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From gallstones to genes: Two hundred years of sterol research. A tribute to George J. Schroepfer Jr.

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Lipids

Abstract

The origins of cholesterol research can be traced to prerevolutionary France. The discovery of cholesterol as a single substance, present in human gallstones, owes much to the scientists of l'Académie Française, including Lavoisier, who contributed so much to the emergence of chemistry as a modern scientific discipline. Since that time, cholesterol probably has been the most intensively scrutinized natural product of all time, and it has been the subject of Nobel Prizes for several who have studied its structure, biosynthesis, and regulation. The pace of research into cholesterol shows no sign of diminishing, and recent discoveries have led to the recognition that the regulation of cholesterol metabolism is intimately linked with that of other metabolic pathways. Details of these interactions are only just emerging, but it is becoming apparent that under some circumstances it is difficult to reconcile, in a conventional manner, changes in regulatory gene expression with corresponding changes in pathway carbon flux. The present review includes some of our studies on the roles of the transcription factors sterol regulatory element-binding protein, liver X-receptor α, and peroxisome proliferator activated receptor α in the coordination of cholesterol and fatty acid synthesis and describes how some of the results obtained can best be interpreted from a Metabolic Control Analysis perspective of the regulation of pathway carbon fluxes.

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Abbreviations

CYP7A1:

cholesterol 7α-hydroxylase

ER:

endoplasmic reticulum

FAS:

fatty acid synthase

LXRα:

liver X-receptor α

MCA:

Metabolic Control Analysis

PPARα:

peroxisome proliferator-activated receptor α

SCAP:

SREBP cleavage-activating protein

SREBP:

sterol regulatory element-binding protein

References

  1. Cornforth, J.W. (1976) Asymmetry and Enzyme Action. in Les Prix Nobel en 1975, pp. 119–132, Nobel Foundation, Stockholm.

    Google Scholar 

  2. Popják, G. (1977) “As I Remember It.” Research on Biosynthesis of Fatty Acids, Triglycerides, Squalene and Cholesterol, J. Am. Oil Chem. Soc. 54, 647A-659A.

    PubMed  Google Scholar 

  3. Schroepfer, G.F., Jr. (2000) Oxysterols: Modulators of Cholesterol Metabolism and Other Processes, Physiol. Rev. 80, 361–554.

    PubMed  CAS  Google Scholar 

  4. Forman, B.M., Ruan, B., Chen, J., Schroepfer, G.J., Jr., and Evans, R.M. (1997) The Orphan Nuclear Receptor LXRα Is Positively and Negatively Regulated by Distinct Products of Mevalonate Metabolism, Proc. Natl. Acad. Sci. USA 94, 10588–10593.

    Article  PubMed  CAS  Google Scholar 

  5. Chevreul, M.E. (1815) Ann. Chim. Phys. 95, 5.

    Google Scholar 

  6. Smeaton, W.A. (1962) Fourcroy: Chemist and Revolutionary 1755–1809, pp. 53–59, Heffer, London.

    Google Scholar 

  7. Fourcroy, A. (1790) Memoire sur les differens états de cadavres trouves dans les fouilles du cimetiere des Innocens en 1786 et 1787, Ann. Chim. 5, 154–185.

    Google Scholar 

  8. Fourcroy, A. (1789) Examen chimique de la substance fueilletee et cristalline continue dans les calculs biliares; et de la nature des concretions cystiques cristallisees, Ann. Chim. 3, 242–252.

    Google Scholar 

  9. Chevreul, M.E. (1816) Examen des graisses d'homme, de mouton, de boeuf, de jaguar et d'oie, Ann. Chim. Phys. 2, 339–372.

    Google Scholar 

  10. Windaus, A. (1910) Über den Gehalt normaler und athermatöser Aorten an Cholesterin und Cholesterinester, Z. Physiol. Chem. 67, 174–184.

    Google Scholar 

  11. Krebs, H.A. (1981) Reminiscences and Reflections, Oxford University Press, Oxford, United Kingdom.

    Google Scholar 

  12. Bernal, J.D. (1932) Carbon Skeleton of the Sterols, Chem. Ind. 51, 466.

    CAS  Google Scholar 

  13. Perutz, M. (2001) The Great Sage, Chem. Br., 37, 56–57.

    CAS  Google Scholar 

  14. Wieland, H., and Dane, E. (1932) Untersuchungen über die Konstitution der Gallensäuren. 39. Mitteilung. Zur Kenntnis der 12-oxy-cholansäure, Zt. Physiol. Chem. 210, 268–281.

