Vitamin B3 consists of two molecules, nicotinamide and nicotinic acid (shown below) and sometimes collectively termed "niacin" (although this term is also used to refer to nicotinic acid exclusively), which, along with the amino acid tryptophan, are ultimately converted to nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate, coenzymes which transfers hydrides and which are essential for many chemical reactions in the cell.
The recommended daily allowance of niacin is 16mg daily in adult men and 14mg daily in adult women, which can easily be obtained from a normal diet, since vitamin B3 and other "niacin equivalents" (molecules that can ultimately be converted to NAD or NAPH) can be found in all animal, plant, and fungal food sources due to its ubiquity in the fundamental biochemistry of most species. However, niacin is most abundant in meat, eggs, fish, dairy products, certain vegetables, and whole wheat. An additional, recently-discovered niacin equivalent known as nicotinamide riboside can be found in cow's milk.
Vitamin B3 is also available in supplements and pharmaceuticals, as discussed in the "Formulations and Variants" section below.
Vitamin B3 is an essential vitamin which is a precursor for molecules which play a critical role in REDOX reactions of a cell, and can ultimately exert antioxidative effects or metabolic effects as an enzymatic cofactor. It exists in two main forms: nicotinamide and nicotinic acid. Regardless of the form ingested, vitamin B3 is eventually converted in the body into the nucleotide known as nicotinamide adenine dinucleotide (NAD) which exists in both oxidized (NAD+) and reduced (NADH) forms; the two together constitute a REDOX couplet. NAD+ can also be phosphorylated to form NADP+ which can be reduced to NADPH. NADH and NADPH act as cofactors for many antioxidative enzymes in the cell (glutathione reductase, catalase, and superoxide dismutase) and provide reducing equivalents for them, and in the process once again form NAD+ and NADP+, respectively.
NADH and NADPH also play a role in REDOX reactions with ADP-ribose, which conributes to many regulatory changes throughout the cell, from calcium channel regulation to endocrine signalling changes and regulation of apoptosis.
Vitamin B3 is converted to NADH and NADPH, which is used by many antioxidant enzymes in the cell to perform REDOX chemistry. Vitamin B3 can interact with a variety of enzymes as a cofactor altering their actions.
Biosynthesis of biologically active Vitamin B3 depends on converting the vitamin (niacin or nicotinamide) into the nicotinamide adenine dinucleotide (NAD+) after ingestion. This conversion involves different pathways for niacin and niacinamide. Niacin first has a phosphoribose group added via the enzyme nicotinate phosphoribosyltransferase, forming nicotinate mononucleotide (NaMN), which is then adenylated by mononucleotide adenylyltransferase to form nicotinate adenine dinucleotide (NaAD) which is finally amidated to form NAD+. Nicotinamide requires one fewer step, being having a phosphoribosyl group added to it by nicotinamide phosphoribosyltransferase followed by adenylation by mononucleotide adenylyltransferase to form NAD+. NAD+ then has the potential to get phosphorylated into NADP+ in peroxisomes or the mitochondria.
In instances when the human diet does not contain sufficient vitamin B3, humans can synthesize NaMN from L-tryptophan at a rate of about 1mg Vitamin B3 per 67mg L-tryptophan ingested making the deficiency syndrome (pellagra) able to be partially remedied by sufficient protein intake.
The biologically active forms of vitamin B3 can be 'recycled' in human cells, as the nicotinamide formed from the turnover of NAD+ can be converted by the enzyme nicotinamide phosphoribosyltransferase (NAMPT aka. visfatin) to reform nicotinamide mononucleotide which can then be converted back into NAD+.
Precursors to biologically active Vitamin B3 become activated when they are bound to a sugar (ribose) and then further modified in the body. In instances of low dietary B3 intake, the amino acid L-tryptophan can be used in place to form Vitamin B3.
Niacin (nicotinic acid) is the main form of Vitamin B3 supplementation, and is often sold as immediate release (IR) niacin which is rapidly digested and absorbed and associated with flushing as a side effect, but niacin also comes in sustained release (SR) forms in which the niacin is released over long periods of time but has also been linked to liver harm. Pharmaceutical tablets which are extended release (ER) exist and have intermediate release rate known as extended release (ER); 'Niaspan' is a brand name for ER niacin, made to improve complaince by reducing flushing which is associated with high peak levels of niacin in the blood while also reducing the potential of liver injury.
Niacin is the primary form of Vitamin B3 used in supplementation. It comes in 3 formulaitons: immediate release (which can cause flushing), sustained release (which has been associated with liver injury), and extended release which seems to be the most well-tolerated of the 3 formulations.
Niacinamide (synonymous with nicotinamide) is not associated with the 'flush' from niacin, since niacin causes the flush by acting on the HM74A receptor, the receptor also associated with its lipid-lowering effects, and niacinamide does not have potent affinity towards this receptor.
Nicotinamide is an amine form of niacin that, while it confers some biological effects, is not associated with either the flush nor the standard cholesterol reduction of niacin.
Nicotinamide riboside is a nucleoside composed of niacinamide and ribose, and appears to be able to increase total NAD concentrations following oral ingestion in animals; it is found in trace amounts in some food products such as whey protein and in baker's yeast. Nicotinamide riboside can also be synthesized in vitro.
Nicotinamide riboside is a relatively new form of Vitamin B3 supplementation that appears to be active following oral ingestion in animals. It may not be associated with a flushing effect due to containing nicotinamide rather than niacin.
Another alternate form is known as inositol hexanicotinate (IHN); Inositol forms the backbone of this molecule, and six niacin molecules are connected to it via carboxylic bonds. It is known to be absorbed from the intestines with approximately 70% bioavailability. It seems to be absorbed intact and then metabolized afterwards to release niacin. An increase in serum niacin has been noted in humans given IHN within 6-12 hours, versus the rapid absorption of free-form niacin that occurs within an hour, but the overall level of niacin release seems insufficient for both the flush and cholesterol reduction. However, it appears to have a some biological effects such as reduction of fibrinogen, improved vasodilation and blood viscosity, and improved oxygen transport.Where 1,000mg niacin results in serum levels of 30µg/mL, the same dose of IHN (conferring 910mg niacin) results in peak plasma levels of 200ng/mL (0.2µg/mL) and elsewhere 2,400mg IHN resulted in serum niacin reaching 0.1µg/mL.
While supplemental inositol hexanicotinate appears to be bioactive following oral supplementation, it does not appear to release enough niacin to exert either a flushing effect or a cholesterol-reducing effect.
Niacin appears to have a few receptors that it can act upon known as nicotinic acid receptors. The main one being designated GRP109A (alternatively named PUMA-G in mice and HM74A in humans) and is a G-protein coupled receptor coupled to Gi. There are two subsets of this receptor, in humans the high affinity subset (HM74A or GRP109A, or HM74b in one report) responds to niacin whereas the low affinity subset (HM74 or GRP109B) does not up to 1mM.
These receptors are primarily located on adipocytes and splenocytes and have also been located on macrophages. Activation of receptors stimulates prostanoid release, which explains the flushing reaction seen with niacin. Other endogneous ligands for this receptor include the short chain fatty acid butyrate and the ketone body β-hydroxybutyrate, while drugs that target it include Acifran and Acipimox and various low-weight phenolic compounds in the diet have also shown affinity.
A receptor known as HM74A is a niacin receptor, and is found in adipocytes and spleen cells. Activation of this receptor causes a few effects thought to be unique to niacin supplements such as the niacin flush, and the lack of affinity of nicotinamide towards this receptor explains its lack of flushing.
Secondary to acting on its receptor, HM74A, niacin induces release prostaglandin D2 (PGD2) via β-Arrestin1 in epidermal cells known as Langerhans. This effect occurs fairly rapidly following oral ingestion of 500mg of niacin in subjects who experience the flush, as assessed by serum levels of its metabolite 9α, 11β-PGF2. As production of prostaglandins requires the activity of cyclooxygenase (COX) enzymes, production of prostaglandins from niacin can be partially reduced with COX inhibitors such as aspirin. The receptor that PGD2 acts upon (the DP1 receptor) can also be blocked which is the mechanism of the pharmaceutical laropiprant, commonly prescribed alongside niacin to improve adherence.
Niacin increases concentrations of the prostaglandin PGD2 in the blood by activating HM74A, which in turn activates the PGD2 receptor and can lead to flushing. Drugs that block cycloocygenase or the DP1 receptor can mitigate this effect.
The ATP-binding cassette transporter A1, more commonly referred to by the acronym ABCA1, is a membrane protein that plays a major role in the manufacture of serum high density lipoprotein (HDL). Its transcription is increased in response to niacin incubation in liver cells through the DR4 regulatory element which binds the LXRα transcription factor; LXRα itself and LXRβ do not have their expression affected by niacin.
