Journal of Nuclear Cardiology

, Volume 9, Issue 6, pp 638–649 | Cite as

The physiology of lipoproteins

Topics in Molecular Biology

Abstract

The seminal studies of Brown and Goldstein (Science 1986;232:34-47) coupled with the findings of the Framingham study revolutionized our understanding of the metabolic basis for vascular disease. These studies led to the widespread use of the coronary risk lipid profile, which uses the total cholesterol/high-density lipoprotein (HDL) ratio (or low-density lipoprotein [LDL]/HDL ratio) in predicting risk for vascular disease and as a tool for therapeutic management of patients at risk for vascular disease. However, although these methods are predictive of coronary artery disease (CAD) in general, it is also well known that the extent of occlusive disease and CAD varies greatly between individuals with similar cholesterol and HDL lipid profiles. For this reason, the National Cholesterol Education Program Expert Panel revised these guidelines and now recommends monitoring LDL and HDL cholesterol in the context of coronary heart disease risk factors and “risk equivalents. ” In addition, more recent findings indicate that specific alterations in individual lipoprotein subclasses may account for the variations in CAD in subjects with similar lipid profiles. For example, a preponderance of small, dense LDL particles correlates with a marked increase in risk for myocardial infarction independent of LDL levels. In particular, the association of small, dense LDL with elevated triglycerides (large, less dense VLDL) and reduced HDL has been defined as the atherogenic lipoprotein profile, and the key metabolic defect driving this profile may be elevated levels of triglycerides, specifically large, less dense VLDL. In an attempt to explain the physiologic basis for lipoprotein variations, this review describes the basic metabolic scheme underlying the traditional view of lipoprotein metabolism and physiology. It then examines the identity and role of the various lipoprotein subfractions in an attempt to distill a working model of how lipoprotein abnormalities might account for vascular disease in general and the metabolic syndrome in particular. (J Nucl Cardiol 2002;9:638-49.)

