American Journal of Cardiology
Volume 101, Issue 8, Supplement , Pages S20-S26 , 17 April 2008

Mechanism of Action of Niacin

  • Vaijinath S. Kamanna, PhD
  • ,
  • Moti L. Kashyap, MD

      Affiliations

    • Corresponding Author InformationAddress for reprints: Moti L. Kashyap, MD, Atherosclerosis Research Center, Department of Veterans Affairs Healthcare System, 5901 East Seventh Street (11/111-I), Long Beach, California 90822.

References 

  1. Altschul R, Hoffer A, Stephen JD. Influence of nicotinic acid on serum cholesterol in man. Arch Biochem Biophys. 1955;54:558–559
  2. Meyers CD, Kamanna VS, Kashyap ML. Niacin therapy in atherosclerosis. Curr Opin Lipidol. 2004;15:659–665
  3. Carlson LA. Nicotinic acid: the broad-spectrum lipid drug (A 50th anniversary review). J Intern Med. 2005;258:94–114
  4. Ganji SH, Zhang L-H, Kamanna VS, Kashyap ML. Effect of niacin on lipoproteins and atherosclerosis. Future Lipidol. 2006;1:549–557
  5. Morgan JM, Capuzzi DM, Baksh RI. Effects of extended-release niacin on lipoprotein subclass distribution. Am J Cardiol. 2003;91:1432–1436
  6. Zambon A, Hokanson JE, Brown BG, Brunzell JD. Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL density. Circulation. 1999;99:1959–1964
  7. Backes JM, Gibson CA. Effect of lipid lowering drug therapy on small-dense low-density lipoprotein. Ann Pharmacother. 2005;39:523–526
  8. McKenney JM, McCormick LS, Schaefer EJ, Black DM, Watkins ML. Effect of niacin and atorvastatin on lipoprotein subclasses in patients with atherogenic dyslipidemia. Am J Cardiol. 2001;88:270–274
  9. Wahlberg G, Walldius G, Olsson AG, Kirstein P. Effect of nicotinic acid on serum cholesterol concentrations of high density lipoprotein subfractions HDL2 and HDL3 in hyperlipoproteinaemia. J Intern Med. 1990;228:151–157
  10. Shepherd J, Betteridge J, Van Gaal L European Consensus Panel. Nicotinic acid in the management of dyslipidemia associated with diabetes and metabolic syndrome: a position paper developed by a European Consensus Panel. Curr Med Res Opin. 2005;21:665–682
  11. Sakai T, Kamanna VS, Kashyap ML. Niacin but not gemfibrozil, selectively increases LP-AI, a cardioprotective subfraction of HDL, in patients with low HDL cholesterol. Arterioscler Thromb Vasc Biol. 2001;21:1783–1789
  12. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, et al Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583–1592
  13. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial biology for the investigation of the treatment effects of reducing cholesterol (ARBITER)2. Circulation. 2004;110:3512–3517
  14. Said HM, Nabokina SM, Balamurgan K, Mohammed ZM, Urbina C, Kashyap ML. Mechanism of nicotinic acid transport in human liver cells: studies with HepG2 cells and primary hepatocytes. Am J Physiol Cell Physiol. 2007;293:C1773–C1778
  15. Nabokina SM, Kashyap ML, Said HM. Mechanism and regulation of human intestinal niacin uptake. Am J Physiol Cell Physiol. 2005;289:C97–C103
  16. Ginsberg HN. Synthesis and secretion of apolipoprotein B from cultured liver cells. Curr Opin Lipidol. 1995;6:275–280
  17. Davis RA. Cell and molecular biology of the assembly and secretion of apolipoprotein B-containing lipoproteins by the liver. Biochim Biophys Acta. 1999;1440:1–31
  18. Grundy SM, Mok HYI, Zech L, Berman M. Influence of nicotinic acid on metabolism of cholesterol and triglycerides in man. J Lipid Res. 1981;22:24–36
  19. Jin FY, Kamanna VS, Kashyap ML. Niacin accelerates intracellular apo B degradation by inhibiting triacylglycerol synthesis in human hepatoblastoma (Hep G2) cells. Arterioscler Thromb Vasc Biol. 1999;19:1051–1059
  20. Ganji SH, Tavintharan S, Zhu D, Xing Y, Kamanna VS, Kashyap ML. Niacin non-competitively inhibits DGAT2 but not DGAT1 activity in HepG2 cells. J Lipid Res. 2004;45:1835–1845
  21. Carlson LA, Oro L. The effect of nicotinic acid on the plasma free fatty acids. Acta Med Scand. 1962;172:641–645
  22. 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