It is possible (but not yet confirmed) that niacin's effects on ABCA1 in liver cells are mediated through the niacin receptor HM74A, as HM74A is known to be coupled to PPARγ expression and induction of its endogenous ligand in macrophages and in adipocytes a pathway extending from PPARγ to ABCA1 via LXRα exists. The macrophage study did note that niacin's effect on PPARγ depends on prostaglandin synthesis via HM74A, acting via phospholipase A2 and COX1.
Niacin increases levels of the membrane protein known as ABCA1, which plays a significant role in HDL formation.
Increased activity of ABCA1 from niacin has been shown in vitro to increase the 'lipidation' of apolipoprotein AI (ApoAI) or the incorporation of cholesterol and phospholipids into the ApoAI structure, leading to increased lipid efflux from the cell. This increased efflux is due to an increase in ABCA1 activity in general, and is not limited to increases induced by niacin. ApoAI is a major constituent of HDL cholesterol (and strongly predictive of cardiovascular disease mortality) and the lipidation process is a major step in HDL's synthesis, so increasing the lipidation of ApoAI via increasing ABCA1 activity ultimately results in an increase in serum HDL cholesterol levels. Niacin does not seem to affect the synthesis of ApoAI itself, however, nor does it seem to increase the synthesis rates of phospholipids or cholesterol in liver cells.
The ability of niacin to suppress vLDL synthesis acutely may also be related to this mechanism, since, while it has not directly been demonstrated with niacin, activation of ABCA1 is known to reduce vLDL secretion rates.
Niacin appears to increase the activity of ABCA1, which results in more lipid efflux from the liver, This mechanism may underlie both an increase in HDL synthesis (by increasing apolipoprotein AI lipidation) and may reduce triglycerides by reducing vLDL secretion.
These effects on ApoAI have been confirmed clinically; an increase in ApoAI-containing lipids in the blood of subjects has been confirmed with niacin supplementation, although this was in subjects with low HDL-C at the start of the study.
Niacin supplementation has been observed to increase serum levels of ApoAI as expected based on its mechanism of action.
The enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is located within a cell's nucleus and, by taking free NAD+ and converting it into ADP-ribose, donates said ADP-ribose to various nuclear transcription factors to help them function properly in a process known as ADP-ribosylation; inhibition of PARP-1 would reduce the activitiy of the transcription factors dependent on it while providing more NAD+ without influencing PARP-1 may increase their activity.
PARP-1 is mostly known to have a role in DNA repair, and its inhibition can sensitize cancer cells to anti-cancer therapies. Targets of PARP-1 for ADP-ribosylation include NF-kB (in a process mediated by CREB-binding protein) and PARP-1 itself as it autoregulates its own function via ADP-ribosylation.
Other proteins interact with PARP-1 not necessarily because they require ADP-ribose, but in situations where NAD+ dwindles; PARP-1 physically interacts with the protein nicotinamide mononucleotide adenylyltransferase 1 (NMNAT-1) to help stimulate local NAD+ production and increases PARP-1 activity in an NAD+-indepenndent manner. PARP-1 also interacts indirectly with sirtuin 1 (SIRT1), a protein that regulates energy balance in the cell, through having a shared NAD+ pool whose levels SIRT1 activity is sensitive to; inhibiting PARP-1 will increase SIRT1 activity.
PARP-1 is a central protein in a cells nucleus which facilitates the action of other proteins, usually those involved in cellular survival, by donating poly-ADP-ribose to them so they can work optimally. This molecule is made from NAD+, which is made from Vitamin B3, and the activity of this protein relies predominately on NAD+ availability.
PARP-1 is regulated by nicotinamide status in a cell, as while niacin provides the NAD+ required for the enzyme to work, nicotinamide (an indirect source of NAD+ via NMNAT enzymes) can inhibit the enzyme in vitro, although whether this effect would be seen in vivo has been questioned.
Nicotinamide is a PARP-1 inhibitor in vitro, but perhaps not in vivo.
Niacin is known to be absorbed from the small intestine fairly rapidly (within 5-20 minutes).
Inositol hexanicotinate (INH), often marketed as "no flush" niacin, tends to be absorbed from in the intestines with an average absorption of 70% (although the absorption is quite variable around the average).
A standard pharmaceutical dose of 1-3g niacin supplementation tends to result in a serum concentration of 100-500µM as a general statement, where the relationship is dose-dependent with 2g resulting in a serum level of approximately 300µM. Peak serum concentrations are reached in 0.5-1 hours after a single dose.
INH, however, reaches much lower peak serum concentrations for a given dose of niacin; 1000mg of INH (delivering about 910mg of niacin) only reaches a peak serum concentration of approximately 2µM. Niacin reaches its peak concentration in the serum when delivered via INH in about 6-12 hours.
Niacin is heavily metabolized by the liver upon absorption in one of two ways: either it is conjugated with glycine (and these metabolites contribute to flushing) or it is amidated to form nicotinamide.
Nicotinamide can be converted into the metabolite 1-methylnicotinamide (MNA) via the enzyme nicotinamide N-methyltransferase in the liver, a metabolic intermediate known to be bioactive orally and topically, and can further be metabolized into 1-methyl-2-pyridone-5-carboxamide (M2PY) or 1-methyl-4-pyridone-5-carboxamide (M4PY) via the enzyme aldehyde oxidase. An alternate metabolic pathway for nicotinamide involves its conversion into nicotinamide N-oxide (N-OX).
When INH is administered, it appears to be absorbed intact, and its rate of hydrolysis to release free niacin into the blood stream is very low, which may account for the relatively low peak niacin concentrations found with INH supplementation.
Approximately 75% of niacin is eliminated through the urine after 96 hours either as unmodified niacin or one of its metabolites.
All three metabolites of nicotinamide, either N-OX or the two products of 1-methylnicotinamide (M2PY and M4PY) can be found in human urine.
In rats, administration of 20-80mg/kg extended release niacin two hours after a stroke (MCAO induced) appears to be help preserve functional measures, while 40mg/kg exclusively reduced infarct size and was associated with higher VEGF and less TNF-α (VEGF being neuroprotective via activating PI3K/Akt). Elsewhere, 40mg/kg niacin has been noted to increase angiogenesis after stroke in rats (angiogenesis also being associated with increased VEGF activity).
Examining the stroke risk of type I diabetic animal models is also useful, as diabetes is associated with an increased risk of stroke and poorer recovery after stroke. When given 24 hours after a stroke and then daily for 28 days in type I diabetic rats, niacin at 40mg/kg has also been associated with improved rates of vascular and axonal remodeling.
It appears that niacin given shortly after a stroke has a protective effect in rats, whereas prolonged niacin supplementation after a stroke is induced in rats may confer some beneficial rehabilitative effects.
Niacin's impact on stroke in human trials, however, is less clear than the positive results found in the animal studies above. An early trial examining 3g niacin in men who have experienced a previous MI found a decrease in stroke risk. One landmark trial, with the acronym AIM-HIGH, tested whether extended-release niacin (up to 2000mg daily) added to simvastatin therapy had any additional cardiovascular benefits in patients with established cardiovascular disease and low HDL with high triglycerides. The study was stopped earlier than planned due to clear failure in the primary outcome being studied, as well as a concern that the addition of niacin may have led to an elevated ischemic stroke risk. Additional analysis revealed that there was a borderline significant increase in stroke (the 95% CI of the hazard ratio being 1.00-3.17; P=0.050), although multivariate analysis found that niacin was a statistically insignificant factor in this elevated risk; nevertheless, niacin had no benefit in this population with regard to stroke.
In addition, meta-analyses of the evidence to date found a lack of evidence in niacin's effect on stroke, with an overall odds ratio (OR) of 0.88 (95% CI: 0.5-1.54), although removal of the AIM-HIGH results from the meta-analysis did indeed result in a significant decrease in stroke risk (OR 95% CI 0.58-0.92). A more recent meta-analysis also found no overall risk of stroke (OR 95% 0.75-1.22), although in the subgroup of studies where the patients were not treated with a statin a borderline significant decrease in the odds of a stroke was found (OR 95% CI 0.61-1.00, P=0.05).
Human evidence, while not completely clear, suggests that niacin alone may lower the risk of stroke in people not currently on a statin, but niacin does not seem to give additional benefit to those already on a statin.
The damage and cell death of human endothelial cells by oxidized LDL, considered a necessary step in the development of atherosclerosis, is reduced by 250-1,000µM niacin in vitro, through reducing pro-inflammation signalling molecules including NF-kB p65 and notch1. while macrophages also secrete less inflammatory cytokines inherently via the same receptor in the range of 500-1,000µM through niacin's action on its receptor, GPR109A in mice (known as HM74A in humans).
