Niacin is the B vitamin that is the precursor of NAD (nicotinamide adenine dinucleotide) and NADP (nicotinamide adenine dinucleotide phosphate) — the two coenzymes that are the foundation of all oxidation-reduction reactions in the body. NAD is the electron carrier that is required for the function of the dehydrogenases of the glycolytic pathway, of the TCA cycle, of the beta-oxidation pathway, and of the mitochondrial electron transport chain; NADP is the reduced form (NADPH) that is the electron donor for the anabolic reactions of fatty acid synthesis, cholesterol synthesis, and nucleotide synthesis, and for the detoxification reactions of the cytochrome P450 system. Without niacin, neither NAD nor NADP can be synthesised, and the oxidation-reduction reactions that are essential for energy metabolism and for biosynthetic reactions cannot proceed. This niacin-dependent vulnerability of energy metabolism is the foundation of the clinical syndrome of pellagra — the disease that results from severe niacin deficiency and that is characterised by the classic triad of dermatitis, diarrhoea, and dementia — and by the more subtle metabolic dysfunction that results from milder degrees of niacin deficiency.
NAD and Energy Metabolism
NAD is the electron carrier that is required for the dehydrogenases of the glycolytic pathway (glyceraldehyde-3-phosphate dehydrogenase, which generates NADH), of the TCA cycle (isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, and malate dehydrogenase, all of which generate NADH), and of the beta-oxidation pathway (the hydroxyacyl-CoA dehydrogenases, which generate NADH). The NADH that is generated by these dehydrogenase reactions is the electron donor for the mitochondrial electron transport chain, where it is oxidised to NAD+ with the simultaneous generation of ATP through oxidative phosphorylation. Without NAD, the glycolytic pathway, the TCA cycle, and the beta-oxidation pathway cannot proceed beyond the steps that require NAD as an electron acceptor, and the mitochondrial electron transport chain cannot generate ATP from the NADH that is produced by these pathways. The result is a catastrophic failure of cellular energy metabolism, which is the primary mechanism of the tissue damage and the systemic illness that characterise severe niacin deficiency.
The clinical importance of NAD for cellular energy metabolism is underscored by the observation that the NAD+ content of cells declines with age and with chronic metabolic stress, and that this decline in NAD+ is associated with the mitochondrial dysfunction, the metabolic dysregulation, and the cellular senescence that are the hallmarks of the ageing process and of the chronic metabolic diseases. The supplementation of NAD+ precursors (including nicotinamide riboside, nicotinamide mononucleotide, and nicotinamide) has been studied as a strategy for restoring NAD+ levels and for ameliorating the age-related decline in mitochondrial function. Multiple clinical trials have demonstrated that NAD+ precursor supplementation increases NAD+ levels in blood and tissues, improves markers of mitochondrial function, and may improve some aspects of metabolic health in older adults.
Niacin and the Treatment of Dyslipidaemia
Niacin is one of the most effective treatments for dyslipidaemia — it raises HDL cholesterol by 15-30%, lowers LDL cholesterol by 5-20%, and lowers triglycerides by 20-50%, 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 G-protein-coupled receptor GPR109A in adipose tissue (which reduces the release of free fatty acids from adipose tissue and thereby reduces the hepatic synthesis of VLDL and LDL) and the inhibition of the hepatic diacylglycerol acyltransferase 2 (DGAT2) enzyme (which reduces the synthesis of triglycerides and of VLDL). Despite its potent lipid-modifying effects, niacin is no longer widely used as a monotherapy for dyslipidaemia because of the flushing side effects and because large clinical trials (including the AIM-HIGH and HPS2-THRIVE trials) failed to show that niacin, when added to statin therapy, reduces cardiovascular events more than statin therapy alone.
Practical Application
For general niacin supplementation, the evidence-based dose is 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 dyslipidaemia, the dose is 1-3g of niacin daily (prescription immediate-release or extended-release nicotinic acid), which should only be used under medical supervision because of the risk of hepatotoxicity and of the metabolic side effects (flushing, glucose intolerance) that are associated with high-dose niacin. For comprehensive energy metabolism support, niacin pairs well with the other B-complex vitamins (which are required for the function of the enzymes of the energy metabolism pathways), with the CoQ10 (which is required for the function of the electron transport chain and which may be depleted by high-dose niacin), and with the omega-3 fatty acids (which have complementary lipid-modifying effects).
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