Role of HCA₂ (GPR109A) in nicotinic acid and fumaric acid ester-induced effects on the skin

Pharmacol Ther. 2012 Oct;136(1):1-7. doi: 10.1016/j.pharmthera.2012.06.003. Epub 2012 Jun 26.


Nicotinic acid (NA) and fumaric acid esters (FAE) such as monomethyl fumarate or dimethyl fumarate are drugs that elicit a cutaneous reaction called flushing as a side effect. NA is used to reduce progression of atherosclerosis through its anti-dyslipidemic activity and lipid-independent mechanisms involving immune cells, whereas FAE are used to treat psoriasis via largely unknown mechanisms. Both, NA and FAE, induce flushing by the activation of the G-protein-coupled receptor (GPCR) Hydroxy-carboxylic acid receptor 2 (HCA₂, GPR109A) in cells of the epidermis. While the wanted effects of NA are at least in part also mediated by HCA₂, it is currently not clear whether this receptor is also involved in the anti-psoriatic effects of FAE. The HCA₂-mediated flushing response to these drugs involves the formation of prostaglandins D₂ and E₂ by Langerhans cells and keratinocytes via COX-1 in Langerhans cells and COX-2 in keratinocytes. This review summarizes recent progress in the understanding of the mechanisms underlying HCA₂-mediated flushing, describes strategies to mitigate it and discusses the potential link between flushing, HCA₂ and the anti-psoriatic effects of FAE.

Publication types

  • Review

MeSH terms

  • Animals
  • Flushing / chemically induced*
  • Fumarates / pharmacology*
  • Humans
  • Niacin / pharmacology*
  • Prostaglandin-Endoperoxide Synthases / physiology
  • Prostaglandins / physiology
  • Psoriasis / drug therapy
  • Receptors, G-Protein-Coupled / physiology*
  • Receptors, Nicotinic / physiology*
  • Skin / drug effects*


  • Fumarates
  • HCAR2 protein, human
  • Prostaglandins
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic
  • Niacin
  • Prostaglandin-Endoperoxide Synthases