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Lipids

, Volume 42, Issue 1, pp 5–14 | Cite as

Rediscovery of Cerebrosterol

  • Ingemar Björkhem
Original Article

Abstract

24S-hydroxycholesterol was identified more than half a century ago and was initially given the name “cerebrosterol” due to the fact that it was abundant in the brain. A decade ago, we showed that the most important mechanism by which cholesterol is eliminated from the mammalian brain involves a hydroxylation into cerebrosterol followed by diffusion of this steroid over the blood–brain barrier. Using an 18O2 inhalation technique, we showed that about two-thirds of the cholesterol synthesis in rat brain is balanced by conversion into cerebrosterol. The hydroxylase responsible for the reaction was found to be dependent upon NADPH and oxygen, consistent with involvement of a species of cytochrome, P-450. The gene coding for the cytochrome P-450 responsible for the reaction was later cloned by the group of David Russell in Dallas and the enzyme was found to be located to neuronal cells in the brain. Recent studies by us and others on this new pathway for elimination of cholesterol from the brain have given new insights into the mechanisms by which cholesterol homeostasis is maintained in this organ. In addition, these studies have resulted in new diagnostic and prognostic tools in connection with neurological and neurodegenerative diseases. An overview of the studies is presented here and the possibility is discussed that the cholesterol 24S-hydroxylase in the brain may be a new drug target in connection with neurodegenerative diseases.

Keywords

Cholesterol Bile Acid Cholesterol Homeostasis 18O2 Desmosterol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The author is grateful to the previous PhD students (and, in some cases, later post doctoral students) in his laboratory working on different parts of the project: Karl Bodin, Olof Breuer, Ewa Ellis, Maura Heverin, Valerio Leoni, Erik Lund, Dieter Lutjohann, and Steve Meaney. In addition, he is grateful for the fruitful collaboration with his colleagues, Leonel Bretillon, Ulf Diczfalusy, Curt Einarsson, Elena Feinstein, Maria Norlin, Yoshihiko Ohyama, Irina Pikuleva, Lars-Olof Wahlund, John Wahren, Kjell Wikvall, Åke Wennmalm, Bengt Winblad, and Jan Sjövall. This work was supported by grants from the Swedish Science Council, the Swedish Heart-Lung Foundation, Foundation “Gamla Tjänarinnor”, Brain Power, Brain Foundation, and Pfizer.

