Current Atherosclerosis Reports

, Volume 2, Issue 1, pp 36–46 | Cite as

Mechanism of action of niacin on lipoprotein metabolism

  • Vaijinath S. Kamanna
  • Moti L. Kashyap


It is generally accepted that the increased concentrations of apolipoprotein (apo) B containing very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL), and decreased levels of apo AI containing high-density lipoproteins (HDL) are correlated to atherosclerotic cardiovascular disease. Current evidence indicates that the post-translational apo-B degradative processes regulate the hepatic assembly and secretion of VLDL and the subsequent generation of LDL particles. The availability of triglycerides (TG) for the addition to apo B during intracellular processing appears to play a central role in targeting apo B for either intracellular degradation or assembly and secretion as VLDL particles. Based on the availability of TG, the liver secretes either dense TG-poor VLDL2 or large TG-rich VLDL1 particles, and these particles serve as precursors for the formation of more buoyant or small, dense LDL particles by lipid transfer protein- and hepatic lipase-mediated processes. HDLs are a heterogenous class of lipoproteins, and apo AI (the major protein of HDL) participates in reverse cholesterol transport, a process by which excess cholesterol is eliminated. Recent studies indicate that HDL particles containing only apo A-I (LPA-I) are more effective in reverse cholesterol transport and more anti-atherogenic than HDL particles containing both apo A-I and apo A-II (LPA-I+A-II).