    CAS  Google Scholar 

  15. Rosenheim, O., and King, H. (1932) The Ring System of Sterols and Bile Acids, Nature 130, 315.

    CAS  Google Scholar 

  16. Florkin, M., and Stotz, E.H. (1979) History of Biochemistry, Comp. Biochem. 33A, 1–26.

    Google Scholar 

  17. Cornforth, J.W. (2002) Sterol Biosynthesis: The Early Days, Biochem. Biophys. Res. Commun. 292, 1129–1138.

    Article  PubMed  CAS  Google Scholar 

  18. Gould, R.G., Taylor, C.B., Hagerman, J.S., Warner, I., and Campbell, D.J. (1953) Cholesterol Metabolism. I. Effect of Dietary Cholesterol on the Synthesis of Cholesterol in Dog Tissues in vitro, J. Biol. Chem. 201, 519–528.

    PubMed  CAS  Google Scholar 

  19. Horton, J.D., Goldstein, J.L., and Brown, M.S. (2002) SREBPs: Activators of the Complete Program of Cholesterol and Fatty Acid Synthesis in the Liver, J. Clin. Invest. 109, 1125–1131.

    Article  PubMed  CAS  Google Scholar 

  20. Ingham, P.W. (2001) Hedgehog Signaling: A Tale of Two Lipids, Science 294, 1879–1881.

    Article  PubMed  CAS  Google Scholar 

  21. Kandutsch, A.A., and Chen, H.W. (1973) Inhibition of Sterol Synthesis in Cultured Mouse Cells by 7α-Hydroxycholesterol, 7β-Hydroxycholesterol and 7-Ketocholesterol, J. Biol. Chem. 248, 8408–8417.

    PubMed  CAS  Google Scholar 

  22. Fell, D., ed. (1997) Understanding the Control of Metabolism, Frontiers in Metabolism Series 2 (Snell, K., series ed.), 300 pp., Portland Press, London.

    Google Scholar 

  23. Janowski, B.A., Willy, P.J., Devi, T.R., Falck, J.R., and Mangelsdorf, D.J. (1996) An Oxysterol Signalling Pathway Mediated by the Nuclear Receptor LXRα, Nature 383, 728–731.

    Article  PubMed  CAS  Google Scholar 

  24. Lehmann, J.M., Kliewer, S.A., Moore, L.B., Smith-Oliver, T.A., Oliver, B.B., Su, J.L., Sundseth, S.S., Winegar, D.A., Blanchard, D.E., Spencer, T.A., and Willson, T.M. (1997) Activation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway, J. Biol. Chem. 272, 3137–3140.

    Article  PubMed  CAS  Google Scholar 

  25. Repa, J.J., Turley, S.D., Lobaccaro, J.A., Medina, J., Li, L., Lustig, K., Shan, B., Heyman, R.A., Dietschy, J.M., and Mangelsdorf, D.J. (2000) Regulation of Absorption and ABC1-Mediated Efflux of Cholesterol by RXR Heterodimers, Science 289, 1524–1529.

    Article  PubMed  CAS  Google Scholar 

  26. Schultz, J.R., Tu, H., Luk, A., Repa, J.J., Medina, J.C., Li, L., Schwendner, S., Wang, S., Thoolen, M., Mangelsdorf, D.J., Lustig, K.D., and Shan, B. (2000) Role of LXRs in Control of Lipogenesis, Genes Dev. 14, 2831–2838.

    Article  PubMed  CAS  Google Scholar 

  27. Saucier, S.E., Kandutsch, A.A., Gayen, A.K., Swahn, D.K., and Spencer, T.A. (1989) Oxysterol Regulators of 3-Hydroxy-3-methylglutaryl-CoA Reductase in Liver. Effect of Dietary Cholesterol, J. Biol. Chem. 264, 6863–6869.

    PubMed  CAS  Google Scholar 

  28. Repa, J.J., Liang, G., Ou, J., Bashmakov, Y., Lobaccaro, J.M., Shimomura, I., Shan, B., Brown, M.S., Goldstein, J.L., and Mangelsdorf, D.J. (2000) Regulation of Mouse Sterol Regulatory Element-Binding Protein-1c Gene (SREBP-1c) by Oxysterol Receptors, LXRα and LXRβ, Genes Dev. 14, 2819–2830.

    Article  PubMed  CAS  Google Scholar 

  29. Matsumoto, M., Ogawa, W., Teshigawara, K., Inoue, H., Miyake, K., Sakaue, H., and Kasuga, M., (2002) Role of the Insulin Receptor Substrate 1 and Phosphatidylinositol 3-Kinase Signaling Pathway in Insulin-Induced Expression of Sterol Regulatory Element Binding Protein 1c and Glucokinase Genes in Rat Hepatocytes, Diabetes 51, 1672–1680.

