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Brainstem Concentrations of Cholesterol are not Influenced by Genetic Ablation of the Low-Density Lipoprotein Receptor

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Abstract

Purpose The low-density lipoprotein receptor (LDLr) mediates the uptake of LDL particles enriched with cholesterol, into several tissues. In contrast to other tissues, the brain is thought to obtain cholesterol solely by de novo synthesis, yet certain brain regions such as the brainstem are highly enriched with the LDLr. The goal of the present study was to assess the role of the LDLr in maintaining cholesterol concentrations in the brainstem of wildtype and LDLr knockout (LDLr−/−) mice. Cholesterol concentrations were also measured in the cortex, which served as a reference point, due to the lower expression of the LDLr, as compared to the brainstem. Methods LDLr−/− and wildtype mice consumed an AIN-93G diet ad libitum until 7 weeks of age. After microwaving, the cortex and anterior brain stem were isolated for cholesterol analysis. Cholesterol was extracted into chloroform/methanol, derivatized in trimethylsilyl chloride and measured by gas chromatography/mass spectrometry. Results Concentrations of cholesterol in the brainstem did not differ statistically between LDLr−/− (18.8 ± 1.6 mg/g wet weight brain) and wildtype (19.1 ± 2.0). Cortical cholesterol concentrations also did not differ statistically between LDLr−/− (11.0 ± 0.4 mg/g wet weight brain) and wildtype (11.1 ± 0.2) mice. Conclusion The LDLr is not necessary for maintaining cholesterol concentrations in the cortex or brainstem, suggesting that other mechanisms are sufficient to maintain brain cholesterol concentrations.

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References

  1. Dietschy JM, Turley SD (2004) Thematic review series: brain Lipids Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 45:1375–1397. doi:10.1194/jlr.R400004-JLR200

    Article  PubMed  CAS  Google Scholar 

  2. Jurevics H, Morell P (1995) Cholesterol for synthesis of myelin is made locally, not imported into brain. J Neurochem 64:895–901

    PubMed  CAS  Google Scholar 

  3. Bennett PJ, Simmonds MA (1996) The influence of membrane cholesterol on the GABAA receptor. Br J Pharmacol 117:87–92

    PubMed  CAS  Google Scholar 

  4. Cortez MA, Cunnane SC, Snead OCIII (2002) Brain sterols in the AY-9944 rat model of atypical absence seizures. Epilepsia 43:3–8. doi:10.1046/j.1528-1157.2002.22401.x

    Article  PubMed  CAS  Google Scholar 

  5. Serbanescu I, Ryan MA, Shukla R, Cortez MA, Snead OCIII, Cunnane SC (2004) Lovastatin exacerbates atypical absence seizures with only minimal effects on brain sterols. J Lipid Res 45:2038–2043. doi:10.1194/jlr.M400097-JLR200

    Article  PubMed  CAS  Google Scholar 

  6. Cooper MK, Wassif CA, Krakowiak PA, Taipale J, Gong R, Kelley RI et al (2003) A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet 33:508–513. doi:10.1038/ng1134

    Article  PubMed  CAS  Google Scholar 

  7. Kovanen PT, Basu SK, Goldstein JL, Brown MS (1979) Low density lipoprotein receptors in bovine adrenal cortex II. Low density lipoprotein binding to membranes prepared from fresh tissue. Endocrinology 104:610–616

    Article  PubMed  CAS  Google Scholar 

  8. Kovanen PT, Faust JR, Brown MS, Goldstein JL (1979) Low density lipoprotein receptors in bovine adrenal cortex I. Receptor-mediated uptake of low density lipoprotein and utilization of its cholesterol for steroid synthesis in cultured adrenocortical cells. Endocrinology 104:599–609

    PubMed  CAS  Google Scholar 

  9. Turley SD, Burns DK, Rosenfeld CR, Dietschy JM (1996) Brain does not utilize low density lipoprotein-cholesterol during fetal and neonatal development in the sheep. J Lipid Res 37:1953–1961

    PubMed  CAS  Google Scholar 

  10. Osono Y, Woollett LA, Herz J, Dietschy JM (1995) Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse. J Clin Invest 95:1124–1132. doi:10.1172/JCI117760

    Article  PubMed  CAS  Google Scholar 

  11. Webber RJ, Edmond J (1979) The in vivo utilization of acetoacetate, d-(−)-3-hydroxybutyrate, and glucose for lipid synthesis in brain in the 18-day-old rat. Evidence for an acetyl-CoA bypass for sterol synthesis. J Biol Chem 254:3912–3920

    PubMed  CAS  Google Scholar 

  12. Hofmann SL, Russell DW, Goldstein JL, Brown MS (1987) mRNA for low density lipoprotein receptor in brain and spinal cord of immature and mature rabbits. Proc Natl Acad Sci USA 84:6312–6316. doi:10.1073/pnas.84.17.6312

