tamburini I (2004) Ageing and oxidative stress: a role for dolichol in the antioxidant machinery of cell membranes? J Alzheimer Dis 6:129–135Google Scholar
  24. 24.
    Seglen PO (1976) Preparation of isolated liver cells. Methods Cell Biol 13:29–83CrossRefPubMedGoogle Scholar
  25. 25.
    Cathcart R, Schwiers E, Ames BN (1983) Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein assay. Anal Biochem 134:111–116CrossRefPubMedGoogle Scholar
  26. 26.
    Crow JP (1997) Dichlorodihydrofluorescein and dihydrorhodamine 123 are sensitive indicators of peroxynitrite in vitro: implications for intracellular measurement of reactive nitrogen and oxygen species. Nitric Oxide 1:145–157CrossRefPubMedGoogle Scholar
  27. 27.
    Burow S, Valet G (1987) Flow-cytometric characterization of stimulation, free radical formation, peroxidase activity and phagocytosis of human granulocytes with 2,7-dichloroflorescein (DCF). Eur J Cell Biol 43:128–133PubMedGoogle Scholar
  28. 28.
    Rastogi RP, Singh SP, Häder DP, Sinha RP (2010) Detection of reactive oxygen species (ROS) by the oxidant-sensing probe 2′,7′-dichlorodihydrofluorescein diacetate in the cyanobacterium Anabaena variabilis PCC 7937. Biochem Biophys Res Commun 397:603–607CrossRefPubMedGoogle Scholar
  29. 29.
    Cavallini G, Dachà M, Potenza L, Ranieri A, Scattino C, Castagna A, Bergamini E (2014) Use of red blood cell membranes to evaluate the antioxidant potential of plant extracts. Plant Foods Hum Nutr 69:108–114CrossRefPubMedGoogle Scholar
  30. 30.
    Grotto D, Santa Maria LD, Boeira S, Valentini J, Charão MF, Moro AM, Nascimento PC, Pomblum VJ, Garcia SC (2007) Rapid quantification of malondialdehyde in plasma by high performance liquid chromatography-visible detection. J Pharm Biomed Anal 43:619–624CrossRefPubMedGoogle Scholar
  31. 31.
    Folch J, Lees M, Sloane-Stanley G (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226:497–509PubMedGoogle Scholar
  32. 32.
    Quartacci MF, Cosi E, Navari-Izzo F (2001) Lipids and NADPH-dependent superoxide production in plasma membrane vesicles from roots of wheat grown under copper deficiency or excess. J Exp Bot 52:77–84CrossRefPubMedGoogle Scholar
  33. 33.
    Pamplona R, Portero-Otín M, Ruiz C, Gredilla R, Herrero A, Barja G (2000) Double bond content of phospholipids and lipid peroxidation negatively correlate with maximum longevity in the heart of mammals. Mech Ageing Dev 112:169–183CrossRefPubMedGoogle Scholar
  34. 34.
    Lang JK, Gohil K, Packer L (1986) Simultaneous determination of tocopherols, ubiquinols, and ubiquinones in blood, plasma, tissue homogenates, and subcellular fractions. Anal Biochem 157:106–116CrossRefPubMedGoogle Scholar
  35. 35.
    Maltese WA, Erdman RA (1989) Characterization of isoprenoid involved in the post-translational modification of mammalian cell proteins. J Biol Chem 264:18168–18172PubMedGoogle Scholar
  36. 36.
    Rupérez FJ, Barbas C, Castro M, Martìnez S, Herrera E (1998) Simplified method for vitamin E determination in rat adipose tissue and mammary glands by high-performance liquid chromatography. J Chromatogr A 823:483–487CrossRefPubMedGoogle Scholar
  37. 37.
    Davies MJ, Forni LG, Willson RL (1988) Vitamin E analogue Trolox C. E.s.r. and pulse-radiolysis studies of free-radical reactions. Biochem J 255:513–522PubMedPubMedCentralGoogle Scholar
  38. 38.
    Ouedraogo GD, Redmond RW (2003) Secondary reactive oxygen species extend the range of photosensitization effects in cells: DNA damage produced via initial membrane photosensitization. Photochem Photobiol 77:192–203CrossRefPubMedGoogle Scholar
  39. 39.
    Besselink GA, van Engelenburg FA, Ebbing IG, Hilarius PM, de Korte D, Verhoeven AJ (2003) Additive effects of dipyridamole and Trolox in protecting human red cells during photodynamic treatment. Vox Sang 85:25–30CrossRefPubMedGoogle Scholar
  40. 40.
    Boaz NT (2002) Evolving health: the origins of illness and how the modern world is making us sick. Wiley, New YorkGoogle Scholar
  41. 41.
    Pattison DI, Davies MJ (2006) Actions of ultraviolet light on cellular structures. EXS 96:131–157PubMedGoogle Scholar
  42. 42.
    Jurkiewicz BA, Buettner GR (1994) Ultraviolet light-induced free radical formation in skin: an electron paramagnetic resonance study. Photochem Photobiol 59:1–4CrossRefPubMedGoogle Scholar
  43. 43.
    Fuchs J, Huflejt ME, Rothfuss LM, Wilson DS, Carcamo G, Packer LJ (1989) Impairment of enzymic and nonenzymic antioxidants in skin by UVB irradiation. Invest Dermatol 93:769–773CrossRefGoogle Scholar
  44. 44.
    Podda M, Traber MG, Weber C, Yan LJ, Packer LJ (1998) UV-irradiation depletes antioxidants and causes oxidative damage in a model of human skin. Free Radic Biol Med 24:55–65CrossRefPubMedGoogle Scholar
  45. 45.