References

  1. 1.
    Sjövall J (2004) Fifty years with bile acids and steroids in health and disease. Lipids 39:703–722PubMedGoogle Scholar
  2. 2.
    Schroepfer GJ Jr (2000) Oxysterols: modulators of cholesterol metabolism and other processes. Physiol Rev 80:361–554PubMedGoogle Scholar
  3. 3.
    Lange Y, Ye J, Strebel F Movement of 25-hydroxycholesterol from the plasma membrane to the rough endoplasmic reticulum in cultured hepatoma cells. J Lipid Res 36:1092–1097Google Scholar
  4. 4.
    Meaney S, Bodin K, Diczfalusy U, Björkhem I (2002) On the rate of translocation in vitro and kinetics in vivo of the major oxysterols in human circulation: critical importance of the position of the oxygen function. J Lipid Res 43:2130–2135PubMedCrossRefGoogle Scholar
  5. 5.
    Björkhem I, Diczfalusy U (2002) Oxysterol. Friends,foes or just fellow passengers? Arterioscl Thromb Vasc Biol 22:734–742PubMedCrossRefGoogle Scholar
  6. 6.
    Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard SE, Spencer TA, Willson TM (1997) Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272:3137–3140PubMedCrossRefGoogle Scholar
  7. 7.
    Björkhem I (2002) Do oxysterols control cholesterol homeostasis? J Clin Invest 110:725–730PubMedCrossRefGoogle Scholar
  8. 8.
    Ercoli IA, Ruggieri P (1953) The constitution of cerebrosterol, a hydroxycholesterol isolated from horse brain. J Am Chem Soc 75:3284CrossRefGoogle Scholar
  9. 9.
    Smith LL, Ray DR, Moody JA, Wells JD, Lier JE (1972) 24-Hydroxycholesterol in human brain. J Neurochem 19:899–904PubMedCrossRefGoogle Scholar
  10. 10.
    Lin YY, Smith LL (1974) Biosynthesis and accumulation of cholest-5-ene-3β, 24-diol (cerebrosterol) in developing rat brain. Biochim Biophys Acta 348:189–196PubMedGoogle Scholar
  11. 11.
    Gustafsson JÅ, Sjövall J (1969) Identification of 22-, 24- and 26-Hydroxycholesterol in the steroid sulphate fraction of faeces from infants. Eur J Biochem 8:467–472PubMedCrossRefGoogle Scholar
  12. 12.
    Breuer O, Björkhem I (1990) Simultaneous quantification of several cholesterol autoxidation and monohydroxylation products by isotope dilution mass spectrometry. Steroids 55:185–192PubMedCrossRefGoogle Scholar
  13. 13.
    Dzeletovic S, Breuer O, Lund E, Diczfalusy U (1995) Determination of cholesterol oxidation products in human plasma by isotope dilution-mass spectrometry. Anal Biochem 225:73–803PubMedCrossRefGoogle Scholar
  14. 14.
    Breuer O, Björkhem I (1995) Use of an 18O2-inhalation technique and mass isotopomer analysis to study oxygenation of cholesterol in rat: evidence for in vivo formation of 7-oxo, 7β-hydroxy, 24-hydroxy-, and 25-hydroxycholesterol. J Biol Chem 270:20278–20284PubMedCrossRefGoogle Scholar
  15. 15.
    Babiker A, Dzeletovic S, Wiklund B, Petterson N, Salonen J, Nyssönen K., Eriksson M, Diczfalusy U, Björkhem I (2005) Patients with atherosclerosis may have increased circulating levels of 27-hydroxycholesterol and cholestenoic acid. Scand J Clin Lab Invest 65:365–376PubMedGoogle Scholar
  16. 16.
    Björkhem I, Reihne´r E, Angelin B, Ewerth S, Åkerlund J.-E., Einarsson K (1987) On the possible use of 7α-hydroxycholesterol as a marker for increased activity of the cholesterol 7α-hydroxylase. J Lipid Res 28:889–894PubMedGoogle Scholar
  17. 17.
    Lutjohann D, Björkhem I, Ose L (1996) Phytosterolemia in a Norwegian family: diagnosis and characterization of the first Scandinavian case. Scand J Clin Lab Invest 56:229–240PubMedGoogle Scholar
  18. 18.
    Lütjohann D, Breuer O, Ahlborg G, Nennesmo I, Sidén Å, Diczfalusy U, Björkhem I (1996) Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci USA 93:9799–9804PubMedCrossRefGoogle Scholar
  19. 19.
    Björkhem I, Lütjohann D, Diczfalusy U, Ståhle L, Ahlborg G, Wahren J (1998) Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J Lipid Res 39:1594–1600PubMedGoogle Scholar
  20. 20.
    Björkhem I, Lütjohann D, Breuer O, Sakinis A, Wennmalm Å (1997) Importance of a novel oxidative mechanism for elimination of brain cholesterol. Turnover of cholesterol and 24(S)-hydroxycholesterol in rat brain as measured with 18O2 techniques in vivo and in vitro. J Biol Chem 272:30178–30184PubMedCrossRefGoogle Scholar
  21. 21.
    Björkhem I, Lewenhaupt A (1979) Preferential utilization of newly synthesized cholesterol as substrate for bile acid biosynthesis. An in vivo study using 18O2-inhalation technique. J Biol Chem 254:5252–5256PubMedGoogle Scholar
  22. 22.
    Lund EG, Guileyardo JM, Russell DW (1999) cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci USA 96:7238–7243PubMedCrossRefGoogle Scholar
  23. 23.
    Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell DW (2003) Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J Biol Chem 278:22980–22988PubMedCrossRefGoogle Scholar
  24. 24.
    Mast N, Norcross R, Andersson U, Shou M, Nakayama K, Björkhem I, Pikuleva I (2003) Broad substrate specificity of human cytocrome P-450 46A1 which initiates cholesterol degradation in the brain. Biochemistry 42:14284–14292PubMedCrossRefGoogle Scholar
  25. 25.