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986;232:34–47.PubMedCrossRefGoogle Scholar
  2. 2.
    Recommendations on Lipoprotein Measurement, in National Cholesterol Education Program Working Group on Lipoprotein Measurement. NIH publication No. 95-3044. Bethesda (MD): National Heart, Lung, and Blood Institute; 1995.Google Scholar
  3. 3.
    Freedman D, Croft J, Anderson A, Byers T, Jacobsen S, Gruchow H, et al. The association of coronary artery disease with levels of total and high-density lipoprotein cholesterol. Epidemiology 1994;5:80–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Grover S, Coupal L, Hu X. Identifying adults at increased risk of coronary disease: how well do the current cholesterol guidelines work? JAMA 1995;274:801–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Rajman I, Maxwell S, Cramb R, Kendall M. Particle size: the key to the atherogenic lipoprotein?Q J Med 1994;87:709–20.Google Scholar
  6. 6.
    Krauss R, Blanche P. Detection and quantitation of LDL subfractions. Curr Opin Lipidol 1992;3:377–83.CrossRefGoogle Scholar
  7. 7.
    Fievet C, Fruchart JC. HDL heterogeneity and coronary heart disease. Diabetes Metab Rev 1991;7:155–62.PubMedCrossRefGoogle Scholar
  8. 8.
    Freedman D, Otvos J, Jeyarajah E, Barboriak J, Anderson A, Walker J. Relation of lipoprotein subclasses as measured by proton nuclear magnetic resonance spectroscopy to coronary artery disease. Arterioscler Thromb Vasc Biol 1998;18:1046–53.PubMedGoogle Scholar
  9. 9.
    2002 Heart and Stroke Statistical Update. Dallas: American Heart Association; 2002.Google Scholar
  10. 10.
    Kannel WB, Castelli WP, Gordon T. Cholesterol in the prediction atherosclerotic disease. New perspectives based on the Framingham study. Ann Intern Med 1979;90:825–36.Google Scholar
  11. 11.
    Gianturco SH, Ramprasad M, Song R, Li R, Brown M, Bradley W. Apolipoprotein B-48 or its apolipoprotein B-100 equivalent mediates the binding of triglyceride-rich lipoproteins to their unique human monocyte-macrophage receptor. Arterioscler Thromb Vasc Biol 1998;18:968–76.PubMedGoogle Scholar
  12. 12.
    Tanaka A, Ai M, Kobayashi T, Tamura M, Shimokado K, Numano F. Metabolism of triglyceride-rich lipoproteins and their role in atherosclerosis. Ann N Y Acad Sci 2001;947:207–12.PubMedCrossRefGoogle Scholar
  13. 13.
    Tulenko TN, Chen M, Mason PE, Mason RP. Physical Effects of cholesterol on arterial smooth muscle membranes: evidence of immiscible cholesterol domains and alterations in bilayer width during atherogenesis. J Lipid Res 1998;39:947–56.PubMedGoogle Scholar
  14. 14.
    Tulenko TN, Lopatofsky D, Cox RH, Mason RP . Cholesterol in cell plasma membranes. In: Encyclopedia of aging. Academic Press; 1996:p. 279–88.Google Scholar
  15. 15.
    Tasaki H, Nakashima YJ, Segawa R, Kouzuma A, Kuroiwa A, Sparks DL, et al. Promotion of aortic smooth muscle cell proliferation by hypercholesterolemic LDL and its suppression by heparin or sulfated glycosaminoglycans. Cell Physiol Biochem 1994;4:57–71.CrossRefGoogle Scholar
  16. 16.
    Chen M, Mason RP, Tulenko TN. Atherosclerosis alters composition, structure and function of arterial smooth muscle plasma membranes. Biochim Biophys Acta 1995;1272:101–122.PubMedGoogle Scholar
  17. 17.
    Liscum L, Munn N. Intracellular cholesterol transport. Biochim Biophys Acta 1999;1438:19–37.PubMedGoogle Scholar
  18. 18.
    Fielding C, Fielding P. Intracellular cholesterol transport. J Lipid Res 1997;38:1503–21.PubMedGoogle Scholar
  19. 19.
    Trigatti B, Rigotti A, Krieger M. The role of high-density lipoprotein receptor SR-BI in cholesterol metabolism. Curr Opin Lipidol 2000;11:123–32.PubMedCrossRefGoogle Scholar
  20. 20.
    Fidge N. High density lipoprotein receptors, binding proteins, and ligands. J Lipid Res 1999;40:187–201.PubMedGoogle Scholar
  21. 21.
    Tall A, Jiang X, Luo Y, Silver D. 1999 George Lyman Duff Memorial Lecture: lipid transfer proteins, HDL metabolism and atherogenesis. Arterioscler Thromb Vasc Biol 2000;20:1185–8.PubMedGoogle Scholar
  22. 22.
    von EckardsteinA, Nofer J-R, Assmann G. High density lipoproteins and arteriosclerosis: role of cholesterol efflux and reverse cholesterol transport. Arterioscler Thromb Vasc Biol 2001;21:13–27.Google Scholar
  23. 23.
    Williams KJ, Tabas I. The response to retention hypothesis of early atherogenesis. Arterioscler Thromb 1995;15:551–61.Google Scholar