    Li Y, Fu J, Yuan X, Hu C (2014) Simvastatin inhibits the proliferation of A549 lung cancer cells through oxidative stress and up-regulation of SOD2. Pharmazie 69:610–614PubMedGoogle Scholar
  46. 46.
    Pallottini V, Martini C, Bassi AM, Romano P, Nanni G, Trentalance A (2006) Rat HMGCoA reductase activation in thioacetamide-induced liver injury is related to an increased reactive oxygen species content. J Hepatol 44:368–374CrossRefPubMedGoogle Scholar
  47. 47.
    Fedorow H, Pickford R, Hook JM, Double KL, Halliday GM, Gerlach M, Riederer P, Garner B (2005) Dolichol is the major lipid component of human substantia nigra neuromelanin. J Neurochem 92:990–995CrossRefPubMedGoogle Scholar
  48. 48.
    Ward WC, Zucca FA, Bellei C, Zecca L, Simon JD (2009) Neuromelanins in various regions of human brain are associated with native and oxidized isoprenoid lipids. Arch Biochem Biophys 484:94–99CrossRefPubMedGoogle Scholar
  49. 49.
    Ishiguro T, Morita-Fujimura Y, Shidoji Y, Sagami H (2014) Dolichol biosynthesis: the occurrence of epoxy dolichol in skipjack tuna liver. Biochem Biophys Res Commun 453:277–281CrossRefPubMedGoogle Scholar
  50. 50.
    Zhou GP, Troy FA 2nd (2005) NMR study of the preferred membrane orientation of polyisoprenols (dolichol) and the impact of their complex with polyisoprenyl recognition sequence peptides on membrane structure. Glycobiology 15:347–359CrossRefPubMedGoogle Scholar
  51. 51.
    Ciepichal E, Jemiola-Rzeminska M, Hertel J, Swiezewska E, Strzalka K (2011) Configuration of polyisoprenoids affects the permeability and thermotropic properties of phospholipid/polyisoprenoid model membranes. Chem Phys Lipids 164:300–306CrossRefPubMedGoogle Scholar
  52. 52.
    Dallner G, Sindelar PJ (2000) Regulation of ubiquinone metabolism. Free Radic Biol Med 29:285–294CrossRefPubMedGoogle Scholar
  53. 53.
    Dini B, Dolfi C, Santucci V, Cavallini G, Donati A, Gori Z, Maccheroni M, Bergamini E (2001) Effects of ageing and increased haemolysis on the levels of dolichol in rat spleen. Exp Gerontol 37:99–105CrossRefPubMedGoogle Scholar
  54. 54.
    Molińska Nee Sosińska E, Klimczak U, Komaszyło J, Derewiaka D, Obiedziński M, Kania M, Danikiewicz W, Swiezewska E (2015) Double bond stereochemistry influences the susceptibility of short-chain isoprenoids and polyprenols to decomposition by thermo-oxidation. Lipids 50:359–370CrossRefGoogle Scholar
  55. 55.
    Komaszylo Née Siedlecka J, Kania M, Masnyk M, Cmoch P, Lozinska I, Czarnocki Z, Skorupinska-Tudek K, Danikiewicz W, Swiezewska E (2016) Isoprenoid alcohols are susceptible to oxidation with singlet oxygen and hydroxyl radicals. Lipids 51:229–244CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    de Ropp JS, Troy FA (1985) 2H NMR investigation of the organization and dynamics of polyisoprenols in membranes. J Biol Chem 260:15669–15674PubMedGoogle Scholar
  57. 57.
    Guarini M, Stabile A, Cavallini G, Donati A, Bergamini E (2007) Effects of oxidative stress on the dolichol content of isolated rat liver cells. Free Radic Res 41:1283–1288CrossRefPubMedGoogle Scholar
  58. 58.
    Bentinger M, Tekle M, Dallner G (2010) Coenzyme Q-biosynthesis and functions. Biochem Biophys Res Commun 396:74–79CrossRefPubMedGoogle Scholar
  59. 59.
    Bassi AM, Cottalasso D, Canepa C, Maloberti G, Casu A, Nanni G (2004) Association of thioacetamide and ethanol treatment: dolichol and retinol in isolated rat liver cells. Drug Chem Toxicol 27:55–67CrossRefPubMedGoogle Scholar
  60. 60.
    Tamburini I, Quartacci MF, Izzo R, Bergamini E (2004) Effects of dietary restriction on age-related changes in the phospholipid fatty acid composition of various rat tissues. Aging Clin Exp Res 16:425–431CrossRefPubMedGoogle Scholar
  61. 61.
    Bergamini E, Cavallini G, Donati A, Gori Z (2004) The role of macroautophagy in the ageing process, anti-ageing intervention and age-associated diseases. Int J Biochem Cell Biol 36:2392–2404CrossRefPubMedGoogle Scholar
  62. 62.
    Magni P, Macchi C, Morlotti B, Sirtori CR, Ruscica M (2015) Risk identification and possible countermeasures for muscle adverse effects during statin therapy. Eur J Intern Med 26:82–88CrossRefPubMedGoogle Scholar

Copyright information

© AOCS 2016

Authors and Affiliations

  • Gabriella Cavallini
    • 1
    Email author
  • Antonella Sgarbossa
    • 2
    • 3
  • Ilaria Parentini
    • 1
  • Ranieri Bizzarri
    • 2
    • 3
  • Alessio Donati
    • 1
  • Francesco Lenci
    • 2
  • Ettore Bergamini
    • 1
  1. 1.Interdepartmental Research Centre on Biology and Pathology of AgingUniversity of PisaPisaItaly
  2. 2.Biophysics Institute of the National Research Council (IBF-CNR)PisaItaly
  3. 3.NESTNanoscience Institute of the National Research Council (NANO-CNR) and Scuola Normale SuperiorePisaItaly

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