Foam cells also are a known contributor to the early phase of atherosclerosis, and are formed when macrophages consume and contain excessive levels of cholesterol. Niacin helps reduce foam cell formation by inducing macrophage PPARγ transcription, which leads to two effects: increasing CD36 formation (a 'scavenger' receptor that senses and uptakes oxidized LDL, and is known to be upregulated by PPARγ) as well as upregulating ABCA1 (also under the control of PPARγ ) which exports the lipids from the cell to HDL particles, leading to an overall decrease in foam cell formation. Niacin may also decrease foam cell formation through another mechanism, as it seems to used by the enzyme CD38 to in the synthesis of the lysosomal signalling molecule NAADP which in turn upregulates cholesterol lysosomal efflux of cholesterol.
Another mechanism by which niacin may prevent atherosclerosis is at the level of differentiation and migration of macrophages; M1 and M2 macrophages are an adaptive balance, with atherosclerotic lesions tending to be formed by M1 macrophages, while M2 macrophages secrete antiinflammatory cytokines; The differentiation of macrophages into an M1 phenotype (induced by IFN-γ) appears to be reduced when niacin acts on its receptor on macrophages (at concentrations comparable to those used for cholesterol reduction) and their chemotaxis into atherosclerotic lesions induced by MCP-1 appears to be reduced.
In vitro studies suggest that niacin could in theory prevent the formation of atherosclerotic plaques by reducing inflammation and damage to the endothelial wall through several mechanisms.
Guinea pigs fed a high dietary level of niacin (100mg/kg diet) experienced less aortic inflammation and lipid deposition in the arterial wall and reductions in atherosclerosis have been noted in mice given niacin (0.3% of the diet; the dose for cholesterol improvement) in a manner dependent on niacin receptor binding but not necessarily through alterations in cholesterol levels.
Limited animal research has observed that dietary niacin, at concentrations comparable to what doses used to reduce cholesterol, reduces the deposition of plaque on the artery wall and delays atherosclerosis.
One placebo-controlled study in humans has found that 1000mg ER niacin daily for a year in patients also treated with a statin with low baseline HDL and established coronary heart disease saw a statistically insignificant trend toward slowing carotid intima-media thickness over placebo (P=0.08). Another study using 1500mg of ER niacin added to statin therapy in patients over 65 years of age with atherosclerosis also saw no additional improvement over placebo in reducing internal carotid artery wall volume after 18 months of treatment, although improvement was indeed seen in both groups. However, a smaller study using a higher dose (2g) of niacin over 1 year in patients treated with a statin with either type 2 diabetes and coronary heart disease or carotid or peripheral atherosclerosis and low HDL did find a significant reduction in carotid artery wall volume over placebo.
Human evidence exists for niacin's effect on the progression of atherosclerosis, but mostly in patients who are already on a statin, with mixed results. Doses of 2g may have some effect in patients with established atherosclerosis when added to a statin, but the efficacy of lower doses is less clear.
One study of niacin supplementation assessing forearm blood flow failed to find an effect of up to 1g daily over the course of two weeks in otherwise healthy subjects, and 1,500mg extended release niacin in men with metabolic syndrome has failed to influence flow-mediated dialation (FMD). One study which failed to find a whole-group effect on patients of niacin on FMD in patients with coronary artery disease did find improvement in a subgroup with low HDL-C.
In subjects with low HDL-C, 1g of extended release niacin for one week has been noted to increase blood flow (via FMD) by 4.5%; this mechanism of effect was unrelated to prostaglandin, since laropiprant a (prostaglandin D2 inhibitor) failed to influence the effect. This effect also coincided with an increase in indirect (but not total) bilirubin by 62%. Since bile acid bilirubin is an endothelial antioxidant, and as the benefits of niacin on endothelial function in this study were thought to be nitric oxide dependent, it was hypothesized that a preserving effect of bilirubin on nitric oxide bioavailability underlied the observed benefit. Both the increase in bilirubin and improvement in blood flow dissipated a week after niacin cessation.
Subjects who previously suffered a myocardial infarction given niacin (w/ laropiprant) have also noted an increase in nitric oxide-dependent blood flow (FMD) after twelve weeks of therapy alongside an improvement in nitroglycerin-induced vasodilation, both of which were not correlated with changes in triglycerides. Similar improvements in blood flow have been noted in HIV-infected patients with low HDL-C treated with niacin alone.l
There may be an improvement in blood flow associated with niacin supplementation that, while moderate in size, is dependent on both continued supplementation and may only affect subjects with initially low HDL-C levels in serum.
Niacin is known to influence blood vessel diameter, most notably in the flush reaction from niacin which is due to cutaneous vasodilation (widening of vessels in the skin), which has led to hypotheses that it could influence blood pressure via increasing the width of arteries and veins. However, one review has noted that a possible blood pressure reducing effect of niacin is independent of the prostaglandin that mediates flushing known as PGD2.
Infusions of niacin have been noted to acutely reduce blood pressure in hypertensives with no effect in subjects with normal blood pressure, and was associated with increased cardiac output and heart rate which was similar in both groups. Another study confirmed this finding, discovering that 24-hour ambulatory blood pressure does not appear to be affected by up to 1g niacin supplementation over two weeks in otherwise healthy subjects.
In terms of chronic niacin's effects on blood pressure, a review that assessed trials that measured blood pressure usually in hypertensives did not notice any statistically significant long-term blood pressure reduction associated with niacin supplementation, although these studies methodologies for measuring blood pressure changes were not ideal according to the review authors. However, the review noted that in one large study (the Coronary Drug Project), which initially failed to find any influence of niacin therapy on blood pressure, found through a post-hoc analysis on only those with metabolic syndrome a mild 2.2mmHg reduction in systolic blood pressure with a moderate 2.9mmHg reduction in diastolic pressure. A post-hoc analysis of another clinical trial found that systolic blood pressure was lowered by 2.2mmHg and systolic presure by 2.7 compared to placebo in dyslipidemic patients over 24 weeks.
Niacin appears to be able to lower blood pressure in the short term in hypertensives, although its long-term blood pressure effects are less clear; some evidence leans toward its ability to lower blood pressure modestly in those with dyslipidemia.
Niacin seems to lower triglycerides in the blood by inhibiting both the synthesis of fatty acids as well as their esterfication to form triglycerides in the liver, which incidentally increases the rate of apolipoprotein B degradation while reducing its secretion from liver cells. One mechanism by which niacin does this is through the direct and noncompetitive inhibition of diacylglycerol acyltransferase 2 (DGAT2), the final enzyme in triglyceride synthesis in liver cells, with no inhibition on DGAT1
The effects of niacin on triglyceride synthesis have been seen to affect very low density lipoprotein (vLDL-C) serum levels, where niacin therapy over 16 weeks in subjects with non-alcoholic fatty liver disease (NAFLD) appears to reduce vLDL-C in serum as well as the complexes with triglycerides (vLDL-TG) and apolipoprotein B (vLDL-ApoB) compared to placebo and with a potency comparable to fenofibrate. Niacin does this by lowering hepatic secretion of vLDL-C, although this does not increase the amount of triglyceride in the liver even in the state of NAFLD.
In addition to its effects upon the liver, niacin can also suppress the release of free fatty acid from adipose tissue which would normally get reesterified as triglyceride in the liver and then secreted via vLDL. However, this specific mechanism, which is mediated by the HM74A receptor, does not appear to be relevant to the triglyceride reducing properties of niacin.
Niacin appears to reduce the synthesis of triglycerides in liver cells, which ultimately reduces serum vLDL and ApoB alongside serum triglycerides. The suppression of free fatty acid release from adipose may not play a relevant role in lowering serum triglycerides, however.
Benefits to triglycerides can occur within a week of supplementation of extended release niacin (1g), although to a minor degree of around 4%.
Supplementation of 1,500-2,000mg time-release niacin for two years with one year followup in people on statin therapy characterized by low HDL-C saw a reduction of triglycerides by 28.6% (statin alone by 8.1%).
Niacin seems to lower triglyceride levels.
There is a phenomena known as the 'fatty acid rebound' associated with niacin supplementation, as the initial action of niacin on it's receptor (HM74A) in adipose tissue can result in less lipolysis and less secretion of non-esterified fatty acids (NEFAs) into the blood and better adipose storage; this is a readily reversible phenomena as within a day of continual exposure there is a net increase in NEFA rather than suppression and alterations in NEFA may not reflect alterations in triglycerides.
