Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphoribosyltransferase in human cells
Open accessAbstract
NAD plays critical roles in various biological processes through the function of SIRT1. Although classical studies in mammals showed that nicotinic acid (NA) is a better precursor than nicotinamide (Nam) in elevating tissue NAD levels, molecular details of NAD synthesis from NA remain largely unknown. We here identified NA phosphoribosyltransferase (NAPRT) in humans and provided direct evidence of tight link between NAPRT and the increase in cellular NAD levels. The enzyme was abundantly expressed in the small intestine, liver, and kidney in mice and mediated [(14)C]NAD synthesis from [(14)C]NA in human cells. In cells expressing endogenous NAPRT, the addition of NA but not Nam almost doubled cellular NAD contents and decreased cytotoxicity by H(2)O(2). Both effects were reversed by knockdown of NAPRT expression. These results indicate that NAPRT is essential for NA to increase cellular NAD levels and, thus, to prevent oxidative stress of the cells. Kinetic analyses revealed that NAPRT, but not Nam phosphoribosyltransferase (NamPRT, also known as pre-B-cell colony-enhancing factor or visfatin), is insensitive to the physiological concentration of NAD. Together, we conclude that NA elevates cellular NAD levels through NAPRT function and, thus, protects the cells against stress, partly due to lack of feedback inhibition of NAPRT but not NamPRT by NAD. The ability of NA to increase cellular NAD contents may account for some of the clinically observed effects of the vitamin and further implies a novel application of the vitamin to treat diseases such as those associated with the depletion of cellular NAD pools.
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Blood NA and NAM can cross the plasma membrane, whereas blood NAD+ cannot be taken up directly and must be converted to smaller uncharged molecules.
“Experimental evidence suggests that blood NA and NAM are able to cross the plasma membrane, while blood NAD+ cannot be taken up by cells directly but needs to be converted to smaller uncharged molecules to enter the cells (Hara et al., 2007; Ratajczak et al., 2016).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Hara et al., 2007
Trigonelline or NA failed to raise NAD+ levels in HepG2 and C2C12 cells, which have low NAPRT expression.
“trigonelline or NA failed to raise NAD+ levels in HepG2 (ref. 34) and C2C12 cells, which have low NAPRT expression (Extended Data Fig. 1g,h)”
From Trigonelline Is an NAD+ Precursor That Improves Muscle Function during Ageing and Is Reduced in Human Sarcopenia (2024) · cites this paper as [34]
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- Authors
- Hara, N., Yamada, K., Shibata, T., Osago, H., Hashimoto, T., & Tsuchiya, M.
- Affiliations
- Shimane University (JP)
- Corresponding author
- Hara, Nobumasa
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-08
- Volume
- 282
- Issue
- 34
- Pages
- 24574-24582
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2083287520
- Cited by
- 205
- References
- 46
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 15 · 2023: 14 · 2022: 23 · 2021: 15 · 2020: 11 · 2019: 7 · 2018: 16 · 2017: 10 · 2016: 8 · 2015: 10 · 2014: 11 · 2013: 8 · 2012: 4
- FWCI
- 4.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Keywords
- nicotinic acid, NAD levels, visfatin, NAD biosynthesis, SIRT1, oxidative stress, hydrogen peroxide cytotoxicity, nicotinamide
- MeSH terms
- Animals, HeLa Cells, Humans, Kinetics, Mice, Inbred BALB C, Models, Biological, Molecular Sequence Data, NAD, Niacin, Pentosyltransferases, Tissue Distribution, Oxidative Stress, RNA, Small Interfering, Mice, Rats
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