    Ohyama Y, Meaney S, Heverin M, Ekström L, Brafman A, Andersson U, Olin M, Eggertsen G, Diczfalusy U, Feinstein E, Björkhem I (2006) Studies on the transcriptional regulation of cholesterol 24-hydroxylase (CYP46A1): marked insensitivity towards different regulatory axes. J Biol Chem 281:3810–3820PubMedCrossRefGoogle Scholar
  26. 26.
    Wechsler A, Brafman A, Shafir M, Heverin M, Gottlieb H, Damari G, Gozlan-Kelner S, Spivak I, Moshkin O, Fridman E, Becker Y, Skaliter R, Einat P, Faerman A, Björkhem I, Feinstein E (2003) Generation of viable cholesterol-free mice. Science 302:2087PubMedCrossRefGoogle Scholar
  27. 27.
    Russell DW (2003) The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 72:137–174PubMedCrossRefGoogle Scholar
  28. 28.
    Pfrieger FW (2003) Outsourcing in the brain: do neurons depend on cholesterol delivery by astrocytes? Bioessays 25:72–78PubMedCrossRefGoogle Scholar
  29. 29.
    Abildayeva K, Jansen PJ, Hirsch-Reinshagen V, Bloks VW, Bakker AHF, Ramackers FCS, deVente J, Groen AK, Wellington CL, Kuipers F, Mulder M (2006) 24S-Hydroxycholesterol participates in a liver X-receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux. J Biol Chem (in press)Google Scholar
  30. 30.
    Norlin M, Toll A, Björkhem I, Wikvall K (2000) 24-Hydroxycholesterol is a substrate for hepatic cholesterol 7α-hydroxylase (CYP7A). J Lipid Res 41:1629–1639PubMedGoogle Scholar
  31. 31.
    Li-Hawkins J, Lund E, Bronson AD, Russell DW (2000) J Biol Chem 275:16543–16549PubMedCrossRefGoogle Scholar
  32. 32.
    Björkhem I, Andersson U, Ellis E, Alvelius G, Ellegård L, Diczfalusy U, Sjövall J, Einarsson C (2001) From brain to bile. Evidence that conjugation and omega-hydroxylation are important for elimination of 24S-hydroxycholesterol (cerebrosterol) in humans. J Biol Chem 276:37004–37010PubMedCrossRefGoogle Scholar
  33. 33.
    Bretillon L, Lutjohann D, Stahle L, Widhe T, Bindl L, Eggertsen G, Diczfalusy U, Björkhem I (2000) Plasma levels of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic metabolism and are inversely related to body surface. J Lipid Res 41:840–845PubMedGoogle Scholar
  34. 34.
    Bretillon L, Side´n A, Wahlund LO, Lutjohann D, Minthon L, Crisby M, Hillert J, Groth CG, Diczfalusy U, Björkhem I (2000) Plasma levels of 24S-hydroxycholesterol in patients with neurological diseases. Neurosci Lett 331:163–166Google Scholar
  35. 35.
    Bogdanovic N, Bretillon L, Lund EG, Diczfalusy U, Lannfelt L, Winblad B, Russell DW, Björkhem I (2001) On the turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci Lett 314:45–48PubMedCrossRefGoogle Scholar
  36. 36.
    Brown J, Theisler C, Silberman S, Magnuson D, Gotthardi-Littell N, Lee JM, Yager D, Crowley J, Sambamurti K, Rahman MM, Wolozin (2004) Differential expression of cholesterol hydroxylases in Alzheimer's disease. J Biol Chem 279:34674–34681PubMedCrossRefGoogle Scholar
  37. 37.
    Leoni V, Masterman T, Diczfalusy U, DeLuca G, Hillert J, Björkhem I (2002) Changes in human plasma levels of the brain specific oxysterol 24S-hydroxycholesterol during progression of multipe sclerosis. Neurosci Lett 331:163–166PubMedCrossRefGoogle Scholar
  38. 38.
    Leoni V, Mastermann T, Mousavi FS, Wretlind B, Wahlund LO, Diczfalusy U, Hillert J, Björkhem I (2004) Diagnostic use of cerebral and extracerebral oxysterols. Clin Chem Lab Med 42:186–191PubMedCrossRefGoogle Scholar
  39. 39.
    Leoni V, Shafaati M, Salomon A, Kivipelto M, Björkhem I, Wahlund LO (2006) Are the CSF-levels of 24S-hydroxycholesterol a sensitive biomarker for mild cognitive impairment? Neurosci Lett 397:83–87PubMedCrossRefGoogle Scholar
  40. 40.
    Heverin M, Bogdanovic N, Lutjohann D, Bayer T, Pikuleva I, Bretillon L, Diczfalusy U, Winblad B, Björkhem I (2004) Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease. J Lipid Res 45:186–193PubMedCrossRefGoogle Scholar
  41. 41.
    Leoni W, Masterman T, Patel P, Meaney S, Diczfalusy U, Björkhem I (2003) Side-chain oxidized oxysterols in cerebrospinal fluid and integrity of blood–brain barrier. J Lipid Res 44:793–799PubMedCrossRefGoogle Scholar
  42. 42.
    Heverin M, Meaney S, Lutjohann D, Diczfalusy U, Wahren J, Björkhem I (2005) Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain. J Lipid Res 46:1047–1052PubMedCrossRefGoogle Scholar
  43. 43.
    Björkhem I, Heverin M, Leoni M, Meaney S, Diczfalusy U (2006) Oxysterols and Alzheimer's disease. Acta Neurol Scand 114 (Suppl 185):43−49Google Scholar
  44. 44.
    Björkhem I, Meaney S (2004) Brain cholesterol: long secret life behind a barrier. Arterioscl Thromb Vasc Biol 24:806–815PubMedCrossRefGoogle Scholar
  45. 45.
    Kölsch H, Lutjohann D, Tulke A, Björkhem I, Rao ML (1999) The neurotoxic effect of 24-hydroxycholesterol on SH-SY5Y human neuroblastoma cells. Brain Res 818:171–175PubMedCrossRefGoogle Scholar

Copyright information

© AOCS 2007

Authors and Affiliations

  1. 1.Department of Laboratory Medicine, Division of Clinical ChemistryKarolinska InstitutetHuddingeSweden

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