Niacin

Before we begin.Which of the B vitamins is the other name for Niacin? B1B3B5B7Which of the B vitamins is the other name for Niacin? B1B3B5B7Which amino acid can Niacin be synthesized from? ProlineAlanineTryptophanTyrosineWhich amino acid can Niacin be synthesized from? ProlineAlanineTryptophanTyrosineNiacin deficiency can lead to:AnemiaSeizuresScurvyPellagraNiacin deficiency can lead to:AnemiaSeizuresScurvyPellagraNiacinKirsten Boestfleisch, Lindsay Edmonds,Lena Husnay, Sarah Johnson

Image: http://healthyetips.com/health-benefits-vitamin-b3/8NiacinVitamin B3 or nicotinic acidInositol hexaniacinate is also another formDirectly converted to nicotinamideNiacin, nicotinic acid, and nicotinamide are cofactors for:NAD+NADP+*Both are involved in energy productionWater soluble (body does not store it)Highest concentrations are found in the liver as NAD+

Niacincommons.wikimedia.org

NicotinamideImages: commons.wikimedia.org

9Food SourcesPlant products Wheat branCornEnriched breads and cerealsLegumesNutsMeat products NAD+ and NADP coenzymesReleased during cookingNeed fortification

Corn is bio-unavailable in its mature form unless prepared in a manner that would release the niacin. Acids or alkaline substances can be used to breakdown the niacin in order for it to be released. Lime juice is an example of an ingredient that can be used.

Images: http://www.worldcommunitycookbook.org/season/guide/photos/corn.jpghttp://www.nutstop.com/media/catalog/product/cache/1/image/9df78eab33525d08d6e5fb8d27136e95/m/i/mixed-nuts-roasted-unsalted.jpg

10Why is Niacin Necessary?Necessary for the metabolism of carbohydrates into glucose, which is used for energyHelps the body use fat and proteinBoost immune system to fight disease Healthy liverProper function of the nervous systemImproves circulation

Specific mechanisms can be seen throughout the PowerPoint!

11Synthesis from TryptophanNicotinamide can be synthesized from tryptophanInefficient process: 1 mg of niacin needs 60 mg of tryptophanNiacin deficiency oftentimes results when both niacin and tryptophan levels are insufficient

Next slide12

Source: http://toxwiki.wikispaces.com/Niacin

13Major Functions1. Energy metabolism NAD+ is reduced to NADH in several reactions:Glycolytic reactionsOxidative decarboxylation of pyruvateOxidation of acetate in the TCA cycleOxidation of alcoholBeta oxidation of fatty acids Many other cellular oxidation reactions

Oxidation of NADH allows transfer of electrons in the electron transport chain to produce ATP.

14Major Functions Continued2. NADP+ is reduced to NADPH Pentose phosphate pathway Malate-pyruvate shuttle (crosses mitochondrial membrane)

NADPH becomes a reducing agent for many cellular macromolecules, manufacture of deoxyribonucleotides, cholesterol synthesis, and fatty acid production.

15Major Functions Continued3. Poly(ADP-ribosyl)ation reactionsDNA metabolism and genomic stability4. Mono(ADP-ribosyl)ation reactionsADP-ribose attaches to amino acid side chains to make mono(ADP-ribose)Aids cyclic ADP-ribose and NAADP formationAllows control of intracellular calcium levels = cellular signaling

Poly(ADP-ribosyl)ation reactions: - break bond between nicotinamide and ADP-ribose; allows ADP-ribose to attach to glutamate side chains and hydroxyl groups of ribose to make poly(ADP-ribose)

Mono(ADP-ribosyl)ation reactions: continued on next slide

16Major Functions Continued*Cyclic ADP-riboseSynthesis: ADP-ribose attaches to an internal ribose linkageImportant regulator of the CICR (calcium-induced calcium release)Other regulators of calcium release:Inositol-1,4,5-triphosphate (IP3) - a type of calcium channel NAADP (a contaminate of NADP found to mobilize calcium)

CICR when one stimuli causes calcium to be released from the cell, another stimulus causes an even greater amount of calcium to flow into the cell;Because calcium levels are normally higher outside of the cell, the smallest increase of calcium inside the cell is important in cell signaling.Calcium regulation is important in cell signaling, control of muscle contractions, and nerve cell activity.

17Major Functions continued5. SIR2 (rats)/SIRT1 (humans) deacetylation reactionsInvolved in genomic stability and expression particularly through:Histones involved in DNA transcriptionProtein p53 tumor suppressor

A deficiency in niacin could result in a more active gene expression in DNA, making DNA more susceptible to structural damage.

NAD+ regulates genomic stability through SIRT1 which is a protein deacetylase and is dependent on NAD. 18Specific AbsorptionSome in stomach liningMostly in small intestineAt low concentrations:Sodium-dependent facilitated diffusionCarrier-mediated transportAnion antiporters19Transport MechanismPortal circulationFacilitated diffusion into erythrocytesNicotinic acid or nicotinamideLiverFormation of NAD from tryptophan, nicotinamide, or nicotinic acidProducts for urinary excretion

Mechanism of Action on Various Tissues

Source: http://www.nature.com/nrendo/journal/v8/n9/fig_tab/nrendo.2012.22_F1.html

Niacin action on adipose tissue, the artery, and liver (left to right)