Niacin Reverse Cholesterol Transport ALLN Nonstatin Drug VLDL Assembly 
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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  1. 1.
    Kwiterovich PO Jr: State-of-the-art update and review. Clinical trials of lipid-lowering agents. Am J Cardiol 1998, 82(12A):3U-17U.PubMedCrossRefGoogle Scholar
  2. 2.
    Stamler M, Wentworth D, Neeaton JD, for the MRFIT: Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intevention Trial (MRFIT). JAMA 1986, 256:2823–2828.PubMedCrossRefGoogle Scholar
  3. 3.
    Ballantyne CM, Herd JA, Dunn JK, et al.: Effects of lipid lowering therapy on progression of coronary and carotid artery disease. Curr Opin Lipidol 1997, 8:354–361.PubMedCrossRefGoogle Scholar
  4. 4.
    Zambon A, Hokanson JE: Lipoprotein classes and coronary disease regression. Curr Opin Lipidol 1998, 9:329–336.PubMedCrossRefGoogle Scholar
  5. 5.
    Kashyap ML: Mechanistic studies of high density lipoproteins. Am J Cardiol 1998, 82:42U-48U.PubMedCrossRefGoogle Scholar
  6. 6.
    Kane JP, Hardman DA, Paulus HE: Heterogeneity of apolipoprotin B. Isolation of a new species from chylomicrons. Proc Natl Acad Sci U S A 1980, 77:2465–2469.PubMedCrossRefGoogle Scholar
  7. 7.
    Le NA, Melish JS, Roach BC, et al.: Direct measurement of apoprotein B specific activity in 125I-labeled lipoproteins. J Lipid Res 1978, 19:578–584.PubMedGoogle Scholar
  8. 8.
    Dixon JL, Ginsberg HN: Regulation of hepatic secretion of apolipoprotein B-containing lipoproteins. Information obtained from cultured liver cells. J Lipid Res 1993, 34:167–179.PubMedGoogle Scholar
  9. 9.
    Kendrick JS, Wilkinson J, Cartwright IJ, et al.: Regulation of assembly and secretion of very low density lipoproteins by the liver. Biol Chem 1998, 379:1033–1040.PubMedGoogle Scholar
  10. 10.
    Ginsberg HN: Synthesis and secretion of apolipoprotein B from cultured liver cells. Curr Opin Lipidol 1995, 6:275–280.PubMedCrossRefGoogle Scholar
  11. 11.
    Bostrom K, Wettesten M, Boren J, et al.: Pulse-chase studies of the synthesis and intracellular transport of apolipoprotein B-100 in Hep G2 cells. J Biol Chem 1986, 261:13800–13806.PubMedGoogle Scholar
  12. 12.
    Borchardt RA, Davis RA: Intrahepatic assembly of very low density lipoproteins. Rate of transport out of the endoplasmic reticulum determines rate of secretion. J Biol Chem 1987, 262:16394–16402.PubMedGoogle Scholar
  13. 13.
    Furukawa S, Sakata N, Ginsberg HN, et al.: Studies on the sites of intracellular degradation of apolipoprotein B in Hep G2 cells. J Biol Chem 1992, 267:22630–22638.PubMedGoogle Scholar
  14. 14.
    Bonnardel JA, Davis RA: In Hep G2 cells, translocation, not degradation, determines the fate of the de novo synthesized apolipoprotein B. J Biol Chem 1995, 270:28892–28896.PubMedCrossRefGoogle Scholar
  15. 15.
    Dixon JL, Furukawa S, Ginsberg HN: Oleate stimulates secretion of apolipoprotein B-containing lipoproteins from Hep G2 cells by inhibiting early intracellular degradation of apolipoprotein B. J Biol Chem 1991, 266:5080–5086.PubMedGoogle Scholar
  16. 16.
    Sakata N, Wu X, Dixon JL, et al.: Proteolysis and lipid facilitated translocation are distinct but competitive processes which regulate secretion of apolipoprotein B in Hep G2 cells. J Biol Chem 1993, 268:22967–22970.PubMedGoogle Scholar
  17. 17.
    Wu X, Sakata N, Lui E, et al.: Evidence for a lack of regulation of the assembly and secretion of apolipoprotein B-containing lipoprotein from Hep G2 cells by cholesteryl ester. J Biol Chem 1994, 269: 12375–12382.PubMedGoogle Scholar
  18. 18.
    Cianflone KM, Yasruel Z, Rodriguez MA, et al.: Regulation of apo B secretion from Hep G2 cells. Evidence for a critical role for cholesteryl ester synthesis in the response to a fatty acid challenge. J Lipid Res 1990, 31:2045–2055.PubMedGoogle Scholar
  19. 19.
    Zhang Z, Cianflone K, Sniderman AD: Role of cholesterol ester mass in regulation of secretion of apo B100 lipoprotein particles by hamster hepatocytes and effects of statins on that relationship. Arterioscl Thromb Vasc Biol 1999, 19:743–752.PubMedGoogle Scholar
  20. 20.
    Jamil H, Gordon DA, Eustice DC, et al.: An inhibition of the microsomal triglyceride transfer protein inhibits apo B secretion from Hep G2 cells. Proc Natl Acad Sci U S A 1996, 93:11991–11995.PubMedCrossRefGoogle Scholar
  21. 21.
    Krauss RM: Heterogeneity of plasma low density lipoproteins and atherosclerosis risk. Curr Opin Lipidol 1994, 5:339–349.PubMedCrossRefGoogle Scholar
