Santral sinir sisteminde kolesterol metabolizması

Amaç: Bu derlemede normal ve patolojik durumlardaki santral sinir sistemi kolesterol metabolizması gözden geçirilmiş ve diğer dokulardaki kolesterol metabolizması ile karşılaştırılmıştır. Ana bulgular: Santral sinir sistemi vücut ağırlığının % 2’sini oluşturmasına rağmen vücutta bulunan serbest kolesterolün yaklaşık % 25’ini içerir. Santral sinir sistemi ile ekstrahepatik dokuların kolesterol metabolizması arasında büyük farklılıklar vardır. Beyin dışındaki dokular ihtiyaçları olan kolesterolü kendileri sentezlerler veya dolaşımdan sağlarlar. Beyinde ise kan beyin bariyeri dolaşımdan beyne kolesterol geçişini engellemekte ve beyindeki bütün kolesterol de novo sentezlenmektedir. Dolaşımdan santral sinir sistemine kolesterol geçişi olmamasına rağmen beyinden dolaşıma kolesterol, 24S-hidroksikolesterol olarak geçmekte ve bunun miktarı da vücutta hareket eden kolesterolün yaklaşık % 0,9’unu oluşturmaktadır. Bu oran Alzheimer ve Nieman Pick tip C gibi nörodejeneratif hastalıklarda değişmektedir. Sonuç: Vücut kolesterol metabolizmasındaki değişiklikler santral sinir sisteminde ApoE yapımı ve sterol resirkülasyonunda değişikliklere sebep olarak nöron ve miyelinin yapısına etki eder. Bundan dolayı, kolesterol turnoveri ve bu olaylardaki kontrol mekanizmalarının açığa çıkarılması nörodejeneratif hastalıkların etyolojisinin en azından bir kısmını anlamamızı sağlayacaktır.

Cholesterol metabolism in the central nervous system

Objective: In this review, cholesterol metabolism of the central nervous system at healthy and pathologic conditions was reviewed and compared with cholesterol metabolism of the other tissues. Main findings: The central nervous system accounts for about 2% of the whole body mass but contains almost 25% of unesterified cholesterol present in the body. The cholesterol metabolism in the central nervous system is significantly different from that in most other extrahepatic tissues. The cellular cholesterol content of tissues other than brain is regulated by de novo synthesis and by cellular uptake of lipoprotein cholesterol from the circulation. Although, the blood-brain barrier effectively prevents uptake of cholesterol from the circulation and de novo synthesis is responsible for practically all cholesterol present in this organ, cholesterol diffuses to circulation as 24S-hydroxycholesterol and this represents about0.9% of cholesterol movement in the whole body. This ratio changes in neurodegenerative disorders such as Alzheimer’s and Niemann-Pick type C disease. Conclusion: Disturbances in cholesterol metabolism, transport, storage and balance in the whole body may effect brain structure and function. Alterations in sterol recycling and ApoE expression within the central nervous system may effect neuron and myelin integrity. Therefore, further evaluation of cholesterol metabolism either in the whole body or in the central nervous system is very important to understand and event prevent a variety of neurodegenerative diseases.

