What is/are Niacin?
Niacin (also known as vitamin B3, nicotinic acid, or less commonly vitamin PP; archaic terms include pellagra-preventive and anti-dermatitis factor) is an organic compound with the formula C6H5NO2 and, depending on the definition used, one of the 40 to 80 essential human nutrients.
Niacin is one of five vitamins (when lacking in human diet) associated with a pandemic deficiency disease: niacin deficiency (pellagra), vitamin C deficiency (scurvy), thiamin deficiency (beriberi), vitamin D deficiency (rickets and osteomalacia), vitamin A deficiency (night blindness and other symptoms). Niacin has been used for over 50 years to increase levels of HDL in the blood and has been found to modestly decrease the risk of cardiovascular events in a number of controlled human trials.
This colorless, water-soluble solid is a derivative of pyridine, with a carboxyl group (COOH) at the 3-position. Other forms of vitamin B3 include the corresponding amide, nicotinamide ("niacinamide"), where the carboxyl group has been replaced by a carboxamide group (CONH2), as well as more complex amides and a variety of esters. Nicotinic acid and niacinamide are convertible to each other with steady world demand rising from 8500 tonnes per year in 1980s to 40,000 in recent years.
Niacin cannot be directly converted to nicotinamide, but both compounds could be converted to NAD and NADP in vivo. Nicotinic acid, nicotinamid, and tryptophan (via quinoline acid) are co-factors for nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD converts to NADP by phosphorylation in the presence of the enzyme NAD+ kinase. NADP and NAD are coenzyme for many dehydrogenases, participating in many hydrogen transfer processes. NAD is important in catabolism of fat, carbohydrate, protein and alcohol as well as cell signaling and DNA repair and NADP mostly in anabolism reaction such as fatty acid and cholesterol synthesis. High energy requirements (brain) or high turnover rate (gut, skin) organs are usually the most susceptible to their deficiency. Although the two are identical in their vitamin activity, nicotinamide does not have the same pharmacological effects (lipid modifying effects) as niacin. Nicotinamide does not reduce cholesterol or cause flushing. Nicotinamide may be toxic to the liver at doses exceeding 3 g/day for adults. Niacin is a precursor to NAD+/NADH and NADP+/NADPH, which play essential metabolic roles in living cells. Niacin is involved in both DNA repair, and the production of steroid hormones in the adrenal gland.
In 1955, Altschul et al. (1955) described niacin as lipid lowering property for the first time that followed by subsequent studies. Niacin is the oldest lipid lowering drug with unique anti atherosclerotic property. It reduces traditional parameters such as low density lipoprotein cholesterol (LDL), very low-density lipoprotein cholesterol (VLDL-C) and triglycerides (TG) but effectively increases high density lipoprotein cholesterol (HDL). Despite the importance of other cardiovascular risk factors, high HDL correlated to lower cardiovascular event independent of LDL reduction Other effects include anti-thrombotic and vascular inflammation, improving endothelial function and plaque stability. Niacin alone or in combination with other lipid lowering agents such as statin or ezetimibe significantly reduces risk of cardiovascular disease and arthrosclerosis progression. Niacin therapeutic effect is mostly through its specific G protein coupled receptor (GPR109A and GPR109B) recently named as hydroxyl carboxylic acid (HCA) receptor 2 that highly expressed in adipose tissue, spleen, immune cells and keratinocytes but not in other expected organs such as liver, kidney, heart or intestine. GPR109A inhibits cyclic adenosine monophosphate production and thus lipolysis and free fatty acids available for liver to produce TG and VLDL and consequently LDL. Decrease in free fatty acids also suppress hepatic expression of apolipoprotein C3 (APOC3) and PPARg coactivator-1b (PGC-1b) thus increase VLDL turn over and reduce its production. It also inhibits diacylglycerol acyltransferase-2 (important hepatic TG synthesis). The mechanism behind increasing HDL is not totally understood but it seems to be done in various ways. Niacin increase apolipoprotein A1 levels due to anti catabolic effects resulting in higher reverse cholesterol transport. It also inhibits HDL hepatic uptake, down regulating production of cholesterol ester transfer protein (CETP) gene. Finally, it stimulates ABCA1 transporter in monocytes and macrophages and up regulates peroxisome proliferator-activated receptor γ results in reverse cholesterol transport. Improving vascular endothelial function