  23. Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, et al. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med. 2003;9:352–355
  24. Wise A, Foord SM, Fraser NJ, Barnes AA, Elshourbagy N, Eiler M, et al Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem. 2003;278:9869–9874
  25. Soga T, Kamohara M, Takasaki J, Matsumoto S-H, Saito T, Ohishi T, et al. Molecular identification of nicotinic acid receptor. Biochem Biophys Res Commun. 2003;303:364–369
  26. Poynten AM, Gan SK, Kriketos AD, O’Sullivan A, Kelly JJ, Ellis BA, et al. Nicotinic acid-induced insulin resistance is related to increased circulating fatty acids and fat oxidation but not muscle lipid content. Metabolism. 2003;52:699–704
  27. Yu XX, Murray SF, Pandey SK, Booten SL, Bao D, Song XZ, et al. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology. 2005;42:362–371
  28. Blum CB, Levy RI, Eisenberg S, Hall M, Goebel RH, Berman M. High density lipoprotein metabolism in man. J Clin Invest. 1977;60:795–807
  29. Shepherd J, Packard CJ, Patsch JR, Gotto M, Taunton OD. Effect 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
  30. 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
  31. Acton S, Riggoti A, Landschutz KT, Xu S, Hobbs HH, Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science. 1996;271:518–520
  32. Martinez LO, Jacquet S, Esteve JP, Rolland C, Cabezon E, Champagne E, et al Ectopic β-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis. Nature. 2003;421:75–79
  33. Zhang LH, Meyers CD, Kamanna VS, Kashyap ML. Niacin inhibits β chain ATP synthase cell surface expression in HepG2 cells (Mechanistic implications for raising HDL). [abstract] Artrioscler Thromb Vasc Biol. 2006;26:E-53
  34. Rubic T, Trottmann M, Lorenz RL. Stimulation of CD36 and the key effector of reverse cholesterol transport ATP-binding cassette A1 in monocytoid cells by niacin. Biochem Pharmacol. 2004;67:411–419
  35. Jacobson EL, Jacobson MK. A biomarker for the assessment of niacin nutriture as a potential preventive factor in carcinogenesis. J Intern Med. 1993;233:59–62
  36. Yan Q, Briehl M, Crowley CL, Payne CM, Bernstein H, Bernstein C. The NAD+ precursors, nicotinic acid and nicotinamide upregulate glyceraldehydes-3-phosphate dehydrogenase and glucose-6-phosphate dehydrogenase mRNA in Jurkat cells. Biochem Biophys Res Commun. 1999;255:133–136
  37. Ganji SH, Qin S, Liu Y, Kamanna VS, Kashyap ML. Niacin inhibits LDL oxidation and redox-sensitive VCAM-1 and MCP-1 expression in human aortic endothelial cells. [abstract] Artrioscler Thromb Vasc Biol. 2004;24:E-125
  38. Morrow JD, Parsons WG, Roberts LJ. Release of markedly increased quantities of prostaglandin D2 in vivo in humans following the administration of nicotinic acid. Prostaglandins. 1989;38:263–274
  39. Benyo Z, Gille A, Bennett CL, Clausen BE, Offermanns S. Nicotinic acid-induced flushing is mediated by activation of epidermal Langerhans cells. Mol Pharmacol. 2006;70:1844–1849
  40. Maciejewski-Lenoir D, Richman JG, Hakak Y, Gaidarov I, Behan DP, Connolly DT. Langerhans cells release prostaglandin D2 in response to nicotinic acid. J Invest Dermatol. 2006;126:2637–2646
  41. Meyers CD, Liu P, Kamanna VS, Kashyap ML. Nicotinic acid induces secretion of prostaglandin D2 in human macrophages: an in vitro model of the niacin flush. Atherosclerosis. 2007;192:253–258
  42. Benyo Z, Gille A, Kero J, Csiky M, Suchankova MC, Nusing RM, et al. GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. J Clin Invest. 2005;115:3634–3640
  43. Cheng K, Wu TJ, Sturino C, Metters K, Gottesdiener K, Wright SD, et al. Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans. Proc Natl Acad Sci U S A. 2006;103:6682–6687

 This work was supported in part by the Merit Review Award Program of the US Department of Veterans Affairs, Washington, DC, and the Southern California Institute for Education and Research, Long Beach, CA.Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

PII: S0002-9149(08)00253-1

doi: 10.1016/j.amjcard.2008.02.029

American Journal of Cardiology
Volume 101, Issue 8, Supplement , Pages S20-S26 , 17 April 2008