Non-esterified fatty acids (NEFA, synonymous with _free fatty acids or FFA) are famously known to be influenced by niacin administration in what is known as a 'rebound' effect, and while this rebound is relevant to some effects of niacin it is mostly independent of the effects of niacin on triglycerides.
The very first mechanism thought to explain niacin's improvement of serum cholesterol profiles was through the reduction of non-esterified fatty acid (NEFA) release from tissue, which is no longer considered a likely mechanism as chronic niacin supplementation is associated with an increase in, rather than suppression of, NEFA while the HM74A receptor appears dispensible in terms of niacin's effects in mice while other ligands of HM74A (Acipimox and MK-0354) were either less effective or ineffective on cholesterol, respectively. It is currently believed that the influence of niacin on serum NEFA is not a major determinant in how it affects cholesterol levels in the body, with current theories reflecting around either its synthesis being increased or its catabolic rate being reduced.
Despite niacin's well-known effects on HDL improvement, there is only a rough grasp on the mechanisms for this effect. The idea that the niacin rebound effect is associated with its effects on cholesterol, however, appears to have fallen out of favor.
The first potential mechanism involves the synthesis of HDL-C in the liver by increasing transcription of the ABCA1 gene (which is dependent on LXRα binding to the DR4 promoter region of this gene). ABCA1 activity promotes the 'lipidation' of HDL's major protein known as apolipoprotein A-I (ApoAI) by increasing the rate it associates with phospholipids and cholesterol, a mandatory step in HDL-C synthesis which is increased by 500-1000µM of niacin in vitro. This mechanism has not been confirmed, as while ApoAI can be increased alongside rising HDL-C in subjects given niacin with low baseline HDL-C, LXRα seems to require a coactivator (PPARγ) to exert these effects, which is activated by the niacin receptor receptor. However, the activity of the niacin receptor has been found to not be required for its effects on cholesterol levels, suggesting that other mechanisms may be relevant.
The other theory pertaining to HDL synthesis from niacin is said to be dependent on cholesteryl ester transfer protein (CETP) despite the reduction in total cholesterol and triglycerides both not requiring this protein. CETP is a protein that facilitates transfer of lipids between different lipoproteins (generally donating a triglyceride from vLDL towards HDL and taking a cholesteryl ester in a process known as reverse cholesterol transport.) Niacin reduces the expression of CETP in the liver and its activity in the blood of mice; a reduction of CETP increases the amount of HDL-C in the blood as HDL/LDL catabolism rates reflect the activity of reverse cholesterol transport and rapidly reach equilibrium, and if CETP is reduced then more HDL would be required to normalized the rates of reverse cholesterol transport. This mechanism may also be related to LXRα, as while a heteromer of LXRα with the Vitamin A nuclear receptor (RXR) activates the DR4 element increases CETP niacin encourages heterodimerization of LXRα and PPARγ which still activates DR4, but in a way that promotes cholesterol efflux. This competitive heterodimerization has not yet been experimentally demonstrated, however, and the one study using 2,000mg niacin in humans failed to find an influence on serum CETP activity despite an increase in HDL.
The last potential mechanism for HDL involves not increasing its synthesis but rather preserving already-constructed HDL cholesterol enriched with apoAI, reducing the rate the lipoprotein is taken into the liver cell despite the donation of cholesterol from HDL towards the liver cell being unaltered due to reducing the expression of the receptor (ATP synthase beta chain) which would normally drag HDL into the cell. This hypothesis works better with observations suggesting that reduced catabolism of HDL is the prime determinant of its higher levels, and also affects apoA1 as its clearance from the blood and uptake by the kidneys are reduced.
Current theories surround how niacin drastically improves HDL levels in the blood circulate either around improving its synthesis by one of two different mechanisms or otherwise preventing HDL from being taken up by the liver (allowing it to stay in the blood and eventually build up).
One week supplementation of extended release niacin (1g) in subjects with low HDL-C does not appear to be long enough to appreciably increase total HDL-C levels, although a reduction in average particle size was noted; the changes in HDL-C may mediate an improvement in nitric oxide-dependent vasodilation, although an increase in indirect bilirubin was also noted.
Prolonged supplementation in diabetics is associated with an increase in the amount of the largest particle size of HDL-C (32.7%) whereas the particles smallest in size are decreased (8.2%).
The increase in HDL appears to take a few weeks to reach peak efficacy, and the subsets of HDL cholesterol appear to be influenced by niacin supplementation.
Niacin has been noted to confer a protective effect on cardiovascular mortality as one meta-analysis noted that in trials of subjects with coronary artery disease that niacin therapy was associated with less risk for coronary artery revascularization (RR of 0.31; 95% CI of 0.15-0.63), nonfatal myocardial infarction (RR of 0.72; 95% CI of 0.60-0.86) and transient ischemic attack (RR of 0.76; 95% CI of 0.61-0.94) while the reduction in overall mortality failed to reach statistical significance (RR 0.883; 95% CI of 0.773-1.008). The seven studies included in this meta-analysis (and one followup) totalled 5137 patients also using various pharmaceuticals of the statin and fibrate class.
In subjects on statin therapy with low HDL cholesterol one trial noted that 1,500-2,000mg of time-release niacin was able to provide additive benefits in improving HDL-C (20%) and reducing LDL-C (17%) relative to placebo, although in regard to the predetermined clinical endpoint (death or hospitalization) both niacin and placebo had an equal amount of responders. This study noted a high percentage of patients with metabolic syndrome (80%) and comments have suggested that due to a possible ability of time-release niacin to deteriorate insulin resistance that its benefits may be offset by this side-effect, while the study itself suggested that the benefits of statins displaced the benefits of niacin.
While an earlier study using high doses of immediate release niacin (3,000mg) found a reduction in death by 14% relative to placebo alongside reductions in total cholesterol, it was noted that this reduction is similar in magnitude to studies combining statins with placebos.
The addition of niacin therapy to statins appears to provide additive effects on biomarkers of cardiovascular health without actually reducing the risk of cardiovascular incidents.
Prolonged niacin intake was noted some time ago to decrease insulin sensitivity, causing a compensatory increase in insulin output by pancreatic β-cells to maintain blood glucose levels. Niacin does not appear to have any direct effects on pancreatic β-cells, however, as perfusion of isolated rat islets with niacin in vitro failed to affect insulin secretion. This indicates that niacin increases insulin output by an indirect mechanism, secondary to causing peripheral insulin resistance. Supplementation has been noted to induce insulin resistance at doses ranging from 500-1,000mg, which is within the range that confers cholesterol-reducing effects.
Notably, chronic niacin supplementation appears to be required to increase insulin output, as acute supplementation has been shown in one study to reduce insulin levels in otherwise healthy subjects before rebounding after one day, while other acute studies have noted little to no effect on insulin levels.
The effects of chronic niacin supplementation on insulin levels may also be population-dependent. Niacin has been noted to cause hyperinsulinemia in otherwise healthy aging subjects (1,000mg/day) and has been shown to nearly double insulin levels in subjects with NAFLD (2,000mg/day). In patients with metabolic syndrome, 6 weeks niacin supplementation at 1,500 mg/day increased insulin levels by 30%.
Fasting insulin concentrations appear to be increased with chronic niacin supplementation. The degree to which this occurs seems to inversely correspond to glucose tolerance at baseline. Thus, niacin supplementation could be problematic in those with severely impaired glucose tolerance.
In obese subjects with nonalcoholic fatty liver disease (NAFLD), supplementation of time-release niacin (titrated up to 2,000mg) daily for 16 weeks appeared to increase the state of insulin resistance in the liver, muscle, and adipose with an inhibitory effect on the actions of insulin in the liver being noted in nondiabetic men with dyslipidemia.
In adult men with metabolic syndrome, 1,500mg extended release niacin has been noted to significantly hinder insulin sensitivity as assessed by HOMA-IR (42%), which was associated with an increase in serum insulin despite an increase in serum adiponectin. This has been noted elsewhere, (22% increase in HOMA-IR), where aspirin taken alongside niacin did not prevent decreased insulin sensitivity.
This effect may persist in otherwise healthy subjects, as subjects given up to 1g niacin for two weeks who are then given a hyperinsulinaemic-euglycaemic clamp require less glucose to maintain homeostasis, which is indicative of reduced glucose uptake (via increased insulin resistance insulin).
Niacin appears to promote insulin resistance in most, if not all, subjects who take more than a gram daily for weeks at a time. This insulin resistance is initially associated with an increase in fasting glucose due to decreased disposal rates (the speed at which glucose is moved from the blood to tissues), with later increases in fasting insulin levels.