has been reported in few experiments using niacin. In an experiment on type 2 diabetes, nicotinic acid improved endothelial function comparing with control. Daily dose of 1 g niacin shows significant lipid modifying properties and reach the plateau using 2 grams. GPR109A in immune cells such as monocytes, macrophages, and dendritic cells is responsible for atherosclerosis effects of niacin by reducing the immune cells’ infiltration of vessel wall It also down regulates endothelial adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1) or of chemokines such as monocyte chemotactic protein 1 (MCP-1) and inflammatory proteins which results in atherosclerotic stabilization and antithrombotic effects. The changes in adhesion molecules and chemokines might be through activation of receptor GPR109A on immune cells. Adipokines are the adipocytes’ produced mediators. Some adipokines such as tumor necrosis factor (TNF)-a, interleukins and chemokines, have pro-inflammatory effect and some others such as adiponectin have anti-inflammatory effect that regulates inflammatory process, decrease vascular progression and atherosclerosis. Nicotinic acid increase adiponectin plasma levels in humans and mice but inhibits pro-inflammatory chemokines such as MCP-1 and fractalkin. Other recently explored therapeutic effect of nicotinic acid are neuroprotective and anti-inflammatory effects, beneficial in animal models of arthritis, chronic renal failure or sepsis however more work needed in this area. Following Coronary Drug Project (CDP) as one of the first experiments being done to study long term clinical lipid lowering effect of niacin in 1960’s to early 1970’s, (JAMA, 1975) many other experiments been done. Their result been summarized in two most recent meta analysis concluded that therapeutic doses of niacin alone or in combination with other lipid modifying agents such as statin reduce cardiovascular event and arthrosclerosis progression significantly. This agrees with current Nation Cholesterol Education Program (NCEP) on high cholesterol treatment. NCEP recommends niacin alone for cardiovascular and atherogenic dyslipidemia in mild or normal LDL levels or in combination for higher LDL levels (NCEP, 2002). 1500 mg Immediate release niacin daily results in 13% LDL, 20% LP, 10% TG reduction and 19% HDL increase comparing to placebo. Extended release niacin alone or with anti-flushing agent (laropiprant) shows similar effects.
Niacin binds to and stimulates a G-protein-coupled receptor, GPR109A, which causes the inhibition of fat breakdown in adipose tissue. Nicotinamide does not bind this receptor which explains why it does not affect blood lipid levels. Lipids that are liberated from adipose tissue are normally used to build very-low-density lipoproteins (VLDL) in the liver, which are precursors of low-density lipoprotein (LDL) or "bad" cholesterol. Because niacin blocks the breakdown of fats, it causes a decrease in free fatty acids in the blood and, as a consequence, decreases the secretion of VLDL and cholesterol by the liver.]
By lowering VLDL levels, niacin also increases the level of high-density lipoprotein (HDL) or "good" cholesterol in blood, and therefore it is sometimes prescribed for people with low HDL, who are also at high risk of a heart attack.
The ARBITER 6-HALTS study, reported at the 2009 annual meeting of the American Heart Association and in the New England Journal of Medicine concluded that, when added to statins, 2000 mg/day of extended-release niacin was more effective than ezetimibe (Zetia) in reducing carotid intima-media thickness, a marker of atherosclerosis. Additionally, a recent meta-analysis covering 11 randomized controlled clinical trials found positive effects of niacin alone or in combination on all cardiovascular events and on atherosclerosis evolution.
However, a 2011 study (AIM-HIGH) was halted early because patients showed no decrease in cardiovascular events, but did experience an increase in the risk of stroke. These patients already had LDL levels well controlled by a statin drug, and the aim of the study was to evaluate extended-release niacin (2000 mg per day) to see if raising HDL levels had an additional positive effect on risk. In this study, it did not have such an effect, and appeared to increase stroke risk. The role of niacin in patients whose LDL is not well-controlled (as in the majority of previous studies with niacin) is still under study and debate. However, it does not seem to offer benefits via raising HDL, in patients already lowering LDL by taking a statin.
This article uses material from the Wikipedia article Niacin, which is released under the Creative Commons Attribution-Share-Alike License 3.0.