Nicotinic acid (niacin), a vitamin of the B complex, has been used for almost 50 years as a lipid-lowering drug1,2. The pharmacological effect of nicotinic acid requires doses that are much higher than those provided by a normal diet3,4. Its primary action is to decrease lipolysis in adipose tissue by inhibiting hormone-sensitive triglyceride lipase5. This anti-lipolytic effect of nicotinic acid involves the inhibition of cyclic adenosine monophosphate (cAMP) accumulation in adipose tissue6 through a Gi-protein-mediated inhibition of adenylyl cyclase7,8,9. A G-protein-coupled receptor for nicotinic acid has been proposed in adipocytes10,11. Here, we show that the orphan G-protein-coupled receptor, 'protein upregulated in macrophages by interferon-γ' (mouse PUMA-G, human HM74)12,13, is highly expressed in adipose tissue and is a nicotinic acid receptor. Binding of nicotinic acid to PUMA-G or HM74 results in a Gi-mediated decrease in cAMP levels. In mice lacking PUMA-G, the nicotinic acid–induced decrease in free fatty acid (FFA) and triglyceride plasma levels was abrogated, indicating that PUMA-G mediates the anti-lipolytic and lipid-lowering effects of nicotinic acid in vivo. The identification of the nicotinic acid receptor may be useful in the development of new drugs to treat dyslipidemia.
NOTE: In the version of this article initially published online, the statements concerning equal author contribution and corresponding authors were incorrect. This mistake has been corrected for the HTML and print versions of the article.
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Knopp, R.H. Drug treatment of lipid disorders N. Engl. J. Med. 341, 498–511 (1999).
Szapary, P.O. & Rader, D.J. Pharmacological management of high triglycerides and low high-density lipoprotein cholesterol. Curr. Opin. Pharmacol. 1, 113–120 (2001).
Hotz, W. Nicotinic acid and its derivatives: a short survey. Adv. Lipid. Res. 20, 195–217 (1983).
Olsson, A.G. Nicotinic acid and derivatives. In Handbook of Experimental Pharmacology vol. 109 (eds. Schettler, G. & Habenicht, A.J.R.) 349–400 (Springer-Verlag, Heidelberg, 1994).
Carlson, L.A. Studies on the effect of nicotinic acid on catecholamine-stimulated lipolysis in adipose tissue in vitro. Acta Med. Scand. 173, 719 (1963).
Butcher, R.W., Baird, C.E. & Sutherland, E.W. Effects of lipolytic and antilipolytic substances on adenosine 3′,5′-monophosphate levels in isolated fat cells. J. Biol. Chem. 243, 17005–17012 (1968).
Aktories, K., Schultz, G. & Jakobs, K.H. Regulation of adenylate cyclase activity in hamster adipocytes. Inhibition by prostaglandins, α-adrenergic agonists and nicotinic acid. Naunyn Schmiedebergs Arch. Pharmacol. 312, 167–173 (1980a).
Fredholm, B.B. Adenosine and lipolysis. Int. J. Obes. 5, 643–649 (1981).
Aktories, K., Schultz, G. & Jakobs K.H. Inactivation of the guanine nucleotide regulatory site mediating inhibition of the adenylate cyclase in hamster adipocytes. Naunyn Schmiedebergs Arch Pharmacol. 321, 247–252 (1982).
Aktories, K., Jakobs, K.H. & Schultz, G. Nicotinic acid inhibits adipocyte adenylate cyclase in a hormone-like manner. FEBS Lett. 115, 11–14 (1980b).
Lorenzen, A. et al. Characterization of a G protein-coupled receptor for nicotinic acid. Mol. Pharmacol. 59, 349–357 (2001).
Nomura, H., Nielsen, B.W. & Matsushima, K. Molecular cloning of cDNAs encoding a LD78 receptor and putative leukocyte chemotactic peptide receptors. Int. Immunol. 5, 1239–1249 (1993).
Schaub, A., Futterer, A. & Pfeffer, K. PUMA-G, an IFN-γ-inducible gene in macrophages is a novel member of the seven transmembrane spanning receptor superfamily. Eur. J. Immunol. 31, 3714–3725 (2001).
Lorenzen, A., Stannek, C., Burmeister, A., Kalvinsh, I. & Schwabe, U. G protein-coupled receptor for nicotinic acid in mouse macrophages. Biochem. Pharmacol. 64, 645–648 (2002).
Yousefi, S., Cooper, P.R., Mueck, B., Potter, S.L. & Jarai, G. cDNA representational difference analysis of human neutrophils stimulated by GM-CSF. Biochem. Biophys. Res. Commun. 277, 401–409 (2000).
Offermanns, S. & Simon, M.I. Gα15 and Gα16 couple a wide variety of receptors to phospholipase C. J. Biol. Chem. 270, 15175–15180 (1995).
Baubet, V. et al. Chimeric green fluorescent protein-aequorin as bioluminescent Ca2+ reporters at the single-cell level. Proc. Natl. Acad. Sci. USA 97, 7260–7265 (2000).
Aktories, K., Schultz, G. & Jakobs, K.H. Inhibition of adenylate cyclase and stimulation of a high affinity GTPase by the antilipolytic agents, nicotinic acid, acipimox and various related compounds. Arzneimittelforschung 33, 1525–1527 (1983).
Rudolph, U., Spicher, K. & Birnbaumer, L. Adenylyl cyclase inhibition and altered G protein subunit expression and ADP-ribosylation patterns in tissues and cells from Gi2α−/− mice. Proc. Natl. Acad. Sci. USA 93, 3209–3214 (1996).
Kather, H., Aktories, K., Schulz, G. & Jakobs, K.H. Islet-activating protein discriminates the antilipolytic mechanism of insulin from that of other antilipolytic compounds. FEBS Lett. 161, 149–152 (1983).
Svedmyr, N., Harthon, L. & Lundholm, L. The relationship between the plasma concentration of free nicotinic acid and some of its pharmacologic effects in man. Clin. Pharmacol. Ther. 10, 559–570 (1969).
Carlson, L.A., Oro, L. & Ostman, J, Effect of a single dose of nicotinic acid on plasma lipids in patients with hyperlipoproteinemia. Acta Med. Scand. 183, 457–465 (1968).
Geigy Scientific Tables vol. 3 (ed. Lentner, C.) 129 (Ciba-Geigy, Basle, Switzerland, 1984).
Hosoi, T. et al. Identification of a novel human eicosanoid receptor coupled to Gi/o . J. Biol. Chem. 277, 31459–31465 (2002).
Rodbell, M. Metabolism of isolated fat cells. J. Biol. Chem. 239, 375–380 (1964).
The authors wish to thank A. Fütterer, J. Meinecke, K. Meyer, K. Mink, E. Schaller and B. Wallenwein for technical assistance and G. Scholze and W. Fiehn for help with triglyceride determinations. J.K. received a fellowship from the Serono Foundation. This work was supported by the Deutsche Forschungsgemeinschaft.
The authors declare no competing financial interests.
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Tunaru, S., Kero, J., Schaub, A. et al. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med 9, 352–355 (2003). https://doi.org/10.1038/nm824
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