Following explanations explained on next slides.1. Inhibition of the enzyme DGAT2 that is used in triglyceride synthesis, which will decrease TG/VLDL/LDL synthesis2. Increases binding of the HCAR2 receptor: decrease lipolysis, leading to the decrease in free fatty acid flux to the liver and consequent decrease in TG/VLDL/LDL synthesis3. Increased ApoB catabolism: allows decrease of ApoB-containing lipoproteins4. Decreases cholesteryl ester transfer protein (CETP) mass and activity: allows decrease in the exchange of cholesteryl esters between TG in LDL and VLDL for HDL; leads to increased HDL5. Decreases beta-chain of ATP synthase: leads to a decrease in HDL uptake, which increases HDL levels6. Increases ApoA-I production and thus, increases levels of HDL cholesterol7. Increases hepatic uptake of apoA-I, which leads to the increase of HDL cholesterol

211 & 2: Niacin Action in the Adipose TissueAffects: adipocyteTargets: HCAR2 receptor Leads to:Decreased lipolysisDecreased VLDL and triglyceridesHCAR2 hydrocarboxylic acid receptor; acts as a receptor for nicotinic acid and regulates adiponectin secretion223 & 4: Niacin Action in the ArteryAffects: endotheliumTargets: NAD+ phosphate Lowers LDL oxidation Decreases vascular inflammationRedox sensitive genes Lowers MCP-1 and VCAM-1 Decreases vascular inflammation

MCP-1 monocyte chemoattactrant protein; ligand and inducible cytokine; acts to recruit immune cells to sites of inflammation

VCAM-1 vascular cell adhesion molecule; aids adhesion of immune cells (lymphocytes, monocytes, etc.) to vascular endothelium235-7: Niacin Action in the LiverAffects: hepatocyteTargets:Enzyme/receptor DGAT2 Decreases triglyceride synthesis and Apo B secretion Lowers VLDL and triglycerides, Apo B, and increases LDL particle sizeBeta-chain ATP synthase Lowers HDL catabolism Increases lipoprotein A-1 and HDL2DGAT2 - diacylglycerol O-acyl transferase 2; gene that encodes for enzymes which catalyze synthesis of triglycerides24ToxicityShort-term:VasodilationFlushing Burning in the face and handsNausea and vomiting

*High dose is considered over 100mg per dayLong-term:HyperpigmentationAbnormal glucose toleranceHyperuricemiaPeptic ulcersHepatomegalyJaundice

25DeficiencySymptoms of mild deficiency: indigestion, fatigue, canker sores, vomiting, depressionPellagra is associated with severe deficiency Characterized by the four Ds:DiarrheaDementiaSun-sensitive dermatitisEven deathAssociated with AIDS, alcohol abuse, anorexia nervosa, cancer patients

Cancer pt often have low niacin and pellagra may be induced by chemotherapy26Pellagra ContinuedCasals NecklaceWidespread in Europe in the 18th centuryHigh incidence in SE states of the US During the early 20th century associated with new imports of corn from EuropeAny guesses why?Led to fortification of nicotinic acid and tryptophan in many foods

www.odermatol.comCorn became a staple in the diet. Although corn contains nicotinic acid, it is not very biologically available (only 35%)27Forms of Niacin as SupplementsNiacin used to treat:Hartnups disease, poor glucose tolerance, IDDM, atherosclerosis, schizophrenia, hyperlipidemia, skin disorders*Lipid soluble derivative of nicotinic acid for hyperlipidemiaNiacinamide used for:Chemotherapy and also IDDM

Tablet or capsuleRegular or extended-released (fewer side effects but increased risk of liver damage)*When supplementing with niacin, it is recommended that liver function tests be performed periodically

Lessens chemotherapy symptoms likely d/t increased blood flow and oxygenation28Clinical InteractionsAntibiotics (tetracycline)AspirinAnti-seizure medicationAnti-coagulants (blood thinners)Blood pressure medications (Alpha-blockers)Cholesterol-lowering medicationsStatinsDiabetes medicationsIsoniazid (INH)Nicotine patches

Take AwayNiacin supplies NAD+ to be reduced to NADHDeficiencies lead to PellagraNiacin can improve cardiovascular health by increasing HDL and lowering LDL

ReferencesBrandt, Mark. Vitamins and Coenzymes. Chemistry and Biochemistry. Rose-Hulman Institute of Technology, n.d. Wed. 18 Nov. 2013. .B-Vitamins and Folate. Eat Right. Academy of Nutrition and Dietetics, n.d. Web. 17 Nov. 2013. . Creider JC, Hegele RA, Joy TR. Niacin: another look at an underutilized lipid-lowering medication. Nat Rev Endocrinol. 2012;8(9):517-28.Kamanna VS, Kashyap ML. Mechanism of action of niacin. Am J Cardiol. 2008;101(8A):20B-26B.Lavigne PM, Karas RH. The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression. J Am Coll Cardiol. 2013;61(4):440-6.New Lowdown on Cholesterol. Havard Health Publications. Havard Medical School, n.d. Web. 18 Nov. 2013. .Niacin. Medline Plus. National Institutes of Health, n.d. Web. 19 Nov. 2013. . Niacin. NMS Labs. Tox Wiki, n.d. Web. 20 Nov. 2013. .Rhodes T, Norquist JM, Sisk CM, et al. The association of flushing bother, impact, treatment satisfaction and discontinuation of niacin therapy. Int J Clin Pract. 2013;67(12):1238-46.Vitamin B3 (Niacin). University of Maryland Medical Center. N.p., 20 June 2013. Web. 17 Nov. 2013. .Zempleni J, Rucker RB, McCormick DB, Suttie JW. (2007) Handbook of Vitamins, pp. 1-570. CRC Press, Boca Raton FL.