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


ABSTRACT: 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.

SUBMITTER: Giroud-Gerbetant J 

PROVIDER: S-EPMC6807296 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Giroud-Gerbetant Judith J   Joffraud Magali M   Giner Maria Pilar MP   Cercillieux Angelique A   Bartova Simona S   Makarov Mikhail V MV   Zapata-Pérez Rubén R   Sánchez-García José L JL   Houtkooper Riekelt H RH   Migaud Marie E ME   Moco Sofia S   Canto Carles C  

Molecular metabolism 20191003


<h4>Objective</h4>A decay in intracellular NAD<sup>+</sup> levels is one of the hallmarks of physiological decline in normal tissue functions. Accordingly, dietary supplementation with NAD<sup>+</sup> precursors can prevent, alleviate, or even reverse multiple metabolic complications and age-related disorders in diverse model organisms. Within the constellation of NAD<sup>+</sup> precursors, nicotinamide riboside (NR) has gained attention due to its potent NAD<sup>+</sup> biosynthetic effects in  ...[more]

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