![]() ![]() Presumably through its beneficial effects on lipid levels, niacin also prevents myocardial infarction (MI), a public health menace in the early 21st century ( 2). Before niacin was added to the food supply, pellagra was a major cause of morbidity and mortality in the early 20th century. It eradicated pellagra, a vitamin deficiency disease caused by a chronic lack of niacin (vitamin B 3) as a source of NAD +. Remarkably, it has played a critical role in preventing a top cause of death in 2 different centuries by 2 seemingly unrelated mechanisms. The therapeutic use of niacin has a long and colorful history ( 1). These efforts bring us one step closer to solving a key limitation of an important cardioprotective drug and reveal that the skin response to niacin is much more complicated than previously thought. They also show that the antipsoriasis drug monomethyl fumarate, itself a GPR109A agonist, provokes vasodilation through the same cells. In this issue of the JCI, Hanson and colleagues raise a serious challenge to this paradigm in showing that the major player in vasodilation is the keratinocyte, which produces PGE 2, stimulating EP 2/4 receptors, shifting the role of the Langerhans/PGD 2/DP 1 pathway to that of an accomplice. The working theory is that niacin provokes Langerhans cells to produce prostaglandin D 2 (PGD 2), stimulating vascular DP1 receptors to cause vasodilation. Niacin causes vasodilation, manifest as rubor (redness) of the head and neck, providing a visible sign associated with other, more bothersome skin complaints. ![]() The use of niacin to improve plasma lipid levels and reduce risk of myocardial infarction is limited by noxious skin effects that result from stimulation of G protein–coupled receptor 109A (GPR109A) in skin immune cells. ![]() These data will help to guide new efficient approaches to mitigate nicotinic acid–induced flushing and may help to exploit the potential antipsoriatic effects of GPR109A agonists in the skin. Thus, the early and late phases of the GPR109A-mediated cutaneous flushing reaction involve different epidermal cell types and prostanoid-forming enzymes. Both monomethyl fumarate and nicotinic acid induced PGE2 formation in isolated keratinocytes through activation of GPR109A and COX-2. Interestingly, the first phase of flushing was blocked by a selective cyclooxygenase-1 (COX-1) inhibitor, and the late phase was sensitive to a selective COX-2 inhibitor. Using cell ablation approaches and transgenic cell type–specific GPR109A expression in Gpr109a–/– mice, we have provided evidence that the early phase of flushing depends on GPR109A expressed on Langerhans cells, whereas the late phase is mediated by GPR109A expressed on keratinocytes. Here we analyzed the mechanisms underlying GPR109A-mediated flushing and show that both Langerhans cells and keratinocytes express GPR109A in mice. Flushing is a troublesome side effect of nicotinic acid, but may be a direct reflection of the wanted effects of monomethyl fumarate. The antidyslipidemic drug nicotinic acid and the antipsoriatic drug monomethyl fumarate induce cutaneous flushing through activation of G protein–coupled receptor 109A (GPR109A). ![]()
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