Biological Effects of Some Products of Cholesterol Autoxidation

  • Andrew A. Kandutsch

Abstract

A wide range of C27 to C30 oxysterols, many of which are products of cholesterol autoxi ation, are potent inhibitors of the enzyme 3-hydroxy-3-meqy4glutaryl-coenzyme A (HMG-CoA) reductase in mammalian cells.1–4 Because HMG-CoA reductase is an important regulatory enzyme in the biosynthesis of isoprene units the oxysterols can suppress the biosynthesis of several isoprenoid compounds (Fig. 1). In human beings and other higher animals, cholesterol is the most abundant and most studied product of isoprene metabolism. However, increasingly attention is being given to two other products of the biosynthetic pathway, dolichol and the side chain of coenzyme Q. Dolichol is a lipid carrier for the assembly of a complex oligosaccharide which is then transferred to asparagine residues of nascent glycoproteins. Coenzyme Q serves as an electron carrier in oxidative phosphorylation. Cholesterol serves several different functions in the organism. It is a major component of plasma membranes; it is a precursor for bile acids and steroid hormones and it functions as a structural component of serum lipoproteins. It seems likely that the major features of the feedback regulatory system depicted in Figure 1 evolved primarily to control the synthesis of cholesterol needed for these functions. The detailed mechanisms of this control system are still speculative. However enough is known to provide a rationale for the inhibitory activities of the oxysterols.

Keywords

Cholesterol Synthesis Sterol Synthesis Autoxidation Product Natural Metabolite Isoprenoid Compound 
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.

