Activation of the G_i protein–coupled receptor GPR109A (HM74A in humans; PUMA-G in mice) can produce differential responses depending on the location of the receptor. It has been proposed that, when nicotinic acid activates GPR109A on adipocytes, the resultant antilipolytic effects contribute to the highly desirable normalization of lipoprotein profiles. However, when nicotinic acid activates GPR109A on dermal dendritic cells or dermal macrophages, the subsequent mobilization of arachidonic acid and its conversion to vasodilatory prostaglandins (PGD₂ and PGE₂) results in the characteristic flushing response. As GPR109A expression extends beyond adipose and immune cells located in the skin (e.g., spleen, lymphoid cells, and lung), it is likely that activation of GPR109A in these cells/tissues may also contribute to the clinical efficacy of nicotinic acid. PLA₂, phospholipase A₂; TG, triglyceride.