A reduced form of nicotinamide riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+ precursor

• Published in: Molecular metabolism (Germany) Vol. 30; pp. 192 - 202
• Main Authors: Giroud-Gerbetant, Judith, Joffraud, Magali, Giner, Maria Pilar, Cercillieux, Angelique, Bartova, Simona, Makarov, Mikhail V., Zapata-Pérez, Rubén, Sánchez-García, José L., Houtkooper, Riekelt H., Migaud, Marie E., Moco, Sofia, Canto, Carles
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01-12-2019; Elsevier
• Subjects: Brief Communication; Metabolism; NAD; Nicotinamide riboside; NAD; Nicotinamide riboside; Metabolism; NAD(+)
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2019.09.013

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.
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.
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.
Our data identify a new pathway for NAD+ synthesis and classify NRH as a promising new therapeutic strategy to enhance NAD+ levels.
•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.