  24. 24.
    Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med 1999;340:115–26.PubMedCrossRefGoogle Scholar
  25. 25.
    Williams K. Atherosclerosis-an inflammatory disease. N Engl J Med 1999;340:1928.PubMedCrossRefGoogle Scholar
  26. 26.
    Williams K. Arterial wall chondroitin sulfate proteoglycans: diverse molecules with distinct roles in lipoprotein retention and atherogenesis. Curr Opin Lipidol 2001;12:477–87.PubMedCrossRefGoogle Scholar
  27. 27.
    Farmer J, Torre-Amione G. Atherosclerosis and inflammation. Curr Atheroscler Rep 2002;4:92–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Libby P, Ridker P, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135–43.PubMedCrossRefGoogle Scholar
  29. 29.
    Crossman D. Opportunities for the treatment of inflammation in cardiovascular disease. Expert Opin Pharmacother 2001;2:1751–633.PubMedCrossRefGoogle Scholar
  30. 30.
    Gorelick P. Stroke prevention therapy beyond antithrombotics: unifying mechanisms in ischemic stroke pathogenesis and implications for therapy: an invited review. Stroke 2002;33:862–755.PubMedCrossRefGoogle Scholar
  31. 31.
    Fredrickson D, Goldstein J, Brown M. The familial hyperlipoproteinemias. In: Stanbury J, Wyngaarden J, Fredrickson D, editors. The metabolic basis of inherited disease. 4th ed. New York: McGraw-Hill; 1978. p. 279–88.Google Scholar
  32. 32.
    Packard C, Shepard J. Lipoprotein heterogeneity and apolipoprotein B metabolism. Arterioscler Thromb Vasc Biol 1997;17:3542–56.PubMedGoogle Scholar
  33. 33.
    Packard C, Shepherd J, Joerns S, Gotto A, Taunton O. Very low density and low density lipoprotein subfractions in type III and type IV hyperlipoproteinemia: chemical and physical properties. Biochim Biophys Acta 1979;572:269–82.PubMedGoogle Scholar
  34. 34.
    Sata T, Havel R, Jones A. Characterization of subfractions of triglyceride-rich lipoproteins separated by gel chromatography from blood plasma of normolipemic and hyperlipemic humans. J Lipid Res 1972;13:757–68.PubMedGoogle Scholar
  35. 35.
    Tan C, Forster L, Caslake M, Bedford D, Watson TD, McConnell M, et al. Relations between plasma lipids and postheparin plasma lipases and VLDL and LDL subfractions in normolipemic men and women. Arterioscler Thromb Vasc Biol 1995;15:1839–48.PubMedGoogle Scholar
  36. 36.
    Dachet C, Cavallero E, Martin C, Girardot G, Jacotot B. Effect of gemfibrozil on the concentration and composition of very low density and low density lipoprotein subfractions in hypertriglyceridemic patients. Atherosclerosis 1995;113:1–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Gaw A, Packard C, Lindsay G, Griffin B, Caslake M, Lorimer A, et al. Overproduction of small very low density lipoproteins (Sf 20-60) in moderate hypercholesterolemia: relationship between apolipoprotein B kinetics and plasma lipoproteins. J Lipid Res 1995;36:158–71.PubMedGoogle Scholar
  38. 38.
    James R, Martin B, Pometta D, Fruchart JC, Duriez P, Puchois P, et al. apolipoprotein B metabolism in homozygous familial hypercholesterolemia. J Lipid Res 1989;30:159–69.PubMedGoogle Scholar
  39. 39.
    Demant T, Carlson L, Holmquist L, Karpe F, Nilsson-Ehle P, Packard C, et al. Lipoprotein metabolism in hepatic lipase deficiency: studies on the turnover of apolipoprotein B and on the effect of hepatic lipase on high density lipoprotein. J Lipid Res 1988;29:1603–11.PubMedGoogle Scholar
  40. 40.
    Musliner T, Giotas C, Krauss R. Presence of multiple subpopulations of lipoproteins of intermediate density in normal subjects. Arteriosclerosis 1986;6:79–87.PubMedGoogle Scholar
  41. 41.
    Superko H. What can we learn about dense low density lipoproteins and lipoprotein particles from clinical trials. Curr Opin Lipidol 1996;7:363–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Krauss RD. Burke Identification of multiple subclasses of plasma lipoproteins in normal humans. J Lipid Res 1981;23:97–1044.Google Scholar
  43. 43.
    Austin M, Breslow J, Hennekens C, Buring J, Willett W, Krauss R. Low-density lipoprotein subclass patterns and risk of myocardial infarction. J Am Med Assoc 1988;260:1917–21.CrossRefGoogle Scholar
  44. 44.
    Austin M, King M, Vranizan K, Krauss R. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation 1990;82:495–506.PubMedGoogle Scholar
  45. 45.
