Niacin (vitamin B3) is the water-soluble vitamin that is the precursor of the nicotinamide adenine dinucleotide (NAD+) and of the nicotinamide adenine dinucleotide phosphate (NADP+) — the two coenzyme forms of niacin that are the essential cofactors for the wide range of oxidation-reduction reactions that are involved in the carbohydrate metabolism, the fatty acid metabolism, the cholesterol metabolism, and the DNA repair. NAD+ is the electron carrier that is required for the function of the dehydrogenases of the glycolysis, of the TCA cycle, and of the beta-oxidation pathway (including the glyceraldehyde-3-phosphate dehydrogenase, the lactate dehydrogenase, the isocitrate dehydrogenase, the alpha-ketoglutarate dehydrogenase, and the hydroxyacyl-CoA dehydrogenases), while NADP+ is the reduced form (NADPH) that is the electron donor for the anabolic reactions (including the fatty acid synthesis, the cholesterol synthesis, and the nucleotide synthesis) and for the detoxification reactions (including the cytochrome P450 system and the glutathione reductase). Without adequate niacin and NAD+, the oxidation-reduction reactions that are fundamental to all cellular metabolism cannot proceed, and the energy production, the biosynthetic reactions, and the detoxification pathways are all compromised — producing the pellagra (the clinical syndrome of niacin deficiency), which is characterised by the classic triad of the dermatitis, the diarrhoea, and the dementia, and by the death if the deficiency is not treated.
NAD+ and the Cellular Energy Metabolism
NAD+ is the electron carrier that is required for the function of the dehydrogenases of the glycolytic pathway, of the TCA cycle, and of the beta-oxidation pathway. In each of these pathways, a dehydrogenase enzyme removes two electrons and one proton from its substrate (forming NADH), and this NADH is then oxidised by the mitochondrial electron transport chain, regenerating the NAD+ and generating the ATP through the oxidative phosphorylation. Without the NAD+, the glycolytic pathway cannot proceed beyond the glyceraldehyde-3-phosphate dehydrogenase step (because NAD+ is required as an electron acceptor), the TCA cycle cannot proceed beyond the isocitrate dehydrogenase and the alpha-ketoglutarate dehydrogenase steps (because NAD+ is required as an electron acceptor), and the beta-oxidation cannot proceed beyond the first dehydrogenation step (because the acyl-CoA dehydrogenases require FAD as the initial electron acceptor and NAD+ as the subsequent electron acceptor). This metabolic block at multiple steps of the carbohydrate and fat metabolism is the primary mechanism of the energy failure that characterises the niacin deficiency.
The clinical importance of the NAD+ for the cellular energy metabolism is underscored by the observation that the niacin deficiency produces a characteristic accumulation of the NAD+ precursors (including the nicotinic acid and the nicotinamide) in the blood and in the urine, and a reduced NAD+/NADH ratio in the tissues — which is the diagnostic marker of the niacin deficiency. The administration of the niacin restores the NAD+ levels and reverses the metabolic dysfunction — confirming the essential role of niacin in the cellular energy metabolism.
Niacin and the Treatment of Dyslipidaemia
Niacin is one of the most effective treatments for the dyslipidaemia — it raises the HDL cholesterol by 15-30%, lowers the LDL cholesterol by 5-20%, lowers the triglycerides by 20-50%, and lowers the lipoprotein(a) by 20-30%, with effects that are larger than those of any other lipid-lowering drug except the fibrates and the statins. The mechanism of the lipid-modifying effects of niacin involves the activation of the GPR109A receptor in the adipose tissue (which reduces the release of the free fatty acids from the adipose tissue and thereby reduces the hepatic synthesis of the VLDL and the LDL) and the inhibition of the hepatic diacylglycerol acyltransferase 2 (DGAT2) enzyme (which reduces the synthesis of the triglycerides and of the VLDL). Despite its potent lipid-modifying effects, niacin is no longer widely used as a monotherapy for the dyslipidaemia because of the flushing side effects (which are caused by the prostaglandin-mediated vasodilation) and because large clinical trials (including the AIM-HIGH and the HPS2-THRIVE trials) failed to show that niacin, when added to the statin therapy, reduces the cardiovascular events more than the statin therapy alone.
Practical Application
For general niacin supplementation, the evidence-based approach is to supplement with 16-50mg of niacin daily (as nicotinic acid or nicotinamide, the two common supplemental forms), which is approximately the RDA of 16mg daily for adult men and 14mg daily for adult women. For the treatment of the dyslipidaemia, the prescription immediate-release or extended-release nicotinic acid at 1-3g daily is used (which should only be used under medical supervision because of the risk of the hepatotoxicity and of the metabolic side effects). For the prevention of the pellagra (which is rare in the developed world but which occurs in the malnourished, the alcoholics, and the people with the carcinoid syndrome), the niacin supplementation at 20-50mg daily is recommended. For comprehensive energy metabolism support, niacin pairs well with the other B-complex vitamins (which are required for the function of the other cofactor-dependent enzymes in the carbohydrate and fat metabolism pathway), with the the omega-3 fatty acids (which have complementary lipid-modifying effects), and with the chromium (which has insulin-sensitising effects that complement the metabolic effects of niacin).
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