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References

  1. 1.
    A. A. Kandutsch, H. W. Chen, and H.-J. Heiniger, The biological activity of some oxygenated sterols, Science 201: 498 (1978).Google Scholar
  2. 2.
    G. J. Schroepfer, Jr., R. A. Pascal, Jr., R. Shaw, and A. A. Kandutsch, Inhibition of sterol biosynthesis by 14ehydroxymethyl sterols, Biochem. Biophys. Res. Comm. 83: 1024 (1978).Google Scholar
  3. 3.
    G. F. Gibbons, C. R. Pullinger, H. W. Chen, W. K. Cavenee, and A. A. Kandutsch, Suppression of cholesterol biosynthesis in cultured cells by probable precursor sterols, J. Biol. Chem. (in press).Google Scholar
  4. 4.
    A. A. Kandutsch and H. W. Chen, Inhibition of cholesterol synthesis by oxygenated sterols, Lipids 13: 704 (1978).Google Scholar
  5. 5.
    A. A. Kandutsch and H. W. Chen, Consequences of blocked sterol synthesis in cultured cells: DNA synthesis and membrane composition, J. Biol. Chem. 252:409 (1977).Google Scholar
  6. 6.
    A. A. Kandutsch and H. W. Chen, Inhibition of sterol synthesis in cultured mouse cells by cholesterol derivatives oxygenated in the side chain, J. Biol. Chem. 249:6057 (1974).Google Scholar
  7. 7.
    A. A. Kandutsch and H. W. Chen, Inhibition of sterol synthesis in cultured mouse cells by 7e-hydroxycholesterol, 78hydroxycholesterol, and 7-ketocholesterol, J. Biol. Chem. 248:8408 (1973).Google Scholar
  8. 8.
    H. W. Chen, W. K. Cavenee, and A. A. Kandutsch, Variant Chinese hamster lung cells selected for resistance to 25-hydroxycholesterol: cross resistance to 7-ketocholesterol, 20ehydroxycholesterol and serum, J. Biol. Chem. 254:715 (1979).Google Scholar
  9. 9.
    W. K. Cavenee, G. F. Gibbons, H. W. Chen, and A. A. Kandutsch, Effects of various oxygenated sterols on cellular sterol biosynthesis in Chinese hamster lung cells resistant to 25-hydroxycholesterol, Biochim. Biophys. Acta 575:255 (1979).Google Scholar
  10. 10.
    A. A. Kandutsch, H. W. Chen, and E. P. Shown, Binding of 25hydroxycholesterol and cholesterol to different cytoplasmic proteins, Proc. Nat. Acad. Sci. 74:2500 (1977).CrossRefGoogle Scholar
  11. 11.
    A. A. Kandutsch and E. B. Thompson, Cytosolic protein(s) that bind oxygenated sterols: cellular distribution, specificity and some properties (submitted).Google Scholar
  12. 12.
    M. J. James and A. A. Kandutsch, Interrelationship between dolichol and sterol synthesis in mammalian cell cultures, J. Biol. Chem. 254:8442 (1979).Google Scholar
  13. 13.
    P. H. Gold and R. E. Olson, Studies on coenzyme Q. The biosynthesis of coenzyme Q in rat tissue slices, J. Biol. Chem. 241:3507 (1966).Google Scholar
  14. 14.
    H. W. Chen, H.-J. Heiniger, and A. A. Kandutsch, Alteration of Rb influx and efflux following depletion of membrane sterol in L cells, J. Biol. Chem. 253:3180 (1978).Google Scholar
  15. 15.
    J. J. Baldassare, Y. Saito, and D. F. Silbert, Effect of sterol depletion on LM cell sterol mutants. Changes in the lipid composition of the plasma membrane and their effects on 3–0-methylglucose transport, J. Biol. Chem. 254:1108 (1979).Google Scholar
  16. 16.
    M. Sinensky, F. PinkerTon, _F. Sutherland, and F. R. Simon, Rate limitation of (Na + K)-stimulated adenosine triphosphatase by membrane acyl chain ordering, Proc. Nat. Acad. Sci. 76:4893 (1979).Google Scholar
  17. 17.
    I. Klein, L. Moore, and I. Pastan, Effect of liposomes containing cholesterol on adenylate cyclase activity of cultured mammalian fibroblasts, Biochim. Biophys. Acta 506:42 (1978).CrossRefGoogle Scholar
  18. 18.
    M. Sinensky, K. Minneman, and P. B. Malinoff, Increased membrane acyl chain ordering activates adenylate cyclase, J. Biol. Chem. 254:9135 (1979).Google Scholar
  19. 19.
    H.-J. Heiniger, A. A. Kandutsch, and H. W. Chen, Depletion of L-cell sterol depresses endocytosis, Nature 263: 515 (1976).CrossRefGoogle Scholar
  20. 20.
    A. F. Horwitz, A. Wight, P. Ludwig, and R. Cornell, Interrelated lipid alterations and their influence on the proliferation and fusion of cultured myogenic cells, J. Cell. Biol. 77:334 (1978).Google Scholar
  21. 21.
    G. M. K. Humphries and H. M. McConnell, Potent immunosuppression by oxidized cholesterol, J. Inuiiunol. 122: 121 (1978).Google Scholar
  22. 22.
