Skip to main content
SpringerLink
Log in

Mechanism of action of niacin on lipoprotein metabolism

  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

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).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  4. Zambon A, Hokanson JE: Lipoprotein classes and coronary disease regression. Curr Opin Lipidol 1998, 9:329–336.

    Article  PubMed  CAS  Google Scholar 

  5. Kashyap ML: Mechanistic studies of high density lipoproteins. Am J Cardiol 1998, 82:42U-48U.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  10. Ginsberg HN: Synthesis and secretion of apolipoprotein B from cultured liver cells. Curr Opin Lipidol 1995, 6:275–280.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  21. Krauss RM: Heterogeneity of plasma low density lipoproteins and atherosclerosis risk. Curr Opin Lipidol 1994, 5:339–349.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  25. Ross R: The pathogenesis of atherosclerosis-an update. N Eng J Med 1986, 314:488–500.

    Article  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  31. Liao JK: Endothelium and acute coronary syndromes. Clin Chem 1998, 44:1799–1808.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  37. Fielding CJ, Fielding PE: Molecular physiology of reverse cholesterol transport. J Lipid Res 1995, 36:211–228.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  43. Banka CL: High density lipoprotein and lipoprotein oxidation. Current Opin Lipidol 1996, 7:139–142.

    CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  47. Rader DJ, Ikewaki K: Unravelling high density lipoprotein-apolipoprotein metabolism in human mutants and animal models. Current Opin Lipidol 1996, 7:117–123.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  50. Warden CH, Hedrick CC, Qiao JH, et al.: Atherosclerosis in transgenic mice overexpressing apolipoprotein A-II. Science 1993, 261:469–472.

    Article  PubMed  CAS  Google Scholar 

  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.

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  60. Steinberg D: A docking receptor for HDL cholesterol esters. Science 1996;271:460–461.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine (Gerontology), University of California, Irvine, California, USA

    Vaijinath S. Kamanna PhD

  2. Department of Veterans Affairs Healthcare System, Cholesterol Research Center, 5901 East Seventh Street (11/111-I), 90822, Long Beach, California, USA

    Moti L. Kashyap MD

Authors
  1. Vaijinath S. Kamanna PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Moti L. Kashyap MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kamanna, V.S., Kashyap, M.L. Mechanism of action of niacin on lipoprotein metabolism. Curr Atheroscler Rep 2, 36–46 (2000). https://doi.org/10.1007/s11883-000-0093-1

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11883-000-0093-1

Keywords

Search

Navigation