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 display a lipid-lowering response influenced by genetic DGAT2 polymorphisms (13Hu M. Chu W.C.W. Yamashita S. Yeung D.K. Shi L. Wang D. Masuda D. Yang Y. Tomlinson B. Liver fat reduction with niacin is influenced by DGAT-2 polymorphisms in hypertriglyceridemic patients.J. Lipid Res. 2012; 53: 802-809Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). Moreover, the hepatic modulation of TG biosynthesis impacts on apo-B-containing VLDLs, and LDLs, the principal transporters of TG and cholesterol, respectively. These lipoproteins require TGs for their formation; therefore, reducing TG synthesis leads to destabilization of VLDL and LDL particles, decreasing circulating lipids. However, recent publications seem to quench the translation of these findings in humans, proving that the in vivo TG-lowering effects of DGAT2 inhibitors observed in murine models are not present in a primate model (14McLaren D.G. Han S. Murphy B.A. Wilsie L. Stout S.J. Zhou H. Roddy T.P. Gorski J.N. Metzger D.E. Shin M.K. et al.DGAT2 inhibition alters aspects of triglyceride metabolism in rodents but not in non-human primates.Cell Metab. 2018; 27: 1236-1248.e6Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). The beneficial effects of niacin on lipid metabolism promoted several clinical trials in patients suffering from different cardiovascular conditions. However, the outcomes of these studies were controversial. The first large clinical study, the Coronary Drug Project, showed a reduced incidence of nonfatal reinfarction and all-cause mortality after 5 years in patients with documented myocardial infarction when compared with placebo (15Berge K.G. Canner P.L. Coronary drug project: experience with niacin. Coronary Drug Project Research Group.Eur. J. Clin. Pharmacol. 1991; 40: S49-S51Crossref PubMed Google Scholar). Following these initial positive results, niacin was tested in combination with other drugs to treat dyslipidemias. First, when it was coadministered with the bile acids sequestrant colestipol, niacin markedly increased HDL and atherosclerotic regression in two trials (16Blankenhorn D.H. Johnson R.L. Nessim S.A. Azen S.P. Sanmarco M.E. Selzer R.H. The Cholesterol Lowering Atherosclerosis Study (CLAS): design, methods, and baseline results.Control. Clin. Trials. 1987; 8: 356-387Abstract Full Text PDF PubMed Scopus (99) Google Scholar, 17Brown G. Albers J.J. Fisher L.D. Schaefer S.M. Lin J.T. Kaplan C. Zhao X.Q. Bisson B.D. Fitzpatrick V.F. Dodge H.T. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B.N. Engl. J. Med. 1990; 323: 1289-1298Crossref PubMed Scopus (1864) Google Scholar). With the discovery of statins and their prominent beneficial effects on cholesterol metabolism, niacin has been investigated as a possible add-on to improve the therapeutic outcome of statins. In five different clinical trials, add-on of niacin to the statin treatment reduced the onset of cardiovascular events with a concomitant increase in HDL (18Brown B.G. Zhao X.Q. Chait A. Fisher L.D. Cheung M.C. Morse J.S. Dowdy A.A. Marino E.K. Bolson E.L. Alaupovic P.A. et al.Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.N. Engl. J. Med. 2001; 345: 1583-1592Crossref PubMed Scopus (1794) Google Scholar, 19Taylor A.J. Sullenberger L.E. Lee H.J. Lee J.K. Grace K.A. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins.Circulation. 2004; 110: 3512-3517Crossref PubMed Scopus (869) Google Scholar, 20Guyton J.R. Brown B.G. Fazio S. Polis A. Tomassini J.E. Tershakovec A.M. Lipid-altering efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in patients with type IIa or type IIb hyperlipidemia.J. Am. Coll. Cardiol. 2008; 51: 1564-1572Crossref PubMed Scopus (84) Google Scholar, 21Sang Z.C. Wang F. Zhou Q. Li Y.H. Li Y.G. Wang H.P. Chen S.Y. Combined use of extended-release niacin and atorvastatin: safety and effects on lipid modification.Chin. Med. J. (Engl.). 2009; 122: 1615-1620PubMed Google Scholar, 22Villines T.C. Stanek E.J. Devine P.J. Turco M. Miller M. Weissman N.J. Griffen L. Taylor A.J. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration.J. Am. Coll. Cardiol. 2010; 55: 2721-2726Crossref PubMed Scopus (215) Google Scholar). The excitement for the potential application of niacin as an add-on to statin therapy has, however, been dampened when two recent, large clinical studies, the AIM-HIGH and the HPS2-THRIVE trials, failed in reproducing the benefits of previous studies. Niacin, in combination with simvastatin, did not improve the risk of major cardiovascular events; however, a significant improvement in HDL and TG levels remained (23Boden W.E. Probstfield J.L. Anderson T. Chaitman B.R. Desvignes-Nickens P. Koprowicz P, K. McBride R. Teo K. Weintraub W. AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.N. Engl. J. Med. 2011; 365: 2255-2267Crossref PubMed Scopus (2278) Google Scholar, 24Landray M.J. Haynes R. Hopewell J.C. Parish S. Aung T. Tomson J. Wallendszus K. Craig M. Jiang L. et al.HPS2-THRIVE Collaborative Group, M. J. Landray. Effects of extended-release niacin with laropiprant in high-risk patients.N. Engl. J. Med. 2014; 371: 203-212Crossref PubMed Scopus (1172) Google Scholar). The main difference from the previous clinical trials, besides the recruitment of a significantly larger group of patients (several thousand vs. hundreds), was the use of statins in the control conditions, as opposed to four out of the five prior studies in which no drug at all or double placebo were used. Interestingly, in AIM-HIGH, niacin treatment abolished the correlation between non-HDL cholesterol and cardiovascular events (23Boden W.E. Probstfield J.L. Anderson T. Chaitman B.R. Desvignes-Nickens P. Koprowicz P, K. McBride R. Teo K. Weintraub W. AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.N. Engl. J. Med. 2011; 365: 2255-2267Crossref PubMed Scopus (2278) Google Scholar). In control conditions, the levels of non-HDL cholesterol were predictors of cardiovascular complications–an association that is lost upon niacin treatment, suggesting the involvement of nonlipoprotein mechanisms. 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Despite the of studies the effects of on lipid metabolism, and large clinical trials on the of on lipid and in humans are Niacin, the oldest has been in the several mechanisms that its significant its interaction with players in lipid metabolism, as β-chain ATP ABCA1, and niacin is of the levels of circulating HDL decreasing TG However, niacin has the to levels of through the Interestingly, levels several of the observed effects of niacin on lipid These effects are mediated by which a role in the modulation of of lipid metabolism as and evidence in to the as a mediator of niacin's studies to niacin acts on its or it from on as for These studies mechanisms of for other as