    H. P. M. Pratt, P. A. Fitzgerald, and A. Sahon, Synthesis of sterol and phospholipid induced by the interaction of phytohemagglutinin and other mitogens with human lymphocytes and their relation to blastogenesis and DNA synthesis, Cell. Immunol. 32:166 (1977).Google Scholar
  23. 23.
    H.-J. Heiniger, K. T. Brunner, and J.-C. Cerottini, Cholesterol is a critical component for T-lymphocyte cytotoxicity, Proc. Nat. Acad. Sci. 75:5683 (1978).Google Scholar
  24. 24.
    H. W. Chen, H.-J. Heiniger, and A. A. Kandutsch, Relationship between sterol synthesis and DNA synthesis in phytohemagglutinin-stimulated mouse lymphocytes, Proc. Nat. Acad. Sci. 72:1950 (1975).Google Scholar
  25. 25.
    S. S. Chen, Enhanced sterol synthesis in concanavalin A-stimulated lymphocytes: correlation with phospholipid synthesis and DNA synthesis, J. Cell. Physiol. 100:147 (1979).Google Scholar
  26. 26.
    S. H. C. Ip, J. Abrahm, and R. A. Cooper, Enhancement of blastogenesis in cholesterol-enriched lymphocytes, J. Immunol. 124: 87 (1980).Google Scholar
  27. 27.
    A. A. Kandutsch and S. E. Saucier, Regulation of sterol synthesis in developing brains of normal and jimpy mice, Arch. Biochem. Biophys. 135:201 (1969).Google Scholar
  28. 28.
    M. J. James and A. A. Kandutsch, Evidence for independent regulation of dolichol and cholesterol synthesis in developing mouse brain (submitted).Google Scholar
  29. 29.
    A. A. Kandutsch, H.-J. Heiniger, and H. W. Chen, Effects of 25-hydroxycholesterol and 7-ketocholesterol, inhibitors of sterol synthesis, administered orally to mice, Biochim. Biophys. Acta 486:260 (1977).Google Scholar
  30. 30.
    A. A. Kandutsch, Sterol metabolism in skin and epidermis, in “The Epidermis,” W. Montagna and W. C. Lobitz, Jr., ed., Academic Press, New York (1964).Google Scholar
  31. 31.
    M. J. James and A. A. Kandutsch, Elevated dolichol synthesis in mouse testes during spermatogenesis, J. Biol. Chem (in press).Google Scholar
  32. 32.
    A. A. Kandutsch and R. L. Hancock, Regulation of the rate of sterol synthesis and the level of 6-hydroxy-6-methyl glutaryl coenzyme A reductase activity in mouse liver and hepatomas, Cancer Res. 31: 1396 (1971).Google Scholar
  33. 33.
    H. W. Chen, A. A. Kandutsch, H.-J. Heiniger, and H. Meier, Elevated sterol synthesis in lymphocytic leukemia cells from two inbred strains of mice, Cancer Res. 33: 2774 (1973).Google Scholar
  34. 34.
    S. K. Erickson, A. D. Cooper, S. M. Matsui, and R. G. Gould, 7-Ketocholesterol. Its effects on hepatic cholesterogenesis and its hepatic metabolism in vivo and in vitro, J. Biol. Chem. 252: 5186 (1977).Google Scholar
  35. 35.
    S. K. Erickson, S. M. Matsui, M. A. Shrewesbury, A. D. Cooper, and R. G. Gould, Effects of 25-hydroxycholesterol on rat hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in vivo, in perifused liver, and in hepatocytes, J. Biol. Chem. 253:4159 (1978).Google Scholar
  36. 36.
    D. L. Raulston, C. 0. Meshaw, E. J. Parish, and G. J. Schroepfer, Jr., Inhibition of hepatic sterol synthesis and reduction of serum cholesterol in rats by 5a-cholester-8(14)-en-36ol-15-one, Biochem. Biophys. Res. Comm. 71: 984 (1976).Google Scholar
  37. 37.
    G. J. Schroepfer, Jr., D. Monger, A. S. Taylor, J. S. Chamberlain, E. J. Parish, A. Kisic, and A. A. Kandutsch, Inhibitors of sterol synthesis. Hypocholesterolemic action of dietary 5a-cholest-8(14)-en-33-o1–15-one in rats and mice, Biochem. Biophys. Res. Comm. 78: 1227 (1977).Google Scholar
  38. 38.
    J. F. Mowbray, Ability of large doses of an a2 plasma protein fraction to inhibit antibody production, Immunology 6: 217 (1963).Google Scholar
  39. 39.
    J. H. Morse, L. D. Witte, and D. S. Goodman, Inhibition of lymphocyte proliferation stimulated by lectins and allogeneic cells by normal plasma proteins, J. Exp. Med. 146:1791 (1977).Google Scholar
  40. 40.
    J. Schuh, A. Novogrodsky, and R. H. Haschemeyer, Inhibition of lymphocyte mitogenesis by autoxidized low-density lipoprotein, Biochem. Biophys. Res. Comm. 84:763 (1978).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1980

Authors and Affiliations

  • Andrew A. Kandutsch
    • 1
  1. 1.The Jackson Laboratory BarHarborUSA

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