Niacin-induced insulin resistance was initially attributed to a rebound effect in adipose tissue where increased non-esterified fatty acids (NEFA) release from niacin impairs the effects of insulin signaling This is plausible, as insulin resistance can be induced with 24-hour NEFA infusion in rodents. Other sources suggest that insulin resistance is not associated with the NEFA rebound, however, since subjects with NAFLD who experience insulin resistance from niacin therapy do not necessarily have increased serum NEFA..
Another possible option is that niacin can noncompetitively inhibit the enzyme known as diacylglycerol acyltransferase 2 (DGAT2) with an IC50 of 100µM (similar potency to about 300µM). Inhibition of this enzyme does not per se cause insulin resistance with niacin, but because DGAT catalyzes the first stage of triglyceride synthesis, its inhibition can promote accumulation of diacylglycerol (DAG) which is the molecule thought to partially explain the insulin resistance from niacin. Since increased DAG in liver cells suppresses insulin signaling, niacin-mediated inhibition of DGAT2 causes insulin resistance, thereby hindering the ability of insulin to suppress glucose synthesis and indirectly promoting a state of hyperglycemia.
Both an increase in serum NEFA as well as a buildup of lipid signaling molecules in the liver are possible explanations for for niacin-mediated insulin resistance.
Although chronic, high-dose niacin supplementation decreases insulin sensitivity, this is not associated with changes in fasting glucose levels. This can be explained by a compensatory increase in insulin production that counteracts the insulin resistance, leaving blood glucose levels essentially unchanged.
Activation of the niacin receptor (HM74A) by some other agonists appears to quickly reduce serum glucose in diabetics while improving insulin sensitivity or otherwise improving glucose disposal rates. This indicates that the niacin receptor itself may have beneficial effects on glucose metabolism, and that niacin-induced insulin resistance does not occur via HM74A activation.
Although chronic high-dose, niacin supplementation decreases insulin sensitivity, compensatory increases in insulin levels leaves blood glucose levels essentially unchanged in healthy individuals.
When looking at skeletal muscle, niacin therapy has been shown to induce insulin resistance in this tissue in obese subjects with NAFLD (2,000mg daily over the course of 16 weeks). One study in fasted rats (fasting increases plasma non-esterified fatty acids (NEFA) similar niacin administration and decreases skeletal muscle glycogen) where 20mg/kg niacin was administered acutely noted that glycogen in the soleus was reduced while the gastrocnemius and liver were unaffected.
Although niacin decreases insulin sensitivity, a limited number of studies suggests that changes in glycogen levels may be tissue-specific. More work is needed to clarify the effects of niacin on muscle glycogen levels in healthy human subjects.
When the process of glycation is tested in vitro, niacin possessed only minor inhibitory effects on the glycation of bovine serum albumin from a known glycating agent (methylglycoxal) despite other tested antioxidants like Zinc (10-25µg/mL) having more potent benefits.
Importantly, any effects of niacin on glycation in vitro need to be interpreted with the caveat that niacin decreases insulin sensitivity. While niacin-induced insulin resistance is well-compensated for in healthy young individuals leaving blood glucose levels essentially unchanged, pancreatic β-cell compensation in older individuals or those with impaired glucose tolerance was incomplete in one study, causing blood glucose levels to increase. Thus, the extent to which niacin may affect glycation in vivo is not clear and likely population-dependent.
Adiponectin, an adipokine that is known to be cardioprotective and thought to be antiobese, is increased in response niacin-mediated activation of the HM74A receptor in mice. Niacin-induced adiponectin production was rapid in this study, increasing adiponectin levels by 37% within 10 minutes of a 30mg/kg dose by injection. Serum levels peaked after 60 minutes, and remained elevated above baseline for up to 24 hours after administration.
Leptin is also known to be increased by niacin in humans, which is thought to occur via a similar mechanism since the pharmaceutical HM74A agonist Acipimox also induces leptin secretion from adipose in vitro as well as in vivo.
Activation of the niacin receptor on fat cells promotes secretion of the adipokines adiponectin and leptin.
Niacin supplementation over the course of six weeks in obese men has been noted to increase serum adiponectin by 43-56%, with approximately half the increase being the high molecular weight form alongside a 26.8% increase in leptin with no observable changes in resistin. Adiponectin was noted elsewhere in obese subjects with NAFLD to increase by approximately 30% in response to niacin therapy (up to 2,000mg daily), which was correlated with increased insulin resistance, leading to the hypothesis that the two are intertwined, perhaps as an adaptive response.
Despite adiponectin being beneficial for insulin sensitivity, the increase in adiponectin noted with niacin therapy is associated with a worsening of insulin resistance. It is hypothesized that this increase in adiponectin levels functions as an adaptive response to insulin resistance in adipose tissue.
Fatty acid ‘spillover’ resulting from inefficient fat storage after a meal increases serum non-esterified fatty acids (NEFAs), which adversely affect hepatic insulin sensitivity, increasing VLDL production and potentially plays a causative role in hepatic steatosis. Acute niacin administration (285mg intravenous) to humans during feeding has been shown to reduce fatty acid spillover, promoting the incorporation of dietary fat into adipose tissue and reducing serum triglycerides as well as NEFAs.
In contrast, prolonged niacin treatment, known to promote insulin resistance in man, has been noted to induce adipocyte insulin resistance, which would promote fatty acid spillover, increasing serum NEFA levels.
Acute niacin administration has been shown to reduce fatty acid spillover after a meal, reducing serum non-esterified fatty acids (NEFAs) and potentially improving hepatic insulin sensitivity. In contrast, chronic niacin administration may have and opposite effect on lipid storage by reducing insulin sensitivity.
Nicotinamide has been noted to suppress 3T3-L1 adipocyte differentiation in a concentration-dependent manner at concentrations above 10mM (the ED50value), reaching full suppression at 20mM after nine days. This is thought to be related to an inhibitory effect on poly(ADP-ribose) synthetase, which nicotinamide is known to inhibit at 50µM while niacin does not. When added after differentiation and under high glucose conditions, nicotinamide appeared to inhibit glucose-6-phosphate dehydrogenase (G6PD) and prevent abnormal oxidative stress.
The nicotinic acid receptor is expressed in adipocytes where its activation suppresses adenylate cyclase. This effect appears to be about 30% more effective in adipocytes when compared to other cell lines (spleen). Because activation of this receptor inhibits adenylate cyclase, and phenolics that act on it also reduce lipolysis rates, the overall effect of nicotinic acid would be to decrease lypolysis in adipocytes, at least in the short-term.
In the long-term, however, the nicotinic acid receptor can be desensitized with chronic exposure to an agonist, and one study in mice noted that adipocytes which became insulin resistant after niacin therapy showed an increased responsiveness of adrenergic receptors (β1 and β2) at increasing cAMP levels in the fat cell, (cAMP normally being suppressed by niacin acting on the GRP109A receptor). This may have been related to niacin-mediated downregulation of genes in the insulin signaling pathway including PDE3B, which normally degrades cAMP, a potential adaptive response in fat cells that has been noted to normalize lipolysis rates (in rats under niacin infusion).
It appears that niacin acts on its receptor to suppress lipolysis (the breaking of triglycerides into free fatty acids for use as fuel). While robust, this effect is short-lived, only lasting for a few hours. Thereafter, changes within the fat cell normalize or even increase the rates of lipolysis alongside an increase in insulin resistance.
One small study in seven otherwise healthy participants taking niacin at 500mg and increasing the dose to 2,000mg over the course of two weeks noted a reduction in fat oxidation rates. Due to an increase in carbohydrate oxidation rates there was no net difference in metabolic rate between niacin and placebo, however.
Mice lacking PARP-1 appear to have higher metabolic rates and lower fat mass; in the absence of PARP, NAD+ concentrations increase, activating SIRT1 which then works to deacetylate various proteins (PGC-1α and FOXO1) to promote energy expenditure via enhanced oxidative metabolism and increased mitochondria.
SIRT2 and SIRT3 are not affected by low PARP-1 activity, and inhibiting ADP-ribosylation by other means such as NMNAT-1 knockdown also seems to confer antiobesity effects in rodents. Feeding acutely increases PARP-1 activity in mice and transiently hinders SIRT1 activity, which is thought to be related to PARP-1 having priority for the use of NAD+ stores.
Oral supplementation of nicotinamide riboside at 400mg/kg in the mouse appeared to increase NAD+ content in skeletal muscle similar to the same dose of niacin (nicotinamide mononucleotide ineffective in this organ) and appeared to increase energy expenditure in high-fat fed mice alongside increasing activity of FOXO1 target genes, suggesting that oral supplementation is effective.
