Mechanism of Action of Niacin

  • Vaijinath S. Kamanna
    Atherosclerosis Research Center, Department of Veterans Affairs Healthcare System, Long Beach, California, USA; and Department of Medicine, University of California, Irvine, Irvine, California, USA.
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  • Moti L. Kashyap
    Address 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.
    Atherosclerosis Research Center, Department of Veterans Affairs Healthcare System, Long Beach, California, USA; and Department of Medicine, University of California, Irvine, Irvine, California, USA.
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      Nicotinic acid (niacin) has long been used for the treatment of lipid disorders and cardiovascular disease. Niacin favorably affects apolipoprotein (apo) B–containing lipoproteins (eg, very-low-density lipoprotein [VLDL], low-density lipoprotein [LDL], lipoprotein[a]) and increases apo A-I–containing lipoproteins (high-density lipoprotein [HDL]). Recently, new discoveries have enlarged our understanding of the mechanism of action of niacin and challenged older concepts. There are new data on (1) how niacin affects triglycerides (TGs) and apo B–containing lipoprotein metabolism in the liver, (2) how it affects apo A-I and HDL metabolism, (3) how it affects vascular anti-inflammatory events, (4) a specific niacin receptor in adipocytes and immune cells, (5) how niacin causes flushing, and (6) the characterization of a niacin transport system in liver and intestinal cells. New findings indicate that niacin directly and noncompetitively inhibits hepatocyte diacylglycerol acyltransferase–2, a key enzyme for TG synthesis. The inhibition of TG synthesis by niacin results in accelerated intracellular hepatic apo B degradation and the decreased secretion of VLDL and LDL particles. Previous kinetic studies in humans and recent in vitro cell culture findings indicate that niacin retards mainly the hepatic catabolism of apo A-I (vs apo A-II) but not scavenger receptor BI–mediated cholesterol esters. Decreased HDL–apo A-I catabolism by niacin explains the increases in HDL half-life and concentrations of lipoprotein A-I HDL subfractions, which augment reverse cholesterol transport. Initial data suggest that niacin, by inhibiting the hepatocyte surface expression of β-chain adenosine triphosphate synthase (a recently reported HDL–apo A-I holoparticle receptor), inhibits the removal of HDL–apo A-I. Recent studies indicate that niacin increases vascular endothelial cell redox state, resulting in the inhibition of oxidative stress and vascular inflammatory genes, key cytokines involved in atherosclerosis. The niacin flush results from the stimulation of prostaglandins D2 and E2 by subcutaneous Langerhans cells via the G protein–coupled receptor 109A niacin receptor. Although decreased free fatty acid mobilization from adipose tissue via the G protein–coupled receptor 109A niacin receptor has been a widely suggested mechanism of niacin to decrease TGs, physiologically and clinically, this pathway may be only a minor factor in explaining the lipid effects of niacin.
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