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1. Ellis GW, Gardner JA. The origin and destiny of cholesterol in the animal organism. Part IV. The cholesterol contents of eggs and chicks. Proc R Soc Ser B Biol Sci 1909;81:129-32
2. Mayes PA. Lipids of physiologic significance. In: Murray RK, Granner DK, Mayes PA, Rodwell VW. Harper’s Biochemistry 24 rd ed. London: Lange medical publication 1996;233-87.
3. Acton SA, Rigotti KT, Landschulz SX, Hobbs HH, Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 1996;271:518-20.
4. Dietschy JM, Turley SD. Thematic review series: brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 2004;45:1375-97.
5. Ishibashi S, Herz J, Maeda N, Goldstein JL, Brown MS. The two-receptor model of lipoprotein clearance: Tests of the hypothesis in "knockout" mice lacking the low density lipoprotein receptor, Apolipoprotein E, or both proteins. Proc Natl Acad Sci USA 1994;91:4431-5.
6. Loftus SK, Morris JA, Carstea ED, Gu JZ, Cummings C, Brown A, et al. Murine model of Niemann-Pick C disease: Mutation in a cholesterol homeostasis gene. Science 1997;277: 232-5.
7. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 1996;271:518–20.
8. Xie C, Turley SD, Dietschy JM. Centripetal cholesterol flow from the extrahepatic organs through the liver is normal in mice with mutated Niemann-Pick type C protein (NPC1). J Lipid Res 2000;41:1278–89.
9. Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tetzloff G, et al. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science 2004;303:1201-4.
10. Yokoyama S. Release of cellular cholesterol: molecular mechanism for cholesterol homeostasis in cells and in the body. Biochim Biophys Acta 2000;1529:231-44.
11. Yu L, Hammer RE, Li-Hawkins J, Bergmann K von, Lutjohann D, Cohen JC, et al. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci USA 2002;99:16237-42.
12. Russell DW. The enzymes, regulation and genetics of bile acid synthesis. Annu Rev Biochem 2003;72:137-74.
13. Borghini I, Barja F, Pometta D, James RW. Characterization of subpopulations of lipoprotein particles isolated from human cerebrospinal fluid. Biochim Biophys Acta 1995;1255:192–200.
14. Bjorkhem I, Meaney S. Brain cholesterol: Long secret life behind a barrier. Arterioscler Thromb Vasc Biol 2004;24:806-15.
15. Andersen JM, Dietschy JM. Absolute rates of cholesterol synthesis in extrahepatic tissues measured with 3H-labeled water and 14C-labeled substrates. J Lipid Res 1979;20:740-52.
16. Muse ED, Jurevics H, Toews AD, Matsushima GK, Morell P. Parameters related to lipid metabolism as markers of myelination in mouse brain. J Neurochem 2001;76: 77–86.
17. Jurevics H, Morell P. Cholesterol for synthesis of myelin is made locally, not imported into brain. J Neurochem 1995;64: 895–901.
18. Chobanian AV, Hollander W. Body cholesterol metabolism in man. I. The equilibration of serum and tissue cholesterol. J Clin Invest 1962;41:1732-7.
19. Wilson JD. The measurement of the exchangeable pools of cholesterol in the baboon. J Clin Invest 1970;49:655-65.
20. Osono Y, Woollett LA, Herz J, Dietschy JM. 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 1995;95:1124–32.
21. Plotz EJ, Kabara JJ, Davis ME, LeRoy GV, Gould RG. Studies on the synthesis of cholesterol in the brain of the human fetus. Am J Obstet Gynecol 1968;101:534-8.
22. Yu L, Bergmann K Von, Lutjohann D, Hobbs H H, Cohen J C. Selective sterol accumulation in ABCG5/ABCG8-deficient mice. J Lipid Res 2004;45:301-7.
23. Sherrill BC, Dietschy JM. Permeability characteristics of the adipocyte cell membrane and partitioning characteristics of the adipocyte triglyceride core. J Membr Biol 1975;23:367-83.
24. Zhang J, Akwa Y, El-Etr M, Baulieu EE, Sjövall J. Metabolism of 27-, 25- and 24-hydroxycholesterol in rat glial cells and neurons. Biochem J 1997;322:175-84.
25. Xie C, Lund EG, Turley SD, Russell DW, Dietschy JM. Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration. J Lipid Res 2003;44:1780-9.
26. Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell D W. Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J Biol Chem 2003;287:22980-8.
27. Bretillon L, Lütjohann D, Ståhle L, Widhe T, Bindl L, Eggersten G, et al. Plasma levels of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic metabolism and are inversely related to body surface. J Lipid Res2000;41:840-5.
28. Björkhem I, Lütjohann D, Diczfalusy U, Ståhle L, Ahlborg G, Wahren J. 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 1998;39:1594-600.
29. Parker CR., Carr Jr BR, Simpson ER, MacDonald PC. Decline in the concentration of low-density lipoprotein-cholesterol in human fetal plasma near term. Metabolism 1983;32:919-23.
30. Sinnett PF, Whyte HM. Epidemiological studies in a total highland population, Tukisenta, New Guinea. Cardiovascular disease and relevant clinical, electrocardiographic, radiological and biochemical findings. J Chronic Dis 1973;26: 265-90.
31. McMurry MP, Cerqueira MT, Connor SL, Wonnor WE. Changes in lipid and lipoprotein levels and body weight in Tarahumara Indians after consumption of an affluent diet. N Engl J Med 1991;325:1704-8.
32. Martin MJ, Hulley SB, Browner WS, Kuller LH, Wentworth D. Serum cholesterol, blood pressure, and mortality: Implications from a cohort of 361 662 men. Lancet 1986;2:933-6
33. Engelberg H. Low serum cholesterol and suicide. Lancet 1992;339:727-9.
34. Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, et al. Midlife vascular risk factors and Alzheimer's disease in later life: Longitudinal, population based study. BMJ 2001;322:1447-51.
35. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet 2000;356:1627-31.
36. Salvati S, Attorri L, Avellino C, Di Biase A, Sanchez M. Diet, lipids and brain development.Dev Neurosci 2000;22:481-7.
37. Kurban S. Diyet yağlarının beyinde lipid peroksidasyonu, AOA, NO ve lipidler üzerine olan etkilerinin araştırılması (Uzmanlık Tezi). Konya: Selçuk Üniversitesi Meram Tıp Fakültesi, Biyokimya Anabilim Dalı; 2005.
38. Salen G, Shefer S, Batta AK, Tint GS, Xu G, Honda A, et al. Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome. J Lipid Res 1996;37:1169-80.
39. Heverin M, Bogdanovic N, Lutjohann D, Bayer T, Pikuleva I, Bretillon L, et al. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease. J Lipid Res 2004;45:186-93.