Limited evidence exists in humans assessing the effects of niacin on metabolic rate, although the lower end of niacin pharmacological dosing (1,000mg) in otherwise healthy subjects failed to increase metabolic rate relative to placebo.
PARP-1 appears to indirectly encourage the accumulation of body fat in the context of excess nutrition. Mice lacking PARP-1 are protected from diet induced obesity due to increased NAD+ concentrations, which activates the antiobese effects of SIRT1 deacetylase. Human studies have failed to show that normal doses of niacin have similar effects. Thus, current research does not support the use of niacin as a fat loss supplement.
Niacin administration in humans has been shown to increase the expression of transcription factors PPARδ and PPARγ coactivator-1α (PGC-1α) in skeletal muscle. Because these transcription factors are important regulators of oxidative metabolism and mitochondrial biogenesis, this suggests that niacin supplementation may play a role in skeletal muscle endurance.
Animal studies have supported this idea, where niacin supplementation was shown to cause a muscle fiber transition from type II (fast-twitch) to type I (slow-twitch), also increasing the overall number of type I fibers in skeletal muscle in obese Zucker rats and growing pigs (750mg niacin/kg diet) as well as sheep (1000mg niacin per day). This effect may be limited to certain animal models, however, as studies in healthy rats have demonstrated that niacin has a negligible effect on muscle fiber-type distribution or metabolic phenotype. Moreover, in spite of niacin increasing the expression of pro-oxidative transcription factors in humans, no studies to date have shown that it enhances performance or skeletal muscle endurance capacity.
Although niacin has been shown in some animal models to have positive effects on muscle oxidative metabolism, promoting a pro- endurance phenotype, these results seem to be dependent on model. Niacin-induced increases in pro-oxidative transcription factor expression in humans have not been shown to increase muscle endurance, suggesting that it is most likely not performance-enchancing.
As a substrate for NAD+ synthesis, adequate niacin may indirectly support oxidative metabolism and muscle endurance, however. In otherwise healthy subjects, mild exercise appears to be associated with an increase in blood NAD+ concentrations relative to a resting state (independent of any supplementation) while when tested in rodents mild exercise also led to an increase in blood NAD+ before it decreased during exhaustive exercise, which has been noted to occur in skeletal muscle as well. At this level of exhaustion there is a concomitant increase in NADH content of skeletal muscle which has been proposed to be indicative of a reduction in electron transfer from NADH towards ATP synthesis.
It has further been proposed that since exercise increases oxidation in exercised tissue and oxidative stressors are known to impair activity of the Kreb's (TCA) cycle and electron transport chain (including NADH dehydrogenase) that provision of antioxidants would increase endurance secondary to preserving intramuscular NAD+/NADH kinetics. When providing 36mg of pycnogenol as antioxidant during exercise to exhaustion, it seems that the decrease in blood NAD+ was reversed into an increase with the effects (both decrease and increase pending on supplementation) being more marked in trained athletes.
Muscle activation seems to initially promote NAD+ production to fuel muscular activity, but near exhaustion the rate of NADH production is increased (or at least its conversion back into NAD+ hindered) and this process is associated with muscular fatigue. Thus, adequate niacin intake may be required for optimal oxidative metabolism, and it is possible that antioxidant supplementation may work partially through altering NAD+ kinetics.
Oral administration of 250mg/kg niacin in mice significally attenuates the rise in IL-1β (54%) and TNF-α (43%) induced by an injection of the inflammatory factor lipopolysaccharide (LPS).
One of the main ways niacin is thought to affect atherosclerosis is through its effect on macrophages. Niacin is known to exert an antiinflammatory effect in macrophages at moderate concentrations (1-100μM) via activation of its receptor, HM74A. This receptor is also upregulated in macrophages from mice given an atherosclerotic diet, where niacin exerts more of an antiinflammatory effect when compared to macrophages derived from healthy mice.
Niacin exerts its antiinflammatory effects by limiting activation of NF-kB p65 and IκBα. HM74A stimulation also activates the nuclear protein known as PPARγ which is also antiinflammatory; when PPARγ is activated in macrophages, ABCA1/ABCG1 expression is increased, causing an efflux of cholesterol that potentially reduces foam cell formation. In turn, this may increase the ability to take up modified lipoproteins via upregulation of the scavenger receptor CD36. Activation of this receptor in a mouse model also reduced macrophage chemotaxis into atherosclerotic lesions.
Niacin appears to promotes the macrophage (M2) phentype, which is antiinflammatory effects and much less likely to become pro-atherosclerotic. This is due to activation of the known antiinflammatory receptor PPARγ and secondary to niacin's own receptor, HM74A.
Agents that would normally promote migration of neutrophils to inflammed tissue (cytokines such as IL-8, LTB4, or the polysaccharide carrageenan) appear less effective when niacin (150-600 mg/kg) is administered thirty minutes prior in mice, an effect that was also noted with nicotinamide (1,000mg/kg in mice) under similar conditions. Although HM74A is expressed in neutrophils, nicotinamide does not activate HM74A, suggesting that niacin and nicotinamide suppress neutrophil migration via an HM74A-independent mechanism. The suppressive effects against LTB4 seem to be strongest, as 1,000mg/kg nicotinamide can reduce LTB4-induced migration by 87.5% with cellular rolling and adhesion also being potently reduced. 
Activation of PARP-1 may also play a role in the inflammatory response, since activity of the pro-inflammatory transcription factor NF-kB is partially dependent on ADP-ribosylation (from NAD+) by PARP-1. If PARP-1 is inhibited, then NF-kB activity is suppressed, resulting in less neutrophil migration. It is not likely that niacin or nicotinamide suppress neutrophil migration via PARP-1, however; although nicotinamide inhibits PARP-1, niacin provides NAD+ to immune cells increasing PARP-1 activity.
Pharmacological doses of nicotinamide or niacin may have antiinflammatory properties at the level of the neutrophil by reducing their migration into inflamed tissue.
Adequate cellular NAD+ levels are important for activation of stress-response proteins including the tumor suppressor protein p53 in response to DNA damage. Moreover, NAD+ appears to have antioxidant activity, which is thought to contribute to the apparent protective effect of increased NAD+ biosynthesis against DNA damage during oxidative stress.
The connection between cellular NAD+ levels and the ability to mount the appropriate response to genotoxic stress is suggestive of a possible role for niacin in cancer prevention. Most of this evidence came from in vitro or animal studies, however; more research is needed to determine if this is relevant to humans.
In a rat study, nicotinamide at 20mg/kg fed an hour before a stomach ulceration-inducing dose of indomethacin prevented ulceration to a level comparable to both control (no ulcers induced) and the reference drug of 400mg/kg sucralfate, which acts locally to form a protective surface for the stomach. This effect occurred alongside preservation of glutathione activity, reduced lipid peroxidation, and enhanced gastric mucus. Similar protective effects against ethanol- and stress-induced ulceration have been noted elsewhere, with the primary metabolite of nicotinamide (1-methylnicotinamide; MNA). This gastroprotective effect was associated with increased prostaglandin activity, namely PGI2, and nicotinamide as well as its metabolite MNA have been implicated in increasing gastric blood flow and reducing microvascular permeability following ulceration.
In animal studies, nicotinamide has been found to have protective effects against stomach ulcers. This occurred in part by preserving gastric mucus, an effect that seemed to be mediated by nicotinamide antioxidant activity. It is not known whether niacin or nicotinamide might have similar gastroprotective effects in humans.
In the colon of mice, the niacin receptor (GPR109A) is required for optimal proliferation of CD4+ T-cells and production of IL-10, which results in an antiinflammatory effect. This GPR109A-driven antiinflammatory effect is mediated by the colonic short-chain fatty acid butyrate, which is an GPR109A agonist and produced through the fermentation of dietary fiber by bacteria in the colon.
The niacin receptor drives antiinflammatory activity in colonic tissue, where a fatty acid produced by intestinal bacteria known as butyrate can activate this receptor to promote a localized antiinflammatory effect. This indicates that the niacin receptor is an important player in crosstalk between the gut microbiome and immune system, with possible implications for inflammatory bowel disorders and colon cancer.
The triglyceride-reducing effect of niacin appears to be traced back to the liver, where secretion of very low density lipoprotein (vLDL) is reduced; because vLDL normally carries triglycerides from the liver to other tissues, reducing vLDL secretion results in lower serum triglycerides.. The decrease in vLDL secretion may be secondary to inhibiting lipolysis in adipose tissue, as the chronic increase in free fatty acids in serum can negatively regulate vLDL secretion.
It appears that acute niacin supplementation (which decreases free fatty acids in serum) also suppresses vLDL production and its complexation with triglycerides. This suggests another possible mechanism, which may occur via acute suppression of the PGC-1β, a protein known to promote secretion of triglycerides from the liver in response to dietary fat ingestion. In accordance with this latter mechanism, the administration of niacin with a high fat meal appears to reduce the normal spike in postprandial triglycerides.
