Niacin induces PPARγ expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways
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 prolif...
| Autores principales: | , , , |
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| Formato: | Journal article |
| Lenguaje: | English |
| Publicado: |
Elsevier
2006
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| Materias: |
| _version_ | 1826289872718004224 |
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| author | Knowles, H Poole, R Workman, P Harris, A |
| author_facet | Knowles, H Poole, R Workman, P Harris, A |
| author_sort | Knowles, H |
| collection | OXFORD |
| description | 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 γ (PPARγ)-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 IFNγ-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-Δ<sup12, 14<="" sup="">-prostaglandin J₂ (15d-PGJ₂), the most potent endogeneous ligand of PPARγ. Both niacin and the structurally distinct HM74/HM74a ligand acifran-induced nuclear expression of PPARγ protein and enhanced PPARγ transcriptional activity of phospholipase A₂ (EC 3.1.1.4), cyclo-oxygenase (EC 1.14.99.1) and prostaglandin D₂ synthase (EC 5.3.99.2). Niacin also induced PPARγ 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 phoshopipase A₂ 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 PPARγ. This suggests a novel mechanism(s) mediating the clinical effects of pharmacological doses of niacin.</sup12,> |
| first_indexed | 2024-03-07T02:35:32Z |
| format | Journal article |
| id | oxford-uuid:a8a5ce26-1079-4f70-878a-ee1cc2aa6ca5 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:35:32Z |
| publishDate | 2006 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:a8a5ce26-1079-4f70-878a-ee1cc2aa6ca52022-03-27T03:03:04ZNiacin induces PPARγ expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathwaysJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a8a5ce26-1079-4f70-878a-ee1cc2aa6ca5Medical sciencesOncologyEnglishOxford University Research Archive - ValetElsevier2006Knowles, HPoole, RWorkman, PHarris, AHM74 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 γ (PPARγ)-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 IFNγ-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-Δ<sup12, 14<="" sup="">-prostaglandin J₂ (15d-PGJ₂), the most potent endogeneous ligand of PPARγ. Both niacin and the structurally distinct HM74/HM74a ligand acifran-induced nuclear expression of PPARγ protein and enhanced PPARγ transcriptional activity of phospholipase A₂ (EC 3.1.1.4), cyclo-oxygenase (EC 1.14.99.1) and prostaglandin D₂ synthase (EC 5.3.99.2). Niacin also induced PPARγ 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 phoshopipase A₂ 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 PPARγ. This suggests a novel mechanism(s) mediating the clinical effects of pharmacological doses of niacin.</sup12,> |
| spellingShingle | Medical sciences Oncology Knowles, H Poole, R Workman, P Harris, A Niacin induces PPARγ expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways |
| title | Niacin induces PPARγ expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways |
| title_full | Niacin induces PPARγ expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways |
| title_fullStr | Niacin induces PPARγ expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways |
| title_full_unstemmed | Niacin induces PPARγ expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways |
| title_short | Niacin induces PPARγ expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways |
| title_sort | niacin induces pparγ expression and transcriptional activation in macrophages via hm74 and hm74a mediated induction of prostaglandin synthesis pathways |
| topic | Medical sciences Oncology |
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