@article{00c44aebe4e44a15bfe25b6df0356227,
title = "Quantitative Analysis of NAD Synthesis-Breakdown Fluxes",
abstract = "The redox cofactor nicotinamide adenine dinucleotide (NAD) plays a central role in metabolism and is a substrate for signaling enzymes including poly-ADP-ribose-polymerases (PARPs) and sirtuins. NAD concentration falls during aging, which has triggered intense interest in strategies to boost NAD levels. A limitation in understanding NAD metabolism has been reliance on concentration measurements. Here, we present isotope-tracer methods for NAD flux quantitation. In cell lines, NAD was made from nicotinamide and consumed largely by PARPs and sirtuins. In vivo, NAD was made from tryptophan selectively in the liver, which then excreted nicotinamide. NAD fluxes varied widely across tissues, with high flux in the small intestine and spleen and low flux in the skeletal muscle. Intravenous administration of nicotinamide riboside or mononucleotide delivered intact molecules to multiple tissues, but the same agents given orally were metabolized to nicotinamide in the liver. Thus, flux analysis can reveal tissue-specific NAD metabolism. Tissue concentrations of the redox cofactor NAD change during aging and disease. Liu et al. developed isotope-tracer methods to quantitate NAD fluxes in cell culture and in mice, revealing that the liver makes nicotinamide from tryptophan and from orally delivered nicotinamide riboside, a nutraceutical. In contrast, other tissues rely on circulating nicotinamide for NAD synthesis.",
keywords = "NAD, NADH, flux quantification, isotope tracers, mass spectrometry, mononucleotide, niacin, nicotinamide, redox cofactor, riboside",
author = "Ling Liu and Xiaoyang Su and Quinn, {William J.} and Sheng Hui and Kristin Krukenberg and Frederick, {David W.} and Philip Redpath and Le Zhan and Karthikeyani Chellappa and Eileen White and Marie Migaud and Mitchison, {Timothy J.} and Baur, {Joseph A.} and Rabinowitz, {Joshua D.}",
note = "Funding Information: We thank Vilhelm A. Bohr for the kind gift of XPA-deficient and XPA-restored cells, Katarzyna Kalemba and Fredric E. Wondisford for preparing mouse primary hepatocytes, and Tim Luongo for technical assistance. This work was supported by NIH grants DP1DK113643 (to J.D.R.), R01CA163591 (to E.W. and J.D.R.), R01DK098656 (to J.A.B.), R01AG043483 (to J.A.B.), P30DK0s19525 (the University of Pennsylvania Diabetes Research Center ), SU2CAACR-DT-20-16 (to J.D.R., Stand Up To Cancer- Pancreatic Cancer Dream Team Research Grant), R01 CA130893 and R01 CA188096 (to E.W.), and P30 CA72720 (to the Rutgers Cancer Institute of New Jersey ), and support from the Biotechnology and Biological Sciences Research Council (BBSRC); BB/N001842/1 (to M.M. and P.R.). S.H. is a Merck Fellow of the Life Sciences Research Foundation. Funding Information: We thank Vilhelm A. Bohr for the kind gift of XPA-deficient and XPA-restored cells, Katarzyna Kalemba and Fredric E. Wondisford for preparing mouse primary hepatocytes, and Tim Luongo for technical assistance. This work was supported by NIH grants DP1DK113643 (to J.D.R.), R01CA163591 (to E.W. and J.D.R.), R01DK098656 (to J.A.B.), R01AG043483 (to J.A.B.), P30DK0s19525 (the University of Pennsylvania Diabetes Research Center), SU2CAACR-DT-20-16 (to J.D.R., Stand Up To Cancer- Pancreatic Cancer Dream Team Research Grant), R01 CA130893 and R01 CA188096 (to E.W.), and P30 CA72720 (to the Rutgers Cancer Institute of New Jersey), and support from the Biotechnology and Biological Sciences Research Council (BBSRC); BB/N001842/1 (to M.M. and P.R.). S.H. is a Merck Fellow of the Life Sciences Research Foundation. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = may,
day = "1",
doi = "10.1016/j.cmet.2018.03.018",
language = "English (US)",
volume = "27",
pages = "1067--1080.e5",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "5",
}