Vitamin B3

Vitamin B3, commonly known as niacin, is a water-soluble vitamin with critical roles in cellular energy production and metabolic regulation. The term "niacin" encompasses several related compounds: nicotinic acid (pyridine-3-carboxylic acid), nicotinamide (niacinamide), and nicotinamide riboside. Each form has distinct properties and clinical applications.

The primary biochemical function of niacin is as a precursor to nicotinamide adenine dinucleotide (NAD) and its phosphorylated form (NADP), coenzymes essential for over 400 enzymatic reactions in the body. These coenzymes participate in redox reactions, transferring electrons in metabolic pathways including glycolysis, the citric acid cycle, and fatty acid oxidation. Without adequate niacin, cells cannot efficiently generate ATP or maintain metabolic homeostasis.

Niacin's most distinctive clinical feature is the "niacin flush" - a prostaglandin-mediated vasodilation that causes skin reddening, warmth, and itching. This occurs primarily with nicotinic acid through activation of the GPR109A receptor on skin Langerhans cells, leading to prostaglandin D2 and E2 release. The flush is harmless but can be uncomfortable, prompting development of extended-release formulations and alternative forms like nicotinamide that don't cause flushing.

Historically, niacin deficiency causes pellagra, a condition characterized by the "3 Ds": dermatitis, diarrhea, and dementia. Pellagra was epidemic in the southern United States in the early 20th century until fortification of flour with niacin eliminated the disease. Today, deficiency is rare in developed countries but can occur with alcoholism, malabsorption syndromes, or certain medications.

Clinically, high-dose niacin (1-3 grams daily) has been used for decades to treat dyslipidemia. It effectively raises HDL cholesterol, lowers triglycerides, and shifts LDL particles to less atherogenic forms. However, large outcome trials (AIM-HIGH, HPS2-THRIVE) failed to show cardiovascular benefit when added to statin therapy, leading to reduced use. Niacin remains valuable for specific lipid disorders and in patients who cannot tolerate statins.

Emerging research explores nicotinamide riboside and other NAD precursors for their potential roles in longevity and metabolic health, though human clinical evidence remains preliminary.

Niacin's fundamental mechanism of action centers on its conversion to nicotinamide adenine dinucleotide (NAD+) and NAD phosphate (NADP+), the predominant coenzymes in cellular redox reactions. These dinucleotides accept and donate electrons in metabolic pathways, enabling the transfer of energy from food molecules to ATP synthesis.

NAD+ and NADP+ function as hydride (H-) acceptors, becoming NADH and NADPH respectively. NADH primarily participates in catabolic reactions, transferring electrons to the electron transport chain for ATP generation. NADPH serves primarily in anabolic reactions, providing reducing equivalents for fatty acid synthesis, cholesterol synthesis, and maintenance of glutathione in its reduced (antioxidant) form. The ratio of NAD+/NADH serves as a cellular redox sensor, influencing metabolic pathways and gene expression.

The niacin flush occurs through a distinct mechanism involving the G protein-coupled receptor GPR109A (also called HM74A or PUMA-G), highly expressed on dermal Langerhans cells and keratinocytes. Nicotinic acid binding activates this receptor, triggering intracellular signaling cascades that activate phospholipase A2 and cyclooxygenase, leading to synthesis and release of prostaglandins D2 and E2. These prostaglandins bind to DP1 and EP2/EP4 receptors on dermal capillaries, causing vasodilation, increased blood flow, and the characteristic flush response. This mechanism is unique to nicotinic acid; nicotinamide does not bind GPR109A and therefore doesn't cause flushing.

Niacin's lipid-modifying effects involve multiple mechanisms. It inhibits hepatic synthesis of VLDL (very low-density lipoprotein), the precursor to LDL, through uncertain mechanisms possibly involving reduced fatty acid mobilization from adipose tissue. HDL elevation occurs through reduced hepatic clearance of apoA-I, the main HDL protein, leading to increased HDL particle half-life. Niacin also increases lipoprotein lipase activity, enhancing triglyceride clearance.

Beyond its role in energy metabolism, NAD+ serves as a substrate for several enzyme families including sirtuins (SIRT1-7), poly(ADP-ribose) polymerases (PARPs), and CD38. These enzymes use NAD+ to modify proteins, influencing DNA repair, gene expression, inflammation, and cellular aging. Declining NAD+ levels with age have prompted interest in NAD+ precursor supplementation for longevity, though clinical evidence is preliminary.

Absorption of niacin occurs efficiently in the stomach and upper small intestine through both facilitated diffusion and sodium-dependent active transport. Nicotinic acid and nicotinamide are both well-absorbed (85-90% bioavailability). Niacin is distributed to all tissues, with highest concentrations in the liver. Excess niacin is methylated and excreted in urine, with unmetabolized niacin also appearing in urine at high doses.

Niacin is widely distributed in foods. The richest sources include meat, poultry, fish, fortified grains, and peanuts. Tryptophan, an amino acid found in protein foods, can be converted to niacin in the body (approximately 60 mg tryptophan = 1 mg niacin), contributing to total niacin equivalents (NE).

Niacin deficiency causes pellagra, historically common in populations dependent on corn-based diets (low in both niacin and tryptophan). The condition affects skin, gastrointestinal tract, and nervous system. Untreated pellagra can be fatal. Modern cases occur primarily with alcoholism, malabsorption, Hartnup disease, or carcinoid syndrome.

Niacin requirements are expressed as niacin equivalents (NE), accounting for both preformed niacin and tryptophan conversion (60 mg tryptophan = 1 mg NE). Requirements are based on urinary excretion of niacin metabolites and prevention of deficiency symptoms.

Niacin supplements come in several forms with distinct properties. Nicotinic acid provides lipid benefits but causes flushing. Nicotinamide (niacinamide) does not cause flushing or lower lipids significantly. Nicotinamide riboside is a newer form marketed for NAD+ boosting. Extended-release formulations reduce flushing but increase hepatotoxicity risk.