The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
Slc12a8 is a nicotinamide mononucleotide transporter
Open accessAbstract
Nicotinamide mononucleotide (NMN) is a biosynthetic precursor of NAD+ known to promote cellular NAD+ production and counteract age-associated pathologies associated with a decline in tissue NAD+ levels. How NMN is taken up into cells has not been entirely clear. Here we show that the Slc12a8 gene encodes a specific NMN transporter. We find that Slc12a8 is highly expressed and regulated by NAD+ in the murine small intestine. Slc12a8 knockdown abrogates the uptake of NMN in vitro and in vivo. We further show that Slc12a8 specifically transports NMN, but not nicotinamide riboside, and that NMN transport depends on the presence of sodium ion. Slc12a8 deficiency significantly decreases NAD+ levels in the jejunum and ileum, which is associated with reduced NMN uptake as traced by doubly labeled isotopic NMN. Finally, we observe that Slc12a8 expression is upregulated in the aged murine ileum, which contributes to the maintenance of ileal NAD+ levels. Our work identifies the first NMN transporter and demonstrates that Slc12a8 has a critical role in regulating intestinal NAD+ metabolism.
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“The expression of a transporter in the gut [76] reinforces that NMN could be made bioavailable through oral delivery.”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [76]
In the citing paper
“A newly reported NMN transporter, the Slc12a8, is highly expressed and regulated by NAD+, in the murine small intestine, and Slc12a8 deficiency abrogates the uptake of NMN in vitro and in vivo (Grozio et al., 2019).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Grozio et al., 2019
In the citing paper
“through a transporter called slc12a8, 26-month-old mice (equivalent to 70 human years) that took NMN increased their NAD+ levels to close to 3 months old (equivalent to 12 human months). The content level in young mice increased the cell energy in aged mice [208].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [208]
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Cites
Cantó, C., Menzies, K. J., & Auwerx, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.023 · Cited by 1,648
Gomes, A. P., Price, N. L., Ling, A. J. Y., Moslehi, J. J., Montgomery, M. K., Rajman, L., White, J. P., Teodoro, J. S., Wrann, C. D., Hubbard, B. P., et al. (2013) · Cell · doi:10.1016/j.cell.2013.11.037 · Cited by 1,482
Yoshino, J., Mills, K. F., Yoon, M. J., & Imai, S.-I. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.08.014 · Cited by 1,340
Self-citationNAD + in aging, metabolism, and neurodegeneration
Verdin, E. (2015) · Science · doi:10.1126/science.aac4854 · Cited by 1,319
Mouchiroud, L., Houtkooper, R. H., Moullan, N., Katsyuba, E., Ryu, D., Cantó, C., Mottis, A., Jo, Y.-S., Viswanathan, M., Schoonjans, K., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.016 · Cited by 1,210
Analysis of Microarray Data Using Z Score Transformation
Cheadle, C., Vawter, M. P., Freed, W. J., & Becker, K. G. (2003) · Journal of Molecular Diagnostics · doi:10.1016/s1525-1578(10)60455-2 · Cited by 1,150
Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD + Biosynthesis
Ramsey, K. M., Yoshino, J., Brace, C. S., Abrassart, D., Kobayashi, Y., Marcheva, B., Hong, H.-K., Chong, J. L., Buhr, E. D., Lee, C., et al. (2009) · Science · doi:10.1126/science.1171641 · Cited by 1,126
Self-citationNAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR
Yoshino, J., Baur, J. A., & Imai, S.-I. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.11.002 · Cited by 1,061
Self-citationRevollo, J. R., Grimm, A. A., & Imai, S.-I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408388200 · Cited by 1,010
Self-citationNAD+ metabolism in health and disease
Belenky, P. A., Bogan, K. L., & Brenner, C. (2006) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.11.006 · Cited by 1,006
Cited by
Sorted by citations
NAD+ metabolism and its roles in cellular processes during ageing
Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00313-x · Cited by 1,617
Self-citationNAD+ metabolism: pathophysiologic mechanisms and therapeutic potential
Xie, N., Zhang, L., Gao, W. Q., Huang, C., Huber, P., Zhou, X., Li, C. L., Shen, G., & Zou, B. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00311-7 · Cited by 1,147
“The solute carrier family 12 member 8 (Slc12a8) has been reported as a specific NMN transporter that is responsible for the uptake of NMN and maintenance of NAD level in the murine small intestine.(98,99) However, it has been reported that the dephosphorylation of NMN into NR by extracellular 5’-nucleotidases is requi…”
BackgroundNAD+ in Brain Aging and Neurodegenerative Disorders
Lautrup, S., Sinclair, D. A., Mattson, M. P., & Fang, E. F. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.001 · Cited by 790
NAD+ homeostasis in health and disease
Katsyuba, E., Romani, M., Hofer, D., & Auwerx, J. (2020) · Nature Metabolism · doi:10.1038/s42255-019-0161-5 · Cited by 627
Immunosenescence: a key player in cancer development
Lian, J., Yue, Y., Yu, W., & Zhang, Y. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00986-z · Cited by 510
Metadata
- Authors
- Grozio, A., Mills, K. F., Yoshino, J., Bruzzone, S., Sociali, G., Tokizane, K., Lei, H. C., Cunningham, R., Sasaki, Y., Migaud, M. E., & Imai, S.-I.
- Affiliations
- Washington University in St. Louis (US)
- University of Genoa (IT)
- USA Mitchell Cancer Institute (US)
- Corresponding author
- Imai, Shin-ichiro
- ORCID
- Venue
- Nature Metabolism
- Published
- 2019-01-07
- Volume
- 1
- Issue
- 1
- Pages
- 47-57
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC6530925
- OpenAlex
- W2903854778
- Cited by
- 287
- References
- 48
- Citations by year
- 2026: 33 · 2025: 37 · 2024: 41 · 2023: 48 · 2022: 39 · 2021: 33 · 2020: 31 · 2019: 22
- FWCI
- 12.04
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-07-12)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- Funders
- National Institutes of Health (1c06rr015502-01, UL1TR002345)
- Biotechnology and Biological Sciences Research Council (BB/N001842/1)
- National Institute on Aging (R01AG024150, R01AG037457, R01AG047902)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056341, P30DK020579)
- National Center for Research Resources (C06-RR-015502)
- National Center for Advancing Translational Sciences
- 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 › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- NAD+ metabolism, small intestine, sodium-dependent transport, aging, nicotinamide riboside, NAD biosynthesis
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