Niacin, also called nicotinic acid or vitamin B-3, powerfully lowers the blood cholesterols (VLDL and LDL) and triglycerides that are risk factors in cardiovascular disease. At the same time, it enhances the good cholesterol, HDL. Unfortunately, this cheap and highly effective drug is not routinely used, because niacin also causes facial reddening in many individuals. Recent research shows that the lipid benefits and the flushing side effects are two separate reactions and there is potential to develop new drugs that will provide the benefits without the disadvantages.
Niacin Increases HDL and Lowers Triglycerides/LDL by Binding to Receptor (GPR109A)
Recent biomedical research has now demonstrated that flushing occurs in the skin by cellular mechanisms that are distinct from the alteration of lipid metabolism. Niacin binds to a protein receptor (G-protein-coupled receptor called GPR109A) on the surface of cells and produces a lowering of an intracellular signal, cyclic AMP, that subsequently alters lipid metabolism and produces the beneficial effects on serum cholesterols.
Inhibiting the Niacin Effect on Lipid Metabolism Still Produces Flushing
When researchers blocked the cyclic AMP lowering effects of niacin using a toxin (pertussis toxin), they found that flushing still occurred. This indicated that the pathway that led to modification of lipid metabolism was independent of the pathway leading to flushing. This also indicated the possibility of developing drugs that altered lipids, but did not cause flushing.
Flushing Is Caused by Prostaglandin Production
Flushing results from dilation of facial capillaries using a mechanism that is typical for inflammation. Activation of an enzyme, cytosolic phospholipase A2, cPLA2, causes a release of arachidonic acid (ARA, the inflammatory fatty acid derived from eating vegetable oils) from membrane phospholipids. The ARA is converted by cycloxidase-2, COX-2, into prostaglandin D2 that leads to vasodilation and flushing.
Aspirin Can Avoid Flushing by Blocking Prostaglandin Production
Aspirin can inhibit and modify the COX-2 enzyme and can be used to permit the use of niacin without flushing. In the presence of aspirin, the beneficial effects of niacin are still observed. The use of aspirin also indicates a divergence of the pathways from binding of niacin to GPR109A, leading to either lipid modification or flushing.
Arrestins Link GPR109A Binding of Niacin with cPLA2 Activation
GPR109A is a receptor on the surface of cells that has multiple interactions with other proteins, e.g. arrestins, that are involved in internalizing the receptor by forming coated vesicles. Binding of niacin to GPR109A, results in aggregation of beta-arrestin to the inner surface of the cell membrane. Recent research showed that aggregated beta-arrestin in turn activates cPLA2, leading to prostaglandin D2 production and flushing. Experimental compounds that avoid arrestin aggregation eliminate flushing.
Lipid Benefits without the Flush
Niacin is the most effective enhancer of HDL and it also lowers problematic triglycerides and LDL. It would be the drug of choice to lower cardiovascular risk associated with serum lipids, because it is cheaper and more effective than the alternatives, such as statins. Niacin has not been used more extensively, because of flushing. The new recognition of the role of arrestins in niacin flushing demonstrates the feasibility of development of new drugs that avoid arrestin action to get the full benefit of niacin without inflammatory flushing.
Reference:
Walters RW, Shukla AK, Kovacs JJ, Violin JD, DeWire SM, Lam CM, Chen JR, Muehlbauer MJ, Whalen EJ, Lefkowitz RJ. 2009. "Beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice." J Clin Invest. 119(5):1312-21.
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