    Gordon D, Rifkind B. Current concepts: high density lipoproteins-the clinical implications of recent studies. N Engl J Med 1989;321:1311–5.PubMedGoogle Scholar
  46. 46.
    Genest J, McNamara J, Salem D, Schaefer E. Prevalence of risk factors in men with premature coronary artery disease. Am J Cardiol 1991;67:1185–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Bolibar I, von Eckardstein A, Assmann G, Thompson S. on behalf of the ECAT Angina Pectoris Study. Short-term prognostic value of lipid measurements for coronary events in patients with angina pectoris. Thromb Hemostas 2000;84:955–611.Google Scholar
  48. 48.
    Genest J, Martin-Munley S, McNamara J, Ordovas JM, Jenner J, Myers RH, et al. Familial lipoprotein disorders in patients with coronary heart disease. Circulation 1992;85:2025–33.PubMedGoogle Scholar
  49. 49.
    Manninen V, Tenkanen L, Koskinen P, Huttunen J, Ma“ntta“ri M, Heinonen O, et al. Joint effects of serum triglycerides and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992;85:37–45.PubMedGoogle Scholar
  50. 50.
    Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999; 341:410–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Fielding C, Fielding P. Molecular physiology of reverse cholesterol transport. J Lipid Res 1995;36:211–28.PubMedGoogle Scholar
  52. 52.
    Chen M, Mason RP, Capuzzi D, Tulenko TN. Reversal of arterial smooth muscle phenotypic alterations by human HDL in dietary atherosclerosis. Abstract in press. FASEB Journal.Google Scholar
  53. 53.
    Miller N. Associations of high density lipoprotein subclasses and apo-lipoproteins with ischemic heart disease and coronary atherosclerosis. Am Heart J 1987;113:589–97.PubMedCrossRefGoogle Scholar
  54. 54.
    Johansson J, Carlson L, Landou C, Hamsten A. High density lipoproteins and coronary atherosclerosis: a strong inverse relation with the largest particles is confined to normotriglyceridemic patients. Arterioscler Thromb 1991;11:174–822.PubMedGoogle Scholar
  55. 55.
    Cheung M, Brown B, Wolf A, Albers J. Altered particle size distribution of apolipoprotein A-I-containing lipoproteins in subjects with coronary artery disease. J Lipid Res 1991;32:383–944.PubMedGoogle Scholar
  56. 56.
    Karlin J, Johnson W, Benedict C, Chacko G, Phillips M, Rothblat G. Cholesterol flux between cells and high density lipoprotein. Lack of relationship to specific binding of the lipoprotein to the cell surface. J Biol Chem 1987;262:12557–64.PubMedGoogle Scholar
  57. 57.
    Rothblat G, de la Llera Moya M, Atger V, Kellner-Weibel G, Williams D, Phillips M. Cell cholesterol efflux: integration of old and new observations provides new insights. J Lipid Res 1999;40:781–96.PubMedGoogle Scholar
  58. 58.
    Nofer J, Kehrel B, Fobker M, Levkau B, Assmann G, Eckardstein A. HDL and arteriosclerosis: beyond reverse cholesterol transport. Atherosclerosis 2002;161:1–16.PubMedCrossRefGoogle Scholar
  59. 59.
    Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285:2486–97.Google Scholar
  60. 60.
    Otvos J, Shalaurova I, Freedman D, Rosenson R. Effects of pravastatin treatment on lipoprotein subclass profiles and particle size in the PLAC-I trial. Atherosclerosis 2001;160:41–8.CrossRefGoogle Scholar
  61. 61.
    Guerin M, Lassel T, Le Goff W, Farnier M, Chapman M. Action of atorvastatin in combined hyperlipidemia. Preferential reduction of cholesteryl ester transfer from HDL to VLDL-1 particles. Arterioscler Thromb Vasc Biol 2000;20:189–97.PubMedGoogle Scholar
  62. 62.
    Guerin M, Egger P, Soudant C, Le Goff W, van Tol A, Dupuis R, et al. Dose-dependent action of atorvastatin in type IIB hyperlipidemia: preferential and progressive reduction of atherogenic apoB-containing lipoprotein subclasses (VLDL-2, IDL, small dense LDL) and stimulation of cellular cholesterol efflux. Atherosclerosis 2002;163:287–96.PubMedCrossRefGoogle Scholar
  63. 63.
    Olson R. Disorders of lipoprotein metabolism. In: Gilbert-Barnes E, Barnes L, editors. Metabolic diseases: foundations of clinical management, genetics and pathology, Volume I. Natick (MA): Eaton Publishing; 2000. p. 283–322.Google Scholar

Copyright information

© American Society of Nuclear Cardiology 2002

Authors and Affiliations

  1. 1.Department of SurgeryThomas Jefferson University College of MedicinePhiladelphia
  2. 2.National Institutes of Health, Diabetes BranchBethesda

Personalised recommendations