Differential tissue and ligand-dependent signaling of GPR109A receptor: implications for anti-atherosclerotic therapeutic potential

Cell Signal. 2013 Oct;25(10):2003-16. doi: 10.1016/j.cellsig.2013.06.008. Epub 2013 Jun 14.


Until recently, the anti-atherosclerotic effects of niacin were attributed primarily to its lipid modification properties mediated by adipocyte G-protein coupled receptor GPR109A, though recent studies have raised significant doubts about this mechanism. In fact, in rodents it has recently been demonstrated that niacin inhibits progression of atherosclerosis through actions on immune cells, particularly via macrophage-expressed GPR109A, independent of lipid-modifying properties. Here, we studied GPR109A signal transduction in human Langerhans cells, macrophages and adipocytes. We find that the consequences of receptor activation are profoundly influenced by cellular context and that ligand-biased signaling significantly impacts functionally relevant signaling. In Langerhans cells, niacin initiates GPR109A-mediated signaling pathways (Erk1/2 and Ca(2+)) responsible for the release of vasodilatory prostanoids, while the synthetic GPR109A agonist MK-0354 fails to elicit any signaling, providing a mechanistic basis for the latter compound's inability to cause flushing. While GPR109A mediates inhibition of cAMP in adipocytes, in macrophages GPR109A signaling via Gβγ subunits results in paradoxical augmentation of intracellular cAMP levels. Also, in macrophages niacin and GPR109A full agonists induce Erk1/2 and Ca(2+) signaling, release of prostanoids, upregulation of cholesterol transporters ABCA1 and ABCG1 and stimulation of reverse cholesterol transport in GPR109A dependent manner. A mechanism is presented in which signals from the autocrine action of released prostanoids and Gi protein mediated cAMP augmentation are integrated leading to modulation of reverse cholesterol transport regulatory components. These studies provide key insights into mechanisms by which GPR109A may influence cholesterol efflux in macrophages; a process that may be at least partially responsible for niacin's anti-atherosclerotic activity. MK-0354 does not induce niacin-like GPR109A signaling in macrophages, suggesting that biased agonists devoid of the flushing side-effect may also lack properties required for macrophage-mediated anti-atherosclerotic effects.

Keywords: ABCA1; Atherosclerosis; Biased signaling; GPR109A; Macrophage; Niacin.

MeSH terms

  • ATP Binding Cassette Transporter 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters / metabolism
  • Adipocytes / metabolism
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Calcium Signaling / drug effects
  • Calcium Signaling / genetics
  • Cholesterol / metabolism*
  • Humans
  • Langerhans Cells / drug effects
  • Langerhans Cells / metabolism*
  • Ligands
  • MAP Kinase Signaling System / drug effects
  • Niacin / administration & dosage
  • Organ Specificity
  • Prostaglandins / metabolism
  • Pyrazoles / pharmacology
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism*
  • Signal Transduction / drug effects
  • Tetrazoles / pharmacology


  • 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydrocyclopentapyrazole
  • ABCA1 protein, human
  • ABCG1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters
  • HCAR2 protein, human
  • Ligands
  • Prostaglandins
  • Pyrazoles
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic
  • Tetrazoles
  • Niacin
  • Cholesterol