title: Niacin induces PPARgamma expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways.
abstract: 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 3.1.1.4), cyclo-oxygenase (EC 1.14.99.1) and prostaglandin D(2) synthase (EC 5.3.99.2). 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.
authors.affiliation: Cancer Research UK Molecular Oncology Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Knowles
authors.forename: Robert H
authors.initials: RH
authors.lastname: te Poele
authors.forename: Robert
authors.initials: R
authors.lastname: Te Poole
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D009525:Niacin / Q000378:metabolism / Q000494:pharmacology*; D047495:PPAR gamma / Q000235:genetics*; D011453:Prostaglandins / Q000096:biosynthesis* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects* / Q000502:physiology
chemical_list: C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; D047495:PPAR gamma; D011453:Prostaglandins; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D009525:Niacin; D000242:Cyclic AMP