  22. 22.
    Millar JS, Packard CJ: Heterogeneity of apolipoprotein B-100-containing lipoproteins. What we have learnt from kinetic studies. Curr Opin Lipidol 1998, 9:197–202.PubMedCrossRefGoogle Scholar
  23. 23.
    Goldstein JL, Ho YK, Basu SK, et al.: Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoproteins, producing massive cholesterol deposition. Proc Natl Acad Sci U S A 1979, 76:333–337.PubMedCrossRefGoogle Scholar
  24. 24.
    Steinberg D, Parthasarathy S, Carew TE, et al.: Beyond cholesterol. Modifications of low density lipoprotein that increase its atherogenicity. N Eng J Med 1989, 320:915–924.CrossRefGoogle Scholar
  25. 25.
    Ross R: The pathogenesis of atherosclerosis-an update. N Eng J Med 1986, 314:488–500.CrossRefGoogle Scholar
  26. 26.
    Kume N, Cybulsky MI, Gimbrone MA Jr: Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells. J Clin Invest 1992, 90:1138–1144.PubMedGoogle Scholar
  27. 27.
    Lehr HA, Krober M, Hubner C, et al.: Stimulation of leukocyte/endothelium interaction by oxidized low density lipoprotein in hairless mice, involvement of CD 11b/CD 18 adhesion receptor complex. Lab Invest 1993, 68:388–395.PubMedGoogle Scholar
  28. 28.
    Cushing SD, Berliner JA, Valente AJ, et al.: Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci U S A 1990, 87:5134–5138.PubMedCrossRefGoogle Scholar
  29. 29.
    Kume N, Gimbrone MA Jr: Lysophosphatidylcholine transcriptionally induces growth factor gene expression in cultured human vascular endothelial cells. J Clin Invest 1994, 93:907–911.PubMedGoogle Scholar
  30. 30.
    Kamanna VS, Bassa BV, Kirschenbaum MA: Atherogenic lipoproteins and human disease. Extending concepts beyond the heart to the kidney. Curr Opin Nephrol Hyperten 1997, 6:205–211.CrossRefGoogle Scholar
  31. 31.
    Liao JK: Endothelium and acute coronary syndromes. Clin Chem 1998, 44:1799–1808.PubMedGoogle Scholar
  32. 32.
    Zambon A, Hokanson JE, Brown BG, et al.: Evidence for a new pathophysiological mechanism for coronary artery disease regression. Circulation 1999, 99:1959–1964.PubMedGoogle Scholar
  33. 33.
    Grundy SM, Mor AYI, Zech L, et al.: Influence of nicotinic acid on metabolism of cholesterol and triglyceride in man. J Lipid Res 1981, 22:24–36.PubMedGoogle Scholar
  34. 34.
    Carlson LA: Studies on the effect of nicotinic acid on catecholamine stimulated lipolysis in adipose tissue in vitro. Acta Med Scand 1963, 173:719–722.PubMedCrossRefGoogle Scholar
  35. 35.
    Lee HM, Ellis RM, Signal MV Jr: Insulin-like effects of nicotinic acid observed with isolated rat epididymal adipose tissue. Biochim Biophys Acta 1961, 49:408–410.PubMedCrossRefGoogle Scholar
  36. 36.
    Jin FY, Kamanna VS, Kashyap ML: Niacin accelerates intracellular apo B degradation by inhibiting triacylglycerol synthesis in human hepatoblastoma (Hep G2) cells. Arterioscl Thromb Vasc Biol 1999, 19:1051–1059.PubMedGoogle Scholar
  37. 37.
    Fielding CJ, Fielding PE: Molecular physiology of reverse cholesterol transport. J Lipid Res 1995, 36:211–228.PubMedGoogle Scholar
  38. 38.
    Kashyap ML: Basic considerations in the reversal of atherosclerosis: significance of high density lipoproteins in stimulating reverse cholesterol transport. Am J Cardiol 1989, 63:56H-59H.PubMedCrossRefGoogle Scholar
  39. 39.
    Barbaras R, Puchois P, Fruchart J-C, et al.: Cholesterol efflux from cultured adipose cells is mediated by LP A-I particles but not by LP A-I:A-II particles. Biochem Biophys Res Commun 1987, 142:63–69.PubMedCrossRefGoogle Scholar
  40. 40.
    Rinninger F, Kaiser T, Windler E, et al.: Selective uptake of cholesteryl esters from high-density lipoprotein-derived LPA-I and LPA-I:A-II particles by hepatic cells in culture. Biochim Biophys Acta 1998, 1393:277–291.PubMedGoogle Scholar
  41. 41.
    Cheung MC, Lum KD, Brouillette CG, et al.: Characterization of apoA-I-containing lipoprotein subpopulations secreted by Hep G2 cells. J Lipid Res 1989, 30:1429–1436.PubMedGoogle Scholar
  42. 42.
    Johnson WJ, Kilsdonk EPS, Tol AV, et al.: Cholesterol efflux from cells to immunopurified subfractions of human high de nsity lipoproteins: LP-A-I and LP-A-I/AII. J Lipid Res 1991, 32:1993–2000.PubMedGoogle Scholar
  43. 43.
    Banka CL: High density lipoprotein and lipoprotein oxidation. Current Opin Lipidol 1996, 7:139–142.Google Scholar
  44. 44.
    Navab M, Imes SS, Hama SY, et al.: Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. J Clin Invest 1991, 88:2039–2046.PubMedGoogle Scholar
