Abstract 829: Pharmacological and Genetic Evidence that GPR109a Mediates Both the Anti-lipolytic and Skin Flushing Effects of Nicotinic Acid
Nicotinic acid (niacin) is a well-known lipid modulatory drug that reduces cardiovascular events and all-cause mortality in humans. Niacin also causes skin flushing, which limits wide-spread use despite its proven efficacy. The g-protein coupled receptor, GPR-109a has recently been identified as a molecular mediator of the pharmacological activities of niacin. To decipher the role of GPR-109a in the lipid modulating and flushing activities of niacin, a complementary genetic and pharmacological strategy was pursued. Vasodilation in the skin, the proximal cause of flushing, and free fatty acid concentrations in the plasma were monitored in littermate GPR109a+/+, GPR-109a+/− and GPR-109a−/− mice after treatment with niacin. As expected, niacin dose-dependently increased vasodilation up to 4.9 ± 0.4 (p>0.05) fold and reduced plasma free fatty acid levels up to 78% ± 14 (p>0.05) in GPR09a+/+ mice. No change in either parameter was observed in GPR109a−/− mice, indicating that this receptor mediates both of these responses. Interestingly, in GPR109a+/− litter mates, while niacin reduced plasma free fatty acid concentrations 56% ± 14 (same as GPR109a+/+), no increase in vasodilation was observed (same as GPR109a−/−). A potent and selective antagonist of GPR-109a, BMS-NARA1 was identified via high throughput screening. This compound reversed GPR109a mediated nicotinic acid second messenger signaling in both recombinant cells (IC50= 86 nM) and primary murine adipocytes (IC50= 160 nM). Pre-administration of BMS-NARA1 to mice partially (58%) prevented the anti-lipolytic effect of niacin. Similarly, pre-treatment of rats with BMS-NARA1 completely prevented niacin stimulated increases in skin temperature, another measure of skin flushing. In conclusion, these results demonstrate that pharmacological blockade and homozygous ablation of the GPR-109a gene block the anti-lipolytic and the skin flushing activities of niacin, thus confirming the role of this receptor in mediating both responses. In addition, the dissimilar responses of the lipid modulatory and skin flushing parameters in GPR109+/− mice suggest it may be possible to separate the desired and undesired activities of niacin based upon differential tissue sensitivity.