    PubMed  CAS  Google Scholar 

  30. Shimomura, I., Matsuda, M., Hammer, R.E., Bashmakov, Y., Brown, M.S., and Goldstein, J.L. (2000) Decreased IRS-2 and Increased SREBP-1c Lead to Mixed Insulin Resistance and Sensitivity in Livers of Lipodystrophic and ob/ob Mice, Mol. Cell. 6, 77–86.

    Article  PubMed  CAS  Google Scholar 

  31. Fleischmann, M., and Iynedjian, P.B. (2000) Regulation of Sterol Regulatory-Element Binding Protein 1 Gene Expression in Liver: Role of Insulin and Protein Kinase B/cAkt, Biochem. J. 349, 13–17.

    Article  PubMed  CAS  Google Scholar 

  32. Shimomura, I., Bashmakov, Y., Ikemoto, S., Horton, J.D., Brown, M.S., and Goldstein, J.L. (1999) Insulin Selectively Increases SREBP-1c mRNA in the Livers of Rats with Streptozotocin-Induced Diabetes, Proc. Natl. Acad. Sci. USA 96, 13656–13661.

    Article  PubMed  CAS  Google Scholar 

  33. Foretz, M., Pacot, C., Dugail, I., Lemarchand, P., Guichard, C., Le-Liepvre, X., Berthelier-Lubrano, C., Spiegelman, B., Kim, J.B., Ferré, P., and Foufelle, F. (1999) ADD1/SREBP-1c Is Required in the Activation of Hepatic Lipogenic Gene Expression by Glucose, Mol. Cell Biol. 19, 3760–3768.

    PubMed  CAS  Google Scholar 

  34. Gibbons, G.F., Patel, D.D., Wiggins, D., and Knight, B.L. (2002) The Functional Efficiency of Lipogenic and Cholesterogenic Gene Expression in Normal Mice and in Mice Lacking the Peroxisomal Proliferator-Activated Receptor α (PPAR-α), Adv. Enzyme Regul. 42, 227–247.

    Article  PubMed  CAS  Google Scholar 

  35. Jungas, R.L. (1968) Fatty Acid Synthesis in Adipose Tissue Incubated in Tritiated Water, Biochemistry 7, 3708–3717.

    Article  PubMed  CAS  Google Scholar 

  36. Gibbons, G.F., Björnsson, O.G., and Pullinger, C.R. (1984) Evidence That Changes in Hepatic 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Activity Are Required Partly to Maintain a Constant Rate of Sterol Synthesis, J. Biol. Chem. 259, 14399–14405.

    PubMed  CAS  Google Scholar 

  37. Patel, D.D., Knight, B.L., Wiggins, D., Humphreys, S.M., and Gibbons, G.F. (2001) Disturbances in the Normal Regulation of SREBP-Sensitive Genes in PPARα-Deficient Mice, J. Lipid Res. 42, 328–333.

    PubMed  CAS  Google Scholar 

  38. Sugden, M.C., Bulmer, K., Gibbons, G.F., Knight, B.L., and Holness, M.J. (2002) Peroxisome-Proliferator-Activated Receptor-α (PPAR-α) Deficiency Leads to Dysregulation of Hepatic Lipid and Carbohydrate Metabolism by Fatty Acids and Insulin, Biochem. J. 364, 361–368.

    Article  PubMed  CAS  Google Scholar 

  39. de Vasconcelos, P.R.L., Kettlewell, M.G.W., Gibbons, G.F., and Williamson, D.H. (1989) Increased Rates of Hepatic Cholesterogenesis and Lipogenesis in Septic Rats in vivo. Evidence for the Possible Involvement of Insulin, Clin. Sci. 76, 205–211.

    PubMed  Google Scholar 

  40. Siperstein, M.D., and Guest, M.J. (1960) Studies on the Site of the Feedback Control of Cholesterol Synthesis, J. Clin. Invest. 39, 642–652.

    Article  PubMed  CAS  Google Scholar 

  41. Shimano, H. (2001) Sterol Regulatory Element-Binding Proteins (SREBPs): Transcriptional Regulators of Lipid Synthetic Genes, Prog. Lipid Res. 40, 439–452.

    Article  PubMed  CAS  Google Scholar 

  42. Shimomura, I., Bashmakov, Y., Shimano, H., Horton, J.D., Goldstein, J.L., and Brown, M.S. (1997) Cholesterol Feeding Reduces Nuclear Forms of Sterol Regulatory Element Binding Proteins in Hamster Liver, Proc. Natl. Acad. Sci. USA 94, 12354–12359.

