Niacin, known also as vitamin B3 or nicotinic acid, has long been seen as one of the best weapons in cholesterol management. It is cheap and effective. It is able to lower levels of fatty acids, triglycerides, and to a lesser extent, LDL- the “bad” cholesterol. At the same time it can impressively raise HDL levels (the “good” cholesterol).
There’s just this one drawback. Nobody likes taking niacin because for most people, it causes alarming and embarrassing flushing, an intense rush of blood to the face and other skin surfaces along with itching, prickling sensations.
But Duke University Medical Center researchers have isolated the molecular pathways that are triggered when niacin enters the body, and they say this knowledge may lead to a revival of niacin-based treatments as therapies of choice. The study will be published in the Journal of Clinical Investigation May 1, 2009 issue.(1)
G Protein Coupled Receptors
The discovery adds to a growing body of knowledge at Duke about G protein coupled receptors. G protein coupled receptors (GPCRs), also known as serpentine receptor, seven transmembrane domain receptors, 7TM receptors, heptahelical receptors, and G protein-linked receptors (GPLR), make up an entire large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses.
These molecules dot cell surfaces throughout the body and manage its response to drugs, hormones, pain, growth factors and many other incoming chemical signals. G protein-coupled receptors, being implicated in many diseases, are the target of around half of all modern medicinal drugs.(2)
Robert Lefkowitz, M.D., senior author of the study, was the first to identify these receptors and some of the roles they play in health and well-being.
“This opens up whole new realms for drug discovery,” according to Robert Walters, M.D., lead author of the study. “Not only could it lead to new niacin-based therapies for cholesterol that patients could actually stick with, but it could also mean new treatments for flushing that comes with some types of allergic reactions, hives and other disorders."
Vitamin B3 in the Body
Lefkowitz and Walters worked together, conducting various laboratory and animal experiments to track precisely what happens when niacin enters the body. Earlier studies had found that it first activates a specific G protein coupled receptor known as GP109A. This receptor then alerts other sets of proteins, including G proteins and a group referred to as beta-arrestins. One particular protein in that group, beta-arrestin1, was found to trigger the chemical reaction that led to flushing.
“Niacin stimulates production of a vasodilator that dramatically increases blood flow to the face, causing the flush and the hot, prickly sensation – and beta-arrestin1 is the culprit that enables that to happen,” says Walters. “Interestingly, however, beta-arrestin1 plays no role whatsoever in niacin’s ability to lower cholesterol and fatty acids. The G proteins do that."
The finding strengthens Lefkowitz’s recent research that demonstrated that beta-arrestins, which frequently work alongside G proteins(3), sometimes work independently of them, initiating their own signals. The discovery, Lefkowitz says, opens up the possibility of developing a “biased ligand,” a drug that would trigger GP109A ( for cholesterol lowering), but not the beta-arrestins (flushing causing). “That might give us a way to keep all the lipid-modifying benefits of niacin, but isolate its downside.”
Don’t Throw Away Your Statins Yet
It might not be as simple as all that, though. Other studies have suggested that enhancing niacin’s ability to boost HDL may be more complex.
“GPR109A receptors are most often found in fat, the spleen, adrenal glands and lungs – they are absent from the liver and intestines, where most HDL is made and metabolized, so there may well be other mechanisms of action for the beneficial effects of niacin in addition to those performed by GPR109A,” says Lefkowitz.
In the present study, analysis of human cell lines found a signaling pathway by which nicotinic acid initiated the flushing response. Said pathway involved the recruitment of beta-arrestin proteins to the GPR109A receptor to which nicotinic acid binds. One interesting point was that mice that lacked beta-arrestin1 showed a decreased flushing response when treated with nicotinic acid, but the drug retained its beneficial effects on the levels of lipids in the blood.
Beta-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice- Robert W. Walters, Arun K. Shukla, Jeffrey J. Kovacs, Jonathan D. Violin, Scott M. DeWire, Christopher M. Lam, J. Ruthie Chen, Michael J. Muehlbauer, Erin J. Whalen and Robert J. Lefkowitz- J. Clin. Invest. doi:10.1172/JCI36806.
Filmore, David (2004). “It’s a GPCR world”. Modern Drug Discovery (American Chemical Society) 2004 (November): 24–28. .
Lefkowitz RJ, Shenoy SK (April 2005). “Transduction of receptor signals by beta-arrestins”. Science (journal) 308 (5721): 512–7. doi:10.1126/science.1109237. PMID 15845844.