Metabolism of orally administered Nicotinamide Riboside and Nicotinamide Mononucleotide in vivo

概要

Decreased nicotinamide adenine dinucleotide (NAD+) levels have been shown to contribute to aging and aging-associated diseases. Supplementation of NAD+ precursors, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have been shown to provide beneficial effects in aging-associated diseases, such as obesity, diabetes, and Alzheimer’s disease by increasing tissue NAD+ levels. Although NR and NMN have demonstrated promising results in preclinical studies, the metabolic fates and pharmacokinetic profiles of orally administered NR and NMN in vivo are not fully understood. In the present study, I show that only a small portion of orally administrated NR and NMN is directly absorbed from the small intestine and contributes to NAD+ synthesis. Most of NR was hydrolyzed to nicotinamide (NAM) by bone marrow stromal cell antigen 1 (BST1) in the small intestine, and was further metabolized by the gut microbiota to nicotinic acid, contributing to generate NAD+ through the Preiss–Handler pathway. Furthermore, I report BST1 has a base-exchange activity against both NR and nicotinic acid riboside (NAR) to generate NAR and NR, respectively, connecting amidated and deamidated pathways. Similarly, orally administered NMN also undergoes gut microbiota-mediated deamidation producing deamidated metabolites, such as NAR and nicotinic acid mononucleotide (NAMN). Blockage of the Preiss-Handler pathway completely suppressed the rise of NAD+ levels in the liver during NMN oral administration. In conclusion, these results highlighted the new concept about NAD+ metabolism, and benefit to develop more efficient NAD+ supplementation therapy against aging and aging- associated diseases.

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