A reduced form of nicotinamide riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+ precursor
| Autor: | Marie E. Migaud, Maria Pilar Giner, Angelique Cercillieux, Judith Giroud-Gerbetant, Carles Cantó, Magali Joffraud, Riekelt H. Houtkooper, Mikhail V. Makarov, Rubén Zapata-Pérez, Simona Bartova, Sofia Moco, Jose L. Sanchez-Garcia |
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| Přispěvatelé: | APH - Aging & Later Life, Laboratory Genetic Metabolic Diseases, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, ARD - Amsterdam Reproduction and Development |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Niacinamide lcsh:Internal medicine ved/biology.organism_classification_rank.species receptors 030209 endocrinology & metabolism Pyridinium Compounds Brief Communication Cell Line nad(+) 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Metabolomics longevity NAD+ homeostasis Animals Model organism lcsh:RC31-1245 Molecular Biology chemistry.chemical_classification life-span nicotinamide riboside ved/biology Kinase molecular-identification Cell Biology Metabolism subcellular compartmentation NAD mitochondrial 3. Good health Rats Phosphotransferases (Alcohol Group Acceptor) 030104 developmental biology Enzyme chemistry Biochemistry Nicotinamide riboside acid mononucleotide NAD+ kinase metabolism Intracellular oxidative-metabolism |
| Zdroj: | Molecular Metabolism, Vol 30, Iss, Pp 192-202 (2019) Molecular metabolism, 30, 192-202. Elsevier GmbH Molecular Metabolism |
| ISSN: | 2212-8778 |
| Popis: | Objective A decay in intracellular NAD+ levels is one of the hallmarks of physiological decline in normal tissue functions. Accordingly, dietary supplementation with NAD+ precursors can prevent, alleviate, or even reverse multiple metabolic complications and age-related disorders in diverse model organisms. Within the constellation of NAD+ precursors, nicotinamide riboside (NR) has gained attention due to its potent NAD+ biosynthetic effects in vivo while lacking adverse clinical effects. Nevertheless, NR is not stable in circulation, and its utilization is rate-limited by the expression of nicotinamide riboside kinases (NRKs). Therefore, there is a strong interest in identifying new effective NAD+ precursors that can overcome these limitations. Methods Through a combination of metabolomics and pharmacological approaches, we describe how NRH, a reduced form of NR, serves as a potent NAD+ precursor in mammalian cells and mice. Results NRH acts as a more potent and faster NAD+ precursor than NR in mammalian cells and tissues. Despite the minor structural difference, we found that NRH uses different steps and enzymes to synthesize NAD+, thus revealing a new NRK1-independent pathway for NAD+ synthesis. Finally, we provide evidence that NRH is orally bioavailable in mice and prevents cisplatin-induced acute kidney injury. Conclusions Our data identify a new pathway for NAD+ synthesis and classify NRH as a promising new therapeutic strategy to enhance NAD+ levels. Highlights • A reduced form of nicotinamide riboside (NRH) is a potent NAD+ precursor in cultured cells and mouse tissues. • NRH leads to NAD+ synthesis through a new, independent path to that of NR. • NRH is orally bioavailable and not degraded in plasma. • NRH alleviates cisplatin-induced acute kidney injury. |
| Databáze: | OpenAIRE |
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