Niacin induces PPARgamma expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways

Biochem Pharmacol. 2006 Feb 28;71(5):646-56. doi: 10.1016/j.bcp.2005.11.019. Epub 2006 Jan 18.


HM74 and HM74a have been identified as receptors for niacin. HM74a mediates the pharmacological anti-lipolytic effects of niacin in adipocytes by reducing intracellular cyclic AMP (cAMP) and inhibiting release of free fatty acids into the circulation. In macrophages, niacin induces peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent and cAMP-dependent expression of genes mediating reverse cholesterol transport, although via an unidentified receptor. We describe constitutive expression of HM74a mRNA and hypoxia- and IFNgamma-inducible expression of HM74 and HM74a in human monocytic cell lines and primary cells in culture. In U937 cells niacin-induced expression of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), the most potent endogenous ligand of PPARgamma. Both niacin and the structurally distinct HM74/HM74a ligand acifran-induced nuclear expression of PPARgamma protein and enhanced PPARgamma transcriptional activity. Niacin-induced PPARgamma transcriptional activity was pertussis toxin sensitive and required activity of phospholipase A(2) (EC, cyclo-oxygenase (EC and prostaglandin D(2) synthase (EC Niacin also induced PPARgamma transcriptional activity in HM74 and HM74a CHO cell transfectants, although not in vector-only control cells. This was sensitive to pertussis toxin and to inhibition of phoshoplipase A(2) and cyclo-oxygenase activity. Additionally, niacin increased intracellular cAMP in U937 via a pertussis toxin and cyclo-oxygenase-sensitive mechanism. These results indicate that HM74 and HM74a can mediate macrophage responses to niacin via activation of the prostaglandin synthesis pathway and induction and activation of PPARgamma. This suggests a novel mechanism(s) mediating the clinical effects of pharmacological doses of niacin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cyclic AMP / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Niacin / metabolism
  • Niacin / pharmacology*
  • PPAR gamma / genetics*
  • Prostaglandins / biosynthesis*
  • Prostaglandins / metabolism
  • Receptors, G-Protein-Coupled / biosynthesis
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / physiology*
  • Receptors, Nicotinic / biosynthesis
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / physiology*
  • Signal Transduction
  • Transcriptional Activation / drug effects*
  • Transcriptional Activation / physiology


  • HCAR2 protein, human
  • HCAR3 protein, human
  • PPAR gamma
  • Prostaglandins
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic
  • Niacin
  • Cyclic AMP