It is not confirmed how niacin reduces vLDL-C, but its ability to stimulate the activity of the ABCA1 gene and increase its protein content in liver cells underlies the increase in HDL-C, which is known to also suppress vLDL-C secretion. Niacin (2,000mg for 16 weeks), despite reducing vLDL-C and the complex with triglycerides, does not appear to significantly increase intrahepatic triglyceride content in subjects with nonalcoholic fatty liver disease (NAFLD).
Niacin appears to lower serum triglycerides via two distinct mechanisms, both of which are driven by reduced vLDL secretion in the liver.
Niacin also appears to act on liver cells to promote accumulation of diacylglycerol (DAG), which is associated with localized insulin resistance. Insulin resistance in liver cells reduces the suppressive effect of insulin on glucose synthesis, which results in increased glucose efflux from the liver into the blood. Because the initial stages of niacin-induced insulin resistance (prior to increases in basal insulin and glucose) have been associated with a reduced requirement for glucose to balance a hyperinsulinaemic euglycaemic clamp, this suggests that the initiation of insulin resistance begins at the level of the liver. The precise role of DAG in this process is uncertain, however. While DAG promotes insulin resistance via activating PKCε, activation of this protein was not observed in liver cells that became insulin resistant with niacin.
The initial stages of niacin-induced insulin resistance appear to occur at the level of the liver, although the precise mechanism by which this occurs has not been elucidated.
Niacin is known to make pancreatic β-cells, (a specialized cell type that secretes insulin in response to glucose) less sensitive to serum glucose. Moreover, the normal reduction in pancreatic β-cell glucose sensitivity associated with aging can be further exacerbated by niacin supplementation (500-1,000mg twice daily). Although there does appear to be a compensatory increase in insulin secretion in response niacin supplementation in humans and a primate model of type I diabetes, this is not sufficient to reduce blood glucose to normal levels, resulting in mild hyperglycemia and hyperinsulinemia after two weeks supplementation.
There appears to be a desensitizing effect of niacin on pancreatic β-cells which reduces their ability to sense glucose, initially resulting in impaired insulin secretion and mild elevations of blood glucose.
NAD+ has been implicated in longevity, in part due to enzymes such as sirtuins (SIRTs), which are NAD+-dependent. Specifically, one such SIRT known as SIRT1 (Sir2 in nonmammals) has been implicated in the increase in longevity associated with caloric restriction by promoting mitochondrial biogenesis and DNA repair. Vitamin B3 may play a role in longevity since niacin is a substrate for NAD+ synthesis, and nicotinamide a product of NAD+ turnover. While nicotinamide can inhibit PARP-1, which leads to increased SIRT1 activity and NAD+ concentrations, nicotinamide is also a general SIRT inhibitor, although the concentrations of nicotinomide are probably well below the IC50 for SIRT inhibition in mammalian cells. Instead, increasing nicotinomide levels instead act as a substrate for the enzyme NAMPT (thought to be the human homologue to Pnc1) to ultimately increase NAD+ concentrations. The NAD+/NADH ratio doesn't seem to influence SIRT1 activity much due to the high concentrations of NADH required to inhibit enzyme activity, however; while NADH is technically a SIRT1 inhibitor, it's IC50 value is 11mM, and intracellular NADH tends to be in the 50-100µM range. Thus, decreasing the NAD+/NADH ratio 10-fold from normal only modifies SIR2 activity by 0.2%.
Anything that can increase intracellular NAD+ concentrations could in theory confer pro-longevity effects. Since niacin is a substrate from which NAD+ is synthesized, it may support mechanisms and signaling pathways known to promote increased longevity.
An in vitro study found that the total content of the NAD+/NADH couplet was reduced by about 16% in adult skin fibroblasts relative to neonatal ones (although this difference was not statistically significant), and a complex containing niacinamide along with other ingredients increased total NAD+ levels in fibroblasts isolated from aged adult human skin. A metabolite of nicotinamide known as 1-methylnicotinamide (MNA) is also thought to possess antiinflammatory effects when applied topically.
Administration of niacinamide has been shown to restore NAD+/NADH levels in adult fibroblasts in vitro to youthful levels.
Low levels of glycosaminoglycan (GAG; made up of long sugar chains) are required for normal dermal structure in healthy skin, increased levels are associated with damaged or wrinkled skin. Niacinamide has been noted to reduce GAG production in aged fibroblasts, although the suppression from 0.5-3mM niacinamide (15-29%) is less effective than 30µM Vitamin A (77%). Niacin’s primary metabolite, MNA, may have the capacity to bind directly to GAG while nicotinamide itself does not.
Acne vulgaris is a chronic skin disorder typically characterized by follicular hyperkeratinization, hormonally-mediated sebum overproduction, and chronic inflammation of the pilosebaceous unit. Research suggests that the damaging of lipids in the skin via free radicals may be responsible for the inflammatory component of acne.
Nicotinamide has been noted for its anti-inflammatory effects in various disorders. The exact mechanism by which nicotinamide exerts its anti-inflammatory effects is unknown, however, it is believed that the anti-inflammatory effects may be a result of inhibition of histamine release by mast cells, blockade of histamine receptors, inhibition of neutrophil chemotaxis, and secretion of inflammatory mediators. Thus, its use as a topical treatment for acne vulgaris has been explored.
A double-blind, randomized, active-controlled trial in 1995, found that patients who applied 4% nicotinamide gel to their faces twice a day, had similar outcomes to patients who applied 1% clindamycin gel to their faces twice a day, with regards to reduction in acne severity and reduction in acne lesion count. The reduction in papulopustule count and reduction in acne severity was more prominent in the nicotinamide group after 8 weeks of therapy, however, these differences were not significant. The acne lesion count decreased from 27.6 ± 2.1 to 13.5 ± 2.8 (-59.5 ± 9.0%) in the nicotinamide-treatment group compared to a reduction from 29.3 ± 2.0 to 17.0 ± 2.4 (-42.7 ±7.8%) in the clindamycin-treatment group. The acne severity ratings decreased to 2.48 ± 0.39 in nicotinamide-treated group (-51.6 + 7.0%) compared to 3.07 ± 0.33 in the clindamycin-treated group (-38.4 ± 6.1%).
A similarly designed study, aimed to compare 4% nicotinamide gel to 1% clindamycin gel with regard to acne severity reduction, however, this study also took into account the type of skin (oily vs. non-oily), which was determined by a sebumeter. The researchers classified the skin types as oily (mean facial sebum > 66 lg/cm2) or non-oily (66 lg/cm2 > mean facial sebum). After 8 weeks of therapy, the results indicated that the clindamycin-treated patients with non-oily skin had the greatest reduction in acne severity, followed by the nicotinamide-treated patients with oily skin, the clindamycin-treated patients with oily skin, and finally, the nicotinamide-treated patients with non-oily skin. However, there were no significant differences in acne severity reduction between the clindamycin-treated group and the nicotinamide-treated group.
It is believed that because excess oil results in more inflammatory pustules, nicotinamide's anti-inflammatory effects make it more desirable as a topical treatment for those with oily skin. It is likely that clindamycin’s anti-bacterial effects are more effective in a non-oily environment because it is less ideal for Propionibacterium acnes, the bacteria linked to acne vulgaris. Because an oily environment is ideal for P. acnes, non-oily skin will have less of these bacteria than oily skin, which means that the use of clindamycin will result in less antibiotic resistant bacteria in non-oily skin types thus, making it the preferable treatment for those who produce less oil on their skin.
4% nicotinamide gel is as effective as 1% clindamycin gel in reducing acne severity and acne lesions after at least 8 weeks of treatment. Nicotinamide is likely to be more effective in those who have oily skin types while clindamycin is likely to be more effective in those who have non-oily skin types.
Proliferation of keratinocytes is not affected by niacinamide.
The process of melanogenesis (production of melanin) and tyrosinase activity in culture does not appear to be influenced by niacinamide up to 10mM. Niacin does appear to induce skin-lightening secondary to reducing transfer of melanosomes (35-68% inhibition at 1mM), suggesting that it may interfere with communication between keratinocytes and melanocytes, since melanosomes transfer melanin to keratinocytes.
Nicotinamide appears to confer skin lightening effects.
Niacinamide is claimed to be the ideal form of vitamin B3 for skin use due to its nonirritating properties and high stability in cosmetic products. Although some other cosmetic additives such as Vitamin A have benefits at high concentrations, they also tend to be irritating, causing skin reddening and increased sensitivity. Other forms of niacin including nicotinic acid and its esters are associated with uncomfortable skin flushing. While niacin causes flushing via acting on its receptor, HM74A, niacinamide does not bind this receptor  and is therefore not associated with skin flushing.