    Article  PubMed  CAS  Google Scholar 

  43. Wang, X., Sato, R., Brown, M.S., Hua, X., and Goldstein, J.L. (1994) SREBP-1, a Membrane-Bound Transcription Factor Released by Sterol-Regulated Proteolysis, Cell 77, 53–62.

    Article  PubMed  CAS  Google Scholar 

  44. Peet, D.J., Turley, S.D., Ma, W., Janowski, B.A., Lobaccaro, J.M., Hammer, R.E., and Mangelsdorf, D.J. (1998) Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the Nuclear Oxysterol Receptor LXRα, Cell 93, 693–704.

    Article  PubMed  CAS  Google Scholar 

  45. Fungwe, T.V., Cagen, L.M., Wilcox, H.G., and Heimberg, M. (1994) Effects of Dietary Cholesterol on Hepatic Metabolism of Free Fatty Acid and Secretion of VLDL in the Hamster, Biochem. Biophys. Res. Commun. 200, 1505–1511.

    Article  PubMed  CAS  Google Scholar 

  46. Fungwe, T.V., Fox, J.E., Cagen, L.M., Wilcox, H.-G., and Heimberg, M. (1994) Stimulation of Fatty Acid Biosynthesis by Dietary Cholesterol and of Cholesterol Synthesis by Dietary Fatty Acid, J. Lipid Res. 35, 311–318.

    PubMed  CAS  Google Scholar 

  47. Reddy, J.K., and Hashimoto, T. (2001) Peroxosomal β-Oxidation and Peroxisome Proliferator-Activated Receptor α: An Adaptive Metabolic System, Annu. Rev. Nutr. 21, 193–230.

    Article  PubMed  CAS  Google Scholar 

  48. Fruchart, J.C., Duriez, P., and Staels, B. (1999) Peroxisome Proliferator-Activated Receptor-α Activators Regulate Genes Governing Lipoprotein Metabolism, Vascular Inflammation and Atherosclerosis, Curr. Opin. Lipidol. 10, 245–257.

    Article  PubMed  CAS  Google Scholar 

  49. Brown, M.S., Goldstein, J.L., and Dietschy, J.M. (1979) Active and Inactive Forms of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase in the Liver of the Rat. Comparison with the Rate of Cholesterol Synthesis in Different Physiological States, J. Biol. Chem. 254, 5144–5149.

    PubMed  CAS  Google Scholar 

  50. Edwards, P.A., Fogelman, A.M., and Tanaka, R.D. (1983) Physiological Control of HMG-CoA Reductase, in 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase (Sabine, J.R., ed.), pp. 93–105, CRC Press, Boca Raton.

    Google Scholar 

  51. Shulman, R.G., and Rothman, D.L. (2001) 13C NMR of Intermediary Metabolism: Implications for Systemic Physiology, Annu. Rev. Physiol. 63, 15–48.

    Article  PubMed  CAS  Google Scholar 

  52. Wildermuth, M.C. (2000) Metabolic Control Analysis: Biological Applications and Insights, Genome Biol. 1, 1031.

    Article  Google Scholar 

  53. Bowden, A.C. (1999) Metabolic Control Analysis in Biotechnology and Medicine, Nat. Biotechnol. 17, 641–643.

    Article  PubMed  CAS  Google Scholar 

  54. Pullinger, C.R., and Gibbons, G.F. (1983) The Role of Substrate Supply in the Regulation of Cholesterol Biosynthesis in Rat Hepatocytes, Biochem. J. 210, 625–632.

    PubMed  CAS  Google Scholar 

  55. Gibbons, G.F., Pullinger, C.R., Munday, M.R., and Williamson, D.H. (1983) Regulation of Cholesterol Synthesis in the Liver and Mammary Gland of the Lactating Rat, Biochem. J. 212, 843–848.

    PubMed  CAS  Google Scholar 

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  1. Metabolic Research Laboratory, Nuffield Department of Clinical Medicine, University of Oxford, OX2 6HE, Oxford, UK

    Geoffrey F. Gibbons

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  1. Geoffrey F. Gibbons
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Correspondence to Geoffrey F. Gibbons.

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Gibbons, G.F. From gallstones to genes: Two hundred years of sterol research. A tribute to George J. Schroepfer Jr.. Lipids 37, 1153–1162 (2002). https://doi.org/10.1007/s11745-002-1015-y

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  • DOI: https://doi.org/10.1007/s11745-002-1015-y

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