Cholesterol Distribution in Golgi, Lysosomes and Endoplasmic Reticulum

  • E. Joan Blanchette-Mackie
  • Peter G. Pentchev


Insight into the effect of exogeneously derived lipoprotein cholesterol on distribution of intracellular membrane cholesterol has been gained from structural studies on normal and Niemann Pick Type C human fibroblasts. Endocytic uptake of LDL enriches Golgi cholesterol in both normal and NPC cells. However, the NPC mutation and treatment of normal cells with progesterone during LDL uptake produces abnormal accumulation of cholesterol in lysosomes and trans Golgi cisternae. This lysosomal/Golgi block in cholesterol trafficking results in the inability of endocytosed cholesterol to induce cellular homestatic responses. In addition to lysosomes and Golgi the endoplasmic reticulum can also be a site along the intracellular cholesterol transport pathway that becomes a temporary depot for cholesterol. Specific inhibition of acyl CoA: cholesterol acyltransferase with S-58035 during endocytic uptake results in a reversable accumulation of cholesterol in membranes of ER. Thus the ER, normally low in intracellular cholesterol, has the capacity to act as a sink for endocytosed cholesterol when esterification is blocked. In contrast to the lysosomal/Golgi cholesterol sequestration, ER accumulation of cholesterol does not compromise but appears to enhance the induction of cellular homeostatic responses.

Key Words

Golgi trans Golgi cisternae lysosomes endoplasmic reticulum intracellular cholesterol 


