Niacin: an old lipid drug in a new NAD+ dress

Nicotinic acid was identified in the beginning of the 20th century by Conrad Elvehjem (1Elvehjem C.A. Madden R.J. Strong F.M. Woolley D.W. The isolation and identification of the anti-black tongue factor.Nutr. Rev. 1974; 32: 48-50Crossref PubMed Scopus (7) Google Scholar) as an effective treatment for pellagra, which at that time was endemic in the United States. The name of nicotinic acid was replaced by niacin in the 1940s to avoid any association with nicotine (2Council on Foods and Nutrition Niacin and niacin amide.J. Am. Med. Assoc. 1942; 118: 819Google Scholar), and a decade later, the lipid-modulating effects of this molecule were described in patients by Rudolf Altschul (3Altschul R. Hoffer A. Effects of salts of nicotinic acid on serum cholesterol.BMJ. 1958; 2: 713-714Crossref PubMed Scopus (10) Google Scholar), making niacin the oldest lipid-lowering drug. Despite the fact that several of the molecular mechanisms underlying its remarkable effects on lipid metabolism have been elucidated since then, the molecular mechanism of how niacin works remains elusive. In pharmacological doses, niacin acts as a broad-spectrum lipid-modulating drug and increases the circulating levels of HDL (4Shepherd J. Packard C.J. Patsch J.R. Gotto A.M. Taunton O.D. Effects of nicotinic acid therapy on plasma high density lipoprotein subfraction distribution and composition and on apolipoprotein A metabolism.J. Clin. Invest. 1979; 63: 858-867Crossref PubMed Scopus (211) Google Scholar) (Fig. 1). This class of lipoproteins, which is particularly enriched with ApoA-I and ApoA-II, are major players in reverse cholesterol transport. Most peripheral tissues indeed rely on HDL for cholesterol clearance and transport to the liver, where cholesterol is either processed or degraded (5Rader D.J. Alexander E.T. Weibel G.L. Billheimer J. Rothblat G.H. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis.J. Lipid Res. 2009; 50: S189-S194Abstract Full Text Full Text PDF PubMed Scopus (454) Google Scholar). Thanks to this scavenging function, low HDL is considered, with few exceptions, an independent risk factor for coronary artery disease (6Boden W.E. High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from Framingham to the Veterans Affairs High–Density Lipoprotein Intervention Trial.Am. J. Cardiol. 2000; 86: 19L-22LAbstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar). Niacin increases HDL availability through different mechanisms (Fig. 1). First, it has a direct effect on ApoA-I stability and function. In fact, niacin boosts the expression of the membrane protein ABCA1, the main regulator of ApoA-I lipidation and consequent stabilization, through the LXR (7Zhang L-H. Kamanna V.S. Ganji S.H. Xiong X-M. Kashyap M.L. Niacin increases HDL biogenesis by enhancing DR4-dependent transcription of ABCA1 and lipidation of apolipoprotein A-I in HepG2 cells.J. Lipid Res. 2012; 53: 941-950Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Moreover, niacin prevents the surface expression of the hepatic HDL receptor β-chain ATP synthase (8Zhang L-H. Kamanna V.S. Zhang M.C. Kashyap M.L. Niacin inhibits surface expression of ATP synthase beta chain in HepG2 cells: implications for raising HDL.J. Lipid Res. 2008; 49: 1195-1201Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). This inhibition decreases HDL uptake in the liver and consequently increases HDL availability for cholesterol scavenging in the blood (9Martinez L.O. Jacquet S. Esteve J-P. Rolland C. Cabezón E. Champagne E. Pineau T. Georgeaud V. Walker J.E. Tercé F. et al.Ectopic beta-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis.Nature. 2003; 421: 75-79Crossref PubMed Scopus (390) Google Scholar). The best-characterized effect of niacin on lipid metabolism is, however, the reduction of triglyceride (TG) and circulating FFA levels (Fig. 1). The first proposed mechanism explaining this outcome involves its inhibitory actions on adipocyte TG lipolysis, which would decrease FFA release and the availability of FFAs to stimulate liver TG synthesis (10Carlson L.A. Studies on the effect of nicotinic acid on catecholamine stimulated lipolysis in adipose tissue in vitro.Acta Med. Scand. 1963; 173: 719-722Crossref PubMed Scopus (134) Google Scholar). However, this hypothesis has been challenged when the niacin receptor, a G-protein-coupled receptor, termed GPR109A, was identified as the mediator of its antilipolytic effect. After niacin administration, Gpr109a-KO mice show the typical serum TG-lowering effect, despite the absence of adipocyte lipolysis. Moreover, GPR109A agonists were shown to inhibit lipolysis in patients with dyslipidemia in the absence of effects on circulating lipids (11Lauring B. Taggart A.K.P. Tata J.R. Dunbar R. Caro L. Cheng K. Chin J. Colletti S.L. Cote J. Khalilieh S. et al.Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression.Sci. Transl. Med. 2012; 4: 148ra115Crossref PubMed Scopus (103) Google Scholar), arguing that mechanisms independent from niacin's antilipolytic function via activation of GPR109A are responsible for its beneficial effects on lipid homeostasis. The most recent hypothesis identifies the liver as the main contributor in the niacin-mediated modulation of serum lipids. More specifically, in vitro evidence suggests that the hepatic lipid-lowering effects of niacin are mediated by a noncompetitive direct interaction of niacin with the final enzyme of TG synthesis, diglyceride acyltransferase 2 (DGAT2) (Fig. 1) (12Ganji S.H. Tavintharan S. Zhu D. Xing Y. Kamanna V.S. Kashyap M.L. Niacin noncompetitively inhibits DGAT2 but not DGAT1 activity in HepG2 cells.J. Lipid Res. 2004; 45: 1835-1845Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar). In support of this, patients on niacin disp