  45. 45.
    Navab M, Hama SY, Hough GP, et al.: High density associated enzymes. Their role in vascular biology. Current Opin Lipidol 1998, 9:449–456.CrossRefGoogle Scholar
  46. 46.
    Cockerill GW, Rye KA, Gamble JR, et al.: HDL inhibits cytokine-induced expression of endothelial cell adhesiom molecules. Arterioscler Thromb Vasc Biol 1995, 15:1987–1994.PubMedGoogle Scholar
  47. 47.
    Rader DJ, Ikewaki K: Unravelling high density lipoprotein-apolipoprotein metabolism in human mutants and animal models. Current Opin Lipidol 1996, 7:117–123.CrossRefGoogle Scholar
  48. 48.
    Rubin EM, Krauss RM, Spangler EA, et al.: Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature 1991, 353:265–267.PubMedCrossRefGoogle Scholar
  49. 49.
    Schultz JR, Verstuyft JG, Gong EL, et al.: Protein composition determines the anti-atherogenic properties of HDL in transgenic mice. Nature 1993, 365:762–764.PubMedCrossRefGoogle Scholar
  50. 50.
    Warden CH, Hedrick CC, Qiao JH, et al.: Atherosclerosis in transgenic mice overexpressing apolipoprotein A-II. Science 1993, 261:469–472.PubMedCrossRefGoogle Scholar
  51. 51.
    Karathanasis SK: Apolipoprotein AI gene regulation by members of the steroid/thyroid hormone receptor superfamily of ligand dependent transcription factors. In High density Lipoprotein and Atherosclerosis III. Edited by Miller NE and Tall AR. Elsevier; 1992:21–31.Google Scholar
  52. 52.
    Higuchi K, Law SW, Hoeg JM, et al.: Tissue-specific expression of apolipoprotein A-I is regulated by the 5′-flanking region of the human apo A-I gene. J Biol Chem 1988, 263:18530–18536.PubMedGoogle Scholar
  53. 53.
    Widom RL, Ladias JAA, Kouidou, et al.: Synergistic interactions between transcription factors control expression of the apolipoprotein AI gene in liver cell. Mol Cell Biol 1991, 11:677–687.PubMedGoogle Scholar
  54. 54.
    Acton S, Riggoti A, Landschutz KT, et al.: Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 1996, 271:518–520.PubMedCrossRefGoogle Scholar
  55. 55.
    Rigotti A, Trigatti BL, Penman M, et al.: A targeted mutation in the murine gene encoding the high density lipoprotein receptor scavenger receptor class B type I reveals its key role in HDL metabolism. Proc Natl Acad Sci U S A 1997, 94:12610–12615.PubMedCrossRefGoogle Scholar
  56. 56.
    Verban ML, Rinninger F, Wang N, et al.: Targeted mutation reveals a central role for SR-BI in hepatic selective uptake of high density lipoprotein cholesterol. Proc Natl Acad Sci U S A 1998, 95:4619–4624.CrossRefGoogle Scholar
  57. 57.
    Kozarsky KF, Donahee MH, Rigotti A, et al.: Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels. Nature 1997, 387:414–417.PubMedCrossRefGoogle Scholar
  58. 58.
    Wang N, Arai T, Ji Y, et al.: Liver-specific overexpression of scavenger receptor BI decreases levels of very low density lipoprotein apoB, low density lipoprotein apoB, and high density lipoprotein in transgenic mice. J Biol Chem 1998, 273:32920–32926.PubMedCrossRefGoogle Scholar
  59. 59.
    Arai T, Wang N, Bezouevski M, et al.: Decreased atherosclerosis in heterozygous low density lipoprotein receptor-deficient mice expressing the scavenger receptor BI transgene. J Biol Chem 1999, 274:2366–2371.PubMedCrossRefGoogle Scholar
  60. 60.
    Steinberg D: A docking receptor for HDL cholesterol esters. Science 1996;271:460–461.PubMedCrossRefGoogle Scholar
  61. 61.
    Blum CB, Levy RI, Eisenberg S, Hall M III, Goebel RH, Berman M. High density lipoprotein metabolism in man. J Clin Invest 1977, 60:795–807.PubMedGoogle Scholar
  62. 62.
    Shepherd J, Packard CJ, Patsch JR, et al.: Effects of nicotinic acid therapy on plasma high density lipoprotein subfraction distribution and composition and on apolipoprotein A metabolism. J Clin Invest 1979, 63:858–867.PubMedCrossRefGoogle Scholar
  63. 63.
    Jin FY, Kamanna VS, Kashyap ML: Niacin decreases removal of high density lipoprotein apolipoprotein A-I but not cholesterol ester by Hep G2 cells. Implications for reverse cholesterol transport. Arterioscler Thromb Vasc Biol 1997, 17:2020–2028.PubMedGoogle Scholar

Copyright information

© Current Science Inc 2000

Authors and Affiliations

  • Vaijinath S. Kamanna
    • 1
  • Moti L. Kashyap
    • 2
  1. 1.Department of Medicine (Gerontology)University of CaliforniaIrvineUSA
  2. 2.Department of Veterans Affairs Healthcare SystemCholesterol Research CenterLong BeachUSA

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