The NAD+ precursors, nicotinic acid and nicotinamide protect cells against apoptosis induced by a multiple stress inducer, deoxycholate.
The bile salt, sodium deoxycholate (NaDOC), is a natural detergent that promotes digestion of fats. At high physiologic levels, NaDOC activates many stress-response pathways and induces apoptosis in various cell types. NaDOC induces DNA damage and activates poly(ADP-ribose) polymerase (PARP), an enzyme that utilizes NAD+ as a substrate to repair DNA. NaDOC also induces oxidative stress, endoplasmic reticulum (ER) stress and contributes to protein malfolding. The NAD+ precursors, nicotinic acid (NA) and nicotinamide (NAM) were found to protect cells against NaDOC-induced apoptosis. NA and NAM also decreased constitutive levels of both activated NF-kappaB and GRP78, two proteins that respond to oxidative stress. However, the mechanism by which NA and NAM protects cells against apoptosis does not involve a reduction in constitutive levels of oxidative stress. NA or NAM treatment increased the protein levels of glyceraldehyde-3-phosphate dehydrogense (GAPDH), a multi-functional enzyme, in the nucleus and cytoplasm, respectively. NAM did not activate the promoter/response elements of 13 stress response genes nor reduce intracellular non-protein thiols, suggesting that it is non-toxic to cells. NAM thus has promise as a dietary supplement to help prevent disorders involving excessive apoptosis.
Crowley
C L
CL
Department of Microbiology and Immunology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
Payne
C M
CM
Bernstein
H
H
Bernstein
C
C
Roe
D
D
D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003840:Deoxycholic Acid / Q000494:pharmacology*; D003902:Detergents / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004792:Enzyme Precursors; D005978:Glutathione / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D019073:HT29 Cells; D006360:Heat-Shock Proteins; D006801:Humans; D019169:Jurkat Cells; D018832:Molecular Chaperones / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009525:Niacin / Q000378:metabolism / Q000494:pharmacology*; D009536:Niacinamide / Q000378:metabolism / Q000494:pharmacology*; D018384:Oxidative Stress
D002352:Carrier Proteins; D003902:Detergents; D000091342:Endoplasmic Reticulum Chaperone BiP; D004792:Enzyme Precursors; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D016328:NF-kappa B; D003840:Deoxycholic Acid; D009243:NAD; D009536:Niacinamide; D009525:Niacin; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D005978:Glutathione