    Article  PubMed  CAS  Google Scholar 

  13. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A et al (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168–176. doi:10.1038/nature05453

    Article  PubMed  CAS  Google Scholar 

  14. Chen CT, Ma DW, Kim JH, Mount HT, Bazinet RP (2008) The low density lipoprotein receptor is not necessary for maintaining mouse brain polyunsaturated fatty acid concentrations. J Lipid Res 49:147–152. doi:10.1194/jlr.M700386-JLR200

    Article  PubMed  CAS  Google Scholar 

  15. Bazinet RP, Lee HJ, Felder CC, Porter AC, Rapoport SI, Rosenberger TA (2005) Rapid high-energy microwave fixation is required to determine the anandamide (N-arachidonoylethanolamine) concentration of rat brain. Neurochem Res 30:597–601. doi:10.1007/s11064-005-2746-5

    Article  PubMed  CAS  Google Scholar 

  16. Adams ML, Sullivan DM, Smith RL, Richter EF (1986) Evaluation of direct saponification method for determination of cholesterol in meats. J Assoc Off Anal Chem 69:844–846

    PubMed  CAS  Google Scholar 

  17. Edmond J, Korsak RA, Morrow JW, Torok-Both G, Catlin DH (1991) Dietary cholesterol and the origin of cholesterol in the brain of developing rats. J Nutr 121:1323–1330

    PubMed  CAS  Google Scholar 

  18. Jurevics HA, Kidwai FZ, Morell P (1997) Sources of cholesterol during development of the rat fetus and fetal organs. J Lipid Res 38:723–733

    PubMed  CAS  Google Scholar 

  19. Quan G, Xie C, Dietschy JM, Turley SD (2003) Ontogenesis and regulation of cholesterol metabolism in the central nervous system of the mouse. Brain Res Dev Brain Res 146:87–98. doi:10.1016/j.devbrainres.2003.09.015

    Article  PubMed  CAS  Google Scholar 

  20. Golovko MY, Murphy EJ (2008) An improved LC-MS/MS procedure for brain prostanoid analysis using brain fixation with head-focused microwave irradiation and liquid-liquid extraction. J Lipid Res 49:893–902. doi:10.1194/jlr.D700030-JLR200

    Article  PubMed  CAS  Google Scholar 

  21. Grange E, Deutsch J, Smith QR, Chang M, Rapoport SI, Purdon AD (1995) Specific activity of brain palmitoyl-CoA pool provides rates of incorporation of palmitate in brain phospholipids in awake rats. J Neurochem 65:2290–2298

    Article  PubMed  CAS  Google Scholar 

  22. Elder GA, Cho JY, English DF, Franciosi S, Schmeidler J, Sosa MA et al (2007) Elevated plasma cholesterol does not affect brain Abeta in mice lacking the low-density lipoprotein receptor. J Neurochem 102:1220–1231. doi:10.1111/j.1471-4159.2007.04614.x

    Article  PubMed  CAS  Google Scholar 

  23. Boleman SL, Graf TL, Mersmann HJ, Su DR, Krook LP, Savell JW et al (1998) Pigs fed cholesterol neonatally have increased cerebrum cholesterol as young adults. J Nutr 128:2498–2504

    PubMed  CAS  Google Scholar 

  24. Pond WG, Mersmann HJ, Su D, McGlone JJ, Wheeler MB, Smith EO (2008) Neonatal dietary cholesterol and alleles of cholesterol 7-alpha hydroxylase affect piglet cerebrum weight, cholesterol concentration, and behavior. J Nutr 138:282–286

    PubMed  CAS  Google Scholar 

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Acknowledgments

Funding for this study was provided by the Natural Sciences and Engineering Research Council of Canada to Dr. R.P. Bazinet and the Canadian Institutes of Health Research Doctoral Research award (Fredrick Bating and Charles Best Canada Graduate Scholarships) to A.Y. Taha.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Ameer Y. Taha

  2. Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, FitzGerlad Bldg, 150 College St., Rm 306, Toronto, ON, Canada, M5S 3E2

    Chuck T. Chen, Zhen Liu & Richard P. Bazinet

  3. Centre for Research in Neurodegenerative Diseases, Department of Medicine (Division of Neurology) and of Physiology, University of Toronto, Toronto, ON, Canada

    John H. Kim & Howard T. J. Mount

Authors
  1. Ameer Y. Taha
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  2. Chuck T. Chen
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  3. Zhen Liu
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  4. John H. Kim
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  5. Howard T. J. Mount
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  6. Richard P. Bazinet
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Correspondence to Richard P. Bazinet.

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Taha, A.Y., Chen, C.T., Liu, Z. et al. Brainstem Concentrations of Cholesterol are not Influenced by Genetic Ablation of the Low-Density Lipoprotein Receptor. Neurochem Res 34, 311–315 (2009). https://doi.org/10.1007/s11064-008-9777-7

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  • DOI: https://doi.org/10.1007/s11064-008-9777-7

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