PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect.
Nicotinic acid (niacin), a vitamin of the B complex, has been used for almost 50 years as a lipid-lowering drug. The pharmacological effect of nicotinic acid requires doses that are much higher than those provided by a normal diet. Its primary action is to decrease lipolysis in adipose tissue by inhibiting hormone-sensitive triglyceride lipase. This anti-lipolytic effect of nicotinic acid involves the inhibition of cyclic adenosine monophosphate (cAMP) accumulation in adipose tissue through a G(i)-protein-mediated inhibition of adenylyl cyclase. A G-protein-coupled receptor for nicotinic acid has been proposed in adipocytes. Here, we show that the orphan G-protein-coupled receptor, 'protein upregulated in macrophages by interferon-gamma' (mouse PUMA-G, human HM74), is highly expressed in adipose tissue and is a nicotinic acid receptor. Binding of nicotinic acid to PUMA-G or HM74 results in a G(i)-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.
Tunaru
Sorin
S
Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany.
Kero
Jukka
J
Schaub
Annette
A
Wufka
Christian
C
Blaukat
Andree
A
Pfeffer
Klaus
K
Offermanns
Stefan
S
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D000960:Hypolipidemic Agents / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009525:Niacin / Q000378:metabolism*; D011869:Radioligand Assay; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D014280:Triglycerides / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; C473652:Hcar2 protein, mouse; D000960:Hypolipidemic Agents; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D014280:Triglycerides; D009525:Niacin; D019204:GTP-Binding Proteins