A reduced form of nicotinamide riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+ precursor
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 o...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-12-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877819309160 |
| _version_ | 1818903402976903168 |
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| author | Judith Giroud-Gerbetant Magali Joffraud Maria Pilar Giner Angelique Cercillieux Simona Bartova Mikhail V. Makarov Rubén Zapata-Pérez José L. Sánchez-García Riekelt H. Houtkooper Marie E. Migaud Sofia Moco Carles Canto |
| author_facet | Judith Giroud-Gerbetant Magali Joffraud Maria Pilar Giner Angelique Cercillieux Simona Bartova Mikhail V. Makarov Rubén Zapata-Pérez José L. Sánchez-García Riekelt H. Houtkooper Marie E. Migaud Sofia Moco Carles Canto |
| author_sort | Judith Giroud-Gerbetant |
| collection | DOAJ |
| description | 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. Keywords: NAD+, Nicotinamide riboside, Metabolism |
| first_indexed | 2024-12-19T20:50:59Z |
| format | Article |
| id | doaj.art-6c4c170dedb84391bff1d462c0934a35 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-19T20:50:59Z |
| publishDate | 2019-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-6c4c170dedb84391bff1d462c0934a352022-12-21T20:06:06ZengElsevierMolecular Metabolism2212-87782019-12-0130192202A reduced form of nicotinamide riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+ precursorJudith Giroud-Gerbetant0Magali Joffraud1Maria Pilar Giner2Angelique Cercillieux3Simona Bartova4Mikhail V. Makarov5Rubén Zapata-Pérez6José L. Sánchez-García7Riekelt H. Houtkooper8Marie E. Migaud9Sofia Moco10Carles Canto11Nestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, 1015, Lausanne, SwitzerlandNestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, 1015, Lausanne, SwitzerlandNestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, 1015, Lausanne, SwitzerlandNestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, 1015, Lausanne, Switzerland; School of Life Sciences, EPFL, Lausanne, 1015, SwitzerlandNestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, 1015, Lausanne, SwitzerlandMitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, 36604, Alabama, USALaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the NetherlandsNestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, 1015, Lausanne, SwitzerlandLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the NetherlandsMitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, 36604, Alabama, USANestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, 1015, Lausanne, SwitzerlandNestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, 1015, Lausanne, Switzerland; School of Life Sciences, EPFL, Lausanne, 1015, Switzerland; Corresponding author. Nestlé Institute of Health Sciences, Nestlé Research EPFL campus, Quartier de l'Innovation, Bâtiment G, Lausanne, CH-1015, Switzerland.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. Keywords: NAD+, Nicotinamide riboside, Metabolismhttp://www.sciencedirect.com/science/article/pii/S2212877819309160 |
| spellingShingle | Judith Giroud-Gerbetant Magali Joffraud Maria Pilar Giner Angelique Cercillieux Simona Bartova Mikhail V. Makarov Rubén Zapata-Pérez José L. Sánchez-García Riekelt H. Houtkooper Marie E. Migaud Sofia Moco Carles Canto A reduced form of nicotinamide riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+ precursor Molecular Metabolism |
| title | A reduced form of nicotinamide riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+ precursor |
| title_full | A reduced form of nicotinamide riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+ precursor |
| title_fullStr | A reduced form of nicotinamide riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+ precursor |
| title_full_unstemmed | A reduced form of nicotinamide riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+ precursor |
| title_short | A reduced form of nicotinamide riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+ precursor |
| title_sort | reduced form of nicotinamide riboside defines a new path for nad biosynthesis and acts as an orally bioavailable nad precursor |
| url | http://www.sciencedirect.com/science/article/pii/S2212877819309160 |
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