The psoriasis drug monomethylfumarate is a potent nicotinic acid receptor agonist.
Nicotinic acid has been used for several decades to treat dyslipidemia. In mice, the lipid-lowing effect of nicotinic acid is mediated by the Gi coupled receptor PUMA-G. In humans, high (GPR109A) and low (GPR109B) affinity nicotinic acid receptors have been characterized. Here we identify monomethylfumarate as a GPR109A agonist. Monomethylfumarate is the active metabolite of the psoriasis drug Fumaderm. We show that monomethylfumarate activates GPR109A in a calcium based aequorin assay, cAMP assay and demonstrate competitive binding with nicotinic acid. We show that GPR109A is highly expressed in neutrophils and epidermal keratinocytes, and that its expression is increased in human psoriatic lesions. Our findings provide evidence that GPR109A is a target for the drug Fumaderm and suggest that niacin should be investigated to treat psoriasis in addition to its role in treating lipid disorders.
Tang
Hua
H
Department of Metabolic Disorders, Amgen San Francisco, 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
Lu
Jenny Ying-Lin
JY
Zheng
Xiaomu
X
Yang
Yuhua
Y
Reagan
Jeff D
JD
D002460:Cell Line; D003879:Dermatologic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000069462:Dimethyl Fumarate; D005650:Fumarates / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008298:Maleates / Q000494:pharmacology* / Q000627:therapeutic use; D009525:Niacin / Q000494:pharmacology* / Q000627:therapeutic use; D011565:Psoriasis / Q000188:drug therapy; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011978:Receptors, Nicotinic
D003879:Dermatologic Agents; D005650:Fumarates; C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; D000960:Hypolipidemic Agents; D008298:Maleates; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; C073341:citraconic acid; D009525:Niacin; D000069462:Dimethyl Fumarate