Nicotinic Acid-Mediated Activation of Both Membrane and Nuclear Receptors towards Therapeutic Glucocorticoid Mimetics for Treating Multiple Sclerosis
Figure 1
Unique mechanisms of action of nicotinic acid on immune function are shown. Nicotinic acid, but not nicotinamide, binds to the high-affinity nicotinic acid G-protein-coupled receptor HM74a/GPR109a that via calcium influx activates phospholipase . This ultimately leads to massive production and release of prostaglandins 15d- and specifically from professional antigen presenting cells (macrophages, dendritic cells, and likely microglia [55]). Thus, nicotinamide, which also provides NAD, functions in part as a negative control for HM74a-dependent effects in experimentation. was previously identified as promoting differentiation of plasmacytoid dendritic cells to a T cell toleragenic phenotype via induction of IDO expression and activity [49, 50]. Consequently nicotinic acid may provide a similar T cell toleragenic effect. 15d- spontaneously degrades to produce 15-, the most potent endogenous activator of PPAR. This may be central to the explanation of how nicotinic acid but not nicotinamide corrects dyslipidemia, raising HDL levels higher than any known pharmaceutical including all PPAR agonists while also lowering LDL, VLDL, and triglycerides [30, 56].