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  1. 1.
    Wattenberg BW, Silbert DF. Sterol partitioning among intracellular membranes. J Biol. Chem 1983;258;2284–2289PubMedGoogle Scholar
  2. 2.
    Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986;232:34–47.PubMedCrossRefGoogle Scholar
  3. 3.
    Liscum L, Dahl NK. Intracellular cholesterol transport J. Lipid Res. 1992;33:1239–1254PubMedGoogle Scholar
  4. 4.
    Sokol J, Blanchette-Mackie EJ, Kruth HS, Dwyer NK, Amende LM, Butler JD, Robinson E, Patel S, Brady RO, Comly ME, Vanier MT, Pentchev PG: Type-C Niemann-Pick Disease: Lysosomal accumulation and defective intracellular mobilization of LDL-cholesterol. J. Biol. Chem. 1988 263:3411–3417PubMedGoogle Scholar
  5. 5.
    Pentchev PG, Comly ME, Kruth HS, Tokoro T, Butler JD, Sokol J, Filling-Katz M, Quirk, J.M, Marshall DC, Patel S, Vanier MT, Brady RO. Group C Niemann-Pick disease: Faulty regulation of low-density lipoprotein uptake and cholesterol storage in cultured fibroblasts. FASEB J. 1987;1:40–45PubMedGoogle Scholar
  6. 6.
    Liscum L, Ruggiero RM, Faust JR. The intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann-Pick type C fibroblasts. J. Cell Biol. 1989;108:1625–16367.PubMedCrossRefGoogle Scholar
  7. 7.
    Blanchette-Mackie EJ, Dwyer NK, Amende LM, Kruth HS, Butler JD, Sokol J, Comly ME, Vanier MT, August JT, Brady RO, Pentchev PG. Type C Niemann-Pick Disease: low density lipoprotein uptake is associated with premature cholesterol accumulation in the Golgi complex and excessive cholesterol storage in lysosomes. Proc Natl Acad. Sci. USA 1988;85:8022–8026PubMedCrossRefGoogle Scholar
  8. 8.
    Martin OC, Comly ME, Blanchette-Mackie EJ, Pentchev PG, Pagano RE. Cholesterol deprivation affects the fluorescence properties of a ceramide analog at the Golgi apparatus of living cells. Proc. Natl. Acad. Sci. 1993;90:2661–2665.PubMedCrossRefGoogle Scholar
  9. 9.
    Pagano RE, Sepanski MA, Martin OC. Molecular trapping of a fluorescent ceramide analogue at the Golgi apparatus of fixed cells: interaction with endogeneous lipids provides a trans-Golgi marker for both light and electron microscopy. J. Cell Biol. 1989;109:2067–2079PubMedCrossRefGoogle Scholar
  10. 10.
    Neufeld EB, Cooney AM, Pitha J, Dawidowitcz EA, Dwyer NK, Pentchev PG, Blanchette-Mackie EJ. Intracellular trafficking of cholesterol monitored with a cyclodextrin, J Biol Chem 1996;271:21604–21613.PubMedCrossRefGoogle Scholar
  11. 11.
    Alcade J, Bonay P, Roa A, Vilaro S, Sandoval V. Assembly and disassembly of the Golgi complex: two processes arranged in a cis-trans direction. J Cell Biol. 1992;6:69–83CrossRefGoogle Scholar
  12. 12.
    Anderson RGW, Pathak RK: Vesicles and cisternae in the trans Golgi Golgi apparatus of human fibroblasts are acidic compartments. Cell 1985;40:635–643PubMedCrossRefGoogle Scholar
  13. 13.
    Coxey RA, Pentchev PG, Campbell G, Blanchette-Mackie EJ. Differential accumulation of cholesterol in Golgi compartments of normal and Niemann-Pick type C fibroblasts incubated with LDL: a cytochemical freeze-fracture study. J. Lipid Res. 1993;34:1165–1176PubMedGoogle Scholar
  14. 14.
    Orci L, Montesano R, Meda P, Malaisse-Lagae F, Brown A, Perrelet A, Vassalli P. Heterogeneous distribution of filipin-cholesterol complexes across cisternae of the Golgi apparatus. Proc. Natl. Acad. Sci USA. 1981;78:293–297.PubMedCrossRefGoogle Scholar
  15. 15.
    Carstea E.D., Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, Gu J., Rosenfeld MA, Pavan WJ, Krizman DB, Nagle J, Polymeropoulos MH, Sturley SL, Ioannou YA, Higgens ME, Comly M, Cooney A, Brown A, Kaneski CR, Blanchette-Mackie EJ, Dwyer NK, Neufeld EB, Chang T-Y, Liscum L, Strauss JF, Ohno K, Zeigler M, Garmi R, Sokol J, Markie D, O’Neill RR, van Diggelen OP, Elleder M, Patterson MC, Brady, Vanier MT, Pentchev PG and DA Tagle. Niemann-Pick C1 disease gene:homology to mediators of cholesterol homeostasis. Science 1997 Jul 11;277(5323):228–231PubMedCrossRefGoogle Scholar
  16. 16.
    Butler J, Blanchette-Mackie EJ, Goldin E, O’Neill RR, Carstea GD, Roff CF, Patterson MC, Patel S, Comly ME, Cooney AM, Vanier MT, Brady RO, Pentchev PG:Progesterone blocks cholesterol translocation from lysosomes. J. Biol. Chem. 1992;267:23797–23805PubMedGoogle Scholar
  17. 17.
    Mellman I, Fuchs R, Helenius A. Acidification of the endocytic and exocytic pathways. Ann. Rev. Biochem. 1986;55:663–700PubMedCrossRefGoogle Scholar
  18. 18.
    Rosenwald AG, Pagano RE:Inhibition of glycoprotein traffic through the secretory pathway by ceraqmide. J. Biol. Chem. 1993;268:4577–4579PubMedGoogle Scholar
  19. 19.
    Klausner RD, Donaldson JG, Lippincott-Schwartz J: Brefeldin A: Insights into the control of membrane traffic and organelle structure. J. Cell Biol. 1992;116:1071–1080PubMedCrossRefGoogle Scholar
  20. 20.
    Furuchi T, Aikawa K, Arai H, Inoue K. Bafilomycin A1, a specific inhibitor of vacuolar H+-ATPase, blocks lysosomal cholesterol trafficking in macrophages. J. Biol. Chem 1993;268:27345–27348PubMedGoogle Scholar
  21. 21.
    Bolender RP. Correlation of morphometry and stereology with biochemical analysis of cell fractions. Int. Rev. Cytology 1978;55:247–289CrossRefGoogle Scholar
  22. 22.
    Voelker DR. Organelle biogenesis and intracellular lipid transport in eukaryotes. Microbiol. Rev. 1991;55:543–560PubMedGoogle Scholar
  23. 23.
    Lange Y. Disposition of intracellular cholesterol in human fibroblasts. J. Lipid Res. 1991;32:329–339PubMedGoogle Scholar
  24. 24.
    Rash JE, Johnson TA, Dinchuk JE, Duch DS, Levinson SR (in Freeze-Fracture Studies of Membranes) 1989; ed. S.W. Hui. CRC Press, Boca Raton, Florida. 41–59.Google Scholar
  25. 25.
    Urbani L, Simoni RD. Cholesterol and vesicular stomatitis virus G protein take separate routes from the endoplasmic reticulum to the plasma membrane. J. Biol. Chem. 1990;265:1919–1923PubMedGoogle Scholar
  26. 26.
    Jamal Z, Siffolk A, Boyd GS, Suckling KE. Metabolism of cholesterol ester in monolayers of bovine adrenal corticla cells. Effect of an inhibitor of acyl-CoA: cholesterol acyltransferase. Biochim. Biophys. Acta 1985;834:230–237PubMedCrossRefGoogle Scholar
  27. 27.
    Amende LM, Blanchette-Mackie, E.J, Scow RO. Demonstration of fatty acid domains in membranes produced by lipolysis in mouse adipose tissue: A freeze-fracture study. Cell Tissue Res. 1986;246:495–508PubMedCrossRefGoogle Scholar
  28. 28.
    Shiratori Y, Okwu AK, Tabas I. Free cholesterol loading of macrophages stimulates phosphatidylcholine biosynthesis and up-regulation of CTP: phosphocholine cytidyltransferase. J. Biol. Chem. 1994;269:11337–11348PubMedGoogle Scholar
  29. 29.
    Hayat M.A. (in Fixation for Electron Microscopy) 1981; ed Hayat, Academic Press, New York, N.Y. 1–50Google Scholar
  30. 30.
    Tabas I, Rosoff WJ, Boykow GC. Acyl-coenzymeA: cholesterol acyltransferase in macrophages utilizes a cellular pool of oxidase accessable cholesterol as substrate. J. Biol. Chem. 1988;263:1266–1272PubMedGoogle Scholar
  31. 31.
    Wang X, Sato R., Brown MS, Hua X, Goldstein JL, SREBP-1, a membrane-bound transcription factor released by sterol regulated proteolysis. Cell 1994;77:53–62PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • E. Joan Blanchette-Mackie
    • 1
  • Peter G. Pentchev
    • 2
  1. 1.National Institutes of Diabetes, Digestive and Kidney DiseasesNational Institutes of HealthBethesdaUSA
  2. 2.Neurological Disorders and StrokeNational Institutes of HealthBethesdaUSA

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