Vitamin B3 (niacin, nicotinic acid, nicotinamide, and the NAD and NADP cofactors) is the water-soluble vitamin that is the precursor of the NAD and NADP cofactors — the two most important electron carriers in the cell, which are required for all oxidation-reduction reactions in the central metabolic pathways, including the glycolysis, the TCA cycle, the beta-oxidation of the fatty acids, the electron transport chain, the cytochrome P450 detoxification reactions, the DNA repair, and the signalling pathways that regulate the gene expression, the cell death, and the stress response. The NAD is the primary electron carrier that is used in the catabolic reactions (the oxidation reactions that generate the ATP from the energy nutrients) — it accepts the electrons from the glycolysis, the TCA cycle, and the beta-oxidation (forming the NADH) and delivers them to the electron transport chain for the oxidative phosphorylation. The NADP is the primary electron carrier that is used in the anabolic reactions (the reductive biosynthesis reactions) — it provides the reducing equivalents for the fatty acid synthesis, for the cholesterol synthesis, for the nucleotide synthesis, and for the glutathione reduction. Without adequate niacin and functional NAD/NADP pools, all oxidation-reduction reactions in the cell are impaired, the ATP synthesis is compromised, and the energy failure develops — producing the pellagra, the dementia, and the death that are the hallmark of the severe niacin deficiency. The typical dietary niacin intake is 15-30mg daily (from the meat, the fish, the poultry, the fortified cereals, and the legumes), and the RDA is 16mg daily for men and 14mg daily for women — but the niacin requirement is dramatically increased in people with the alcoholism, with the carcinoid syndrome, and with the Hartnup disease (an inherited disorder of the tryptophan absorption that impairs the endogenous synthesis of the niacin from the tryptophan).
NAD and the Oxidation-Reduction Reactions
The NAD (nicotinamide adenine dinucleotide) is the central electron carrier in all living cells — it exists in two forms, the oxidised NAD+ and the reduced NADH, and it shuttles between these two forms as it accepts the electrons from the catabolic reactions and delivers them to the anabolic reactions or to the electron transport chain. The NAD+ is reduced to the NADH during the oxidation of the energy nutrients (the glycolysis, the TCA cycle, and the beta-oxidation), and the NADH is oxidised back to the NAD+ in the electron transport chain (where the electrons are transferred to the oxygen, generating the ATP by oxidative phosphorylation). This NAD+/NADH shuttle is the primary mechanism by which the cell couples the catabolism of the energy nutrients to the synthesis of the ATP — without the NAD+/NADH shuttle, the catabolic reactions cannot proceed (because the NAD+ that is required for the oxidation reactions would be depleted), and the ATP synthesis would stop. The NAD+ is also the substrate for the PARP enzymes (poly-ADP-ribose polymerases) and for the sirtuins (NAD+-dependent deacetylases) — the PARP enzymes are involved in the DNA repair and the genomic stability, and the sirtuins are involved in the regulation of the gene expression, of the metabolic rate, and of the longevity.
The clinical importance of the niacin for the NAD metabolism is underscored by the observation that the niacin supplementation improves the lipid profile and reduces the cardiovascular risk in people with the dyslipidaemia. The niacin supplementation (at 1-3g daily of nicotinic acid) is one of the most effective interventions for raising the HDL cholesterol (by 15-30%), for lowering the LDL cholesterol (by 5-10%), for lowering the triglycerides (by 20-50%), and for lowering the lipoprotein(a) (by 15-30%) — making it one of the most comprehensive lipid-modifying interventions available, with an efficacy that is superior to the statins for the HDL raising and the triglyceride lowering. The mechanism of these lipid-modifying effects involves the inhibition of the hepatic diacylglycerol acyltransferase 2 (DGAT2) and of the hepatocyte VLDL secretion, and the activation of the GPR109A receptor in the adipose tissue (which reduces the free fatty acid release and thereby reduces the hepatic VLDL triglyceride synthesis).
Niacin and the Pellagra
The pellagra is the classic clinical syndrome of the niacin deficiency — it is characterised by the triad of the dermatitis, the diarrhoea, and the dementia (the “3 Ds”), and by the fourth D of the death (if left untreated). The pellagra is caused by the severe niacin deficiency and/or by the deficiency of the tryptophan (the amino acid precursor of the niacin). The pellagra was endemic in the southern United States and in other parts of the world where the corn (maize) was the dietary staple — because the corn is very low in niacin and in tryptophan, and because the niacin in the corn is bound in a form that is not bioavailable. The pellagra was a major public health problem in the early 20th century (with over 100,000 cases and 10,000 deaths per year in the United States alone in the 1920s), until the niacin fortification of the flour was introduced in the 1940s and the pellagra was virtually eliminated in the developed world. The pellagra still occurs in the developing world and in people with the alcoholism, with the malabsorption, and with the Hartnup disease — and it remains a reminder of the devastating effects of the niacin deficiency on the human health.
Practical Application
For general niacin supplementation for the NAD metabolism and for the lipid profile improvement, the evidence-based approach is to supplement with 500-2000mg of niacin daily (as nicotinic acid or as inositol hexanicotinate, the flush-free form). The nicotinic acid form is preferred for the lipid profile improvement (because it has the most potent lipid-modifying effects), and the inositol hexanicotinate form is preferred for the NAD metabolism support (because it is gentle on the liver and does not cause the flushing). The niacin at high doses (above 1000mg daily) should be used under the supervision of a healthcare professional, because it can cause the liver toxicity, the glucose intolerance, and the gastrointestinal symptoms. The RDA of niacin is 16mg daily for men and 14mg daily for women, and the tolerable upper intake level is 35mg daily for adults (above which the niacin can cause the flushing, the pruritus, and the gastrointestinal symptoms). For comprehensive NAD support and lipid management, niacin pairs well with the vitamin B1 (which is required for the NAD synthesis from the tryptophan), with the vitamin B2 (which is required for the FAD synthesis and for the mitochondrial function), with the vitamin B6 (which is required for the tryptophan-to-niacin conversion pathway), and with the chromium (which has complementary effects on the lipid profile and which works synergistically with niacin for the improvement of the HDL and the triglycerides).
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