Red blotchiness appears to be reduced after 12 weeks treatment of 5% niacinamide cream even though there was no benefit noted after 4-8 weeks.
Skin yellowing appears to be reduced in a time-dependent manner with 8 or more weeks of 5% niacinamide cream applied to the face, which has been noted elsewhere with a 2% cream over four weeks in tanned japanese women.
Fine wrinkling (crow's feet) appears to be reduced in a time-dependent manner with a 5% niacinamide facial cream, with no effects being noted after 4 weeks while benefits increased progressively after 8 and 12 weeks.
Skin elasticity also appears to be improved in middle-aged subjects given 5% niacinamide cream for 12 weeks relative to placebo.
Application of a 5% niacinamide cream to the face of japanese women with brown skin pigmentation appeared to reduce hyperpigmentation after four weeks before reaching a plateau. In women who were visibly tanned, 2% niacinamide showed a skin lightening effect that was not additive with sunscreen.
When applied topically for a prolonged period of time, niacinamide has been shown to increase the quality and appearance of skin.
Secondary to acting on its receptor, HM74A, niacin stimulates the release prostaglandin D2 (PGD2). This appears to occur rapidly following oral ingestion of flush-inducing 500mg dose of niacin, as assessed by serum levels of its metabolite 9α, 11β-PGF2. PGD2 is known to have a negative role in hair growth, since in male pattern baldness (androgenic alopecia), PGD2 is increased via hormonal upregulation of its synthetic enzyme, prostaglandin D2 synthase (PTGDS). Amplified PGD2 levels result in increased binding to its receptor, GPR44. Moreover, PGD2 levels have been confirmed to be higher specifically in the bald region in men with male pattern baldness, where GPR44 is also implicated. Another PGD2 receptor known as PTGDR does not appear to be implicated in male pattern baldness, however.
Niacin can increase PGD2 levels, which has been implicated in male pattern baldness. Although niacin (but not nicotinamide) increases PGD2 levels in serum associated with the flush, there is currently no direct evidence linking niacin to balding.
Niacinamide has been included in compound formulations (including Caffeine, panthenol, dimethicone, and a polymer) which collectively have anti-thinning properties in hair follicles. Notably, niacinamide itself is capable of penetrating hair follicles when administered topically.
Plasma levels of apolipoprotein A1 (ApoA1) appear to be correlated with Parkinson's Disease (PD), where lower apoA1 is associated with earlier onsent of PD and greater putaminal dopamine transporter deficits. Reduced apoA1 is further associated with PD when the single nucleotide polymorphism (SNP) rs670 is homozygous for the G allele. These studies suggest that serum apoA1 could be a useful biomarker for PD, amongst other possible options. Since niacin has been seen to affect apoA1 serum levels, and dietary niacin intake has been seen to be related to the risk of PD in some observational studies (but not others), niacin may in theory affect the risk of developing PD.
In actuality, it is uncertain if niacin supplementation could play a role in mitigating disease risk; the topic has not been researched to date, and currently there is only one case study where niacin added to a multidrug regimen improved physical symptoms of PD (rigidity and bradykinesia) while having some psychoactive side effects.
Aspirin is sometimes used alongside niacin in an attempt to reduce the flushing sensation that occurs with high dose supplementation, with 325mg aspirin being able to reduce the flush associated with 500mg to 2,000mg niacin. It has further been shown that 325mg aspirin is more effective than 80mg for reducing flushing symptoms. This reduction in flushing also appears to apply to extended-release niacin formulations. Combination-therapy of aspirin with a gradual titration of the niacin dose from 500mg up to 2,000mg over two weeks is considered an ideal way to reduce flushing symptoms. It seems that aspirin does not completely reduce flushing, however, since the parasympathetic nervous system also contributes to flushing and aspirin does not affect this pathway.
Aspirin's reduction in flushing from niacin is due to blocking COX-1, which is stimulated downstream of the nicotinic acid receptor HM74A. This leads to production of various prostaglandins; prostaglandin D2 (PGD2) and PGE2 (but not PGI2) seem to be the main prostaglandins responsible for the flushing response. PGD2 is known to be released in high amounts into serum following nicotinic acid therapy in humans, which tends to affect the skin to a large degree and initiates the flushing response. Coadministration of agents that block the PGD2 receptor, namely laropiprant, can reduce flushing from niacin although this is not additive with aspirin since both work at different points along the same pathway.
One experiment in humans has shown that 200mg ibuprofen has a suppressive effect on the niacin-flush with a potency comparable to 165mg aspirin, but less than 325mg aspirin.
Niacin binds to and activates its receptor HM47A, which then induces flushing via increased prostaglandins such as PGD2. This can be markedly suppressed with aspirin or laropiprant, which has been shown to reduce flushing frequency and intensity by as much as 50%.
Apple pectin (2,000mg), a soluble fiber, has been demonstrated to reduce the duration of flushing from a single dose of extended release niacin (1,000mg). This occured alongside a nonsignificant reduction in overall incidence and time until first signs of flushing; the benefits being about as potent as 325mg aspirin but not additive when coingested. It is thought that apple pectin works by reducing the absorption rate of niacin, since this is a known effect of pectin on oral drugs, where it can prolong gastric emptying.
Apple pectin is thought to reduce the niacin flush secondary to slowing its absorption. This appears to be somewhat effective at reducing the flush based on preliminary evidence.
NAD+ is the sole substrate for poly-ADP-ribose polymerase-1 (PARP-1), a nuclear enzyme that is known to regulate a variety of genotoxic insults to the cell via 'sensing' damage, binding to single or double strand breaks in DNA, and by forming complexes between ADP-ribose polymers and various acceptor proteins. PARP-1 is its own acceptor protein, which prevents excessive activation. Other acceptor proteins include nuclear repair enzymes such as topoisomerases (I and II), DNA ligases (I and II), and DNA polymerases; these complexes can be cleaved by Poly(ADP-ribose) glycohydrolase (PARG) to reform free ADP-ribose molecules.
PARP-1 has additional roles in genomic stability by modulating chromatin structure and is involved in a few DNA repair pathways including nucleotide excision repair (NER) and base excision repair (BER). Thus, one overall function of PARP-1 is to help stabilize genetic material, as evidenced by mice that lack PARP-1, which are more sensitive to genomic damage. This is relevant to vitamin B3, since the activity of PARP-1 relies on a reservoir of NAD+.
It should be mentioned that this protective effect may also be undesirable in some cases, as PARP-1 inhibition has been investigated as a potential adjuvant for chemotherapy or radiation, since PARP-1 expressed in a cancer cell will still exert a protective effect on the cancer cell's genome. Indeed, interfering with PARP-1 has shown some efficacy in human cancer patients.
An NAD+-dependent enzyme known as PARP-1 is heavily involved in stabilizing the genome from cellular and environmental stressors. It is a somewhat indiscriminate, however, protecting normal cells from stressors that can cause cancer and protecting cancerous cells from toxic stressors that would otherwise kill the cancer cell.
Nicotinamide has been used successfully to attenuate genomic damage as evidenced by the streptozotocin-nicotinamide model of inducing experimental diabetes in rats. Streptozotocin is toxic to pancreatic β-cells, working by entering the nucleus and depleting NAD+ Coadministration of various doses of nicotinamide can both inhibit PARP-1 and provide NAD+ to attenuate streptozotocin, resulting in a dual cytoprotective effect. Doses used in these studies are moderately high, as the range used with efficacy (100-350mg/kg in the rat) would correspond to at minimum 1g for a 150lb human.
A few case studies have noted possible toxicity associated with niacin, including young men taking very large (undisclosed) doses of niacin in attempts to obscure urine drug testing. These case studies tend to note alterations in renal and liver function and problems with blood coagulation and cognitive function.
High doses of niacin used in an attempt to obscure drug testing have been associated with hospitalization in numerous case studies secondary to multiorgan failure.
In all cases of overdose subjects returned to normal after emergency care, and there appears to be a single case study of hepatotoxicity associated with a moderate (2g) dose of sustained release niacin although other medicines may have confounded the case. This may oddly be tied into sustained release niacin rather than other forms, as another case study noted a subject who tolerated 6g of crystalline niacin experienced liver failure after switching to sustained release and elsewhere sustained release niacin has been implicated in harm at 500mg over eight weeks.
There are a few case studies where sustained release niacin, rather than acute release or extended release, have resulted in toxicity to the liver at doses normally used in the treatment of dyslipidemia.