Endogenous nicotinamide riboside metabolism protects against diet-induced liver damage

A. Sambeat; J. Ratajczak; M. Joffraud; J.L. Sanchez-Garcia; M.P. Giner; A. Valsesia; J. Giroud-Gerbetant; M. Valera-Alberni; A. Cercillieux; M. Boutant; S.S. Kulkarni; S. Moco; C. Canto

doi:10.1038/s41467-019-12262-x

Endogenous nicotinamide riboside metabolism protects against diet-induced liver damage

A. Sambeat
, J. Ratajczak
, M. Joffraud
, J.L. Sanchez-Garcia
, M.P. Giner
, A. Valsesia
, J. Giroud-Gerbetant
, M. Valera-Alberni
, A. Cercillieux
, M. Boutant
, S.S. Kulkarni
, S. Moco
, C. Canto

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

© 2019, The Author(s).Supplementation with the NAD+ precursor nicotinamide riboside (NR) ameliorates and prevents a broad array of metabolic and aging disorders in mice. However, little is known about the physiological role of endogenous NR metabolism. We have previously shown that NR kinase 1 (NRK1) is rate-limiting and essential for NR-induced NAD+ synthesis in hepatic cells. To understand the relevance of hepatic NR metabolism, we generated whole body and liver-specific NRK1 knockout mice. Here, we show that NRK1 deficiency leads to decreased gluconeogenic potential and impaired mitochondrial function. Upon high-fat feeding, NRK1 deficient mice develop glucose intolerance, insulin resistance and hepatosteatosis. Furthermore, they are more susceptible to diet-induced liver DNA damage, due to compromised PARP1 activity. Our results demonstrate that endogenous NR metabolism is critical to sustain hepatic NAD+ levels and hinder diet-induced metabolic damage, highlighting the relevance of NRK1 as a therapeutic target for metabolic disorders.

Original language	English
Article number	4291
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12262-x
Publication status	Published - 1 Dec 2019
Externally published	Yes

Funding

We thank members of the Cantó laboratory for helpful discussions, the members of the EPFL animal facility for technical support and the EPFL Histology Core Facility. M.V.-A. is supported by the EU Marie Skłodowska-Curie ITN-ChroMe (H2020-MSCA-ITN-Project number 675610).

Funders	Funder number
EU Marie Skłodowska-Curie ITN-ChroMe
Horizon 2020 Framework Programme	675610

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Sambeat, A., Ratajczak, J., Joffraud, M., Sanchez-Garcia, J. L., Giner, M. P., Valsesia, A., Giroud-Gerbetant, J., Valera-Alberni, M., Cercillieux, A., Boutant, M., Kulkarni, S. S., Moco, S., & Canto, C. (2019). Endogenous nicotinamide riboside metabolism protects against diet-induced liver damage. Nature Communications, 10(1), Article 4291. https://doi.org/10.1038/s41467-019-12262-x

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abstract = "{\textcopyright} 2019, The Author(s).Supplementation with the NAD+ precursor nicotinamide riboside (NR) ameliorates and prevents a broad array of metabolic and aging disorders in mice. However, little is known about the physiological role of endogenous NR metabolism. We have previously shown that NR kinase 1 (NRK1) is rate-limiting and essential for NR-induced NAD+ synthesis in hepatic cells. To understand the relevance of hepatic NR metabolism, we generated whole body and liver-specific NRK1 knockout mice. Here, we show that NRK1 deficiency leads to decreased gluconeogenic potential and impaired mitochondrial function. Upon high-fat feeding, NRK1 deficient mice develop glucose intolerance, insulin resistance and hepatosteatosis. Furthermore, they are more susceptible to diet-induced liver DNA damage, due to compromised PARP1 activity. Our results demonstrate that endogenous NR metabolism is critical to sustain hepatic NAD+ levels and hinder diet-induced metabolic damage, highlighting the relevance of NRK1 as a therapeutic target for metabolic disorders.",

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AU - Sambeat, A.

AU - Ratajczak, J.

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AU - Sanchez-Garcia, J.L.

AU - Giner, M.P.

AU - Valsesia, A.

AU - Giroud-Gerbetant, J.

AU - Valera-Alberni, M.

AU - Cercillieux, A.

AU - Boutant, M.

AU - Kulkarni, S.S.

AU - Moco, S.

AU - Canto, C.

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AB - © 2019, The Author(s).Supplementation with the NAD+ precursor nicotinamide riboside (NR) ameliorates and prevents a broad array of metabolic and aging disorders in mice. However, little is known about the physiological role of endogenous NR metabolism. We have previously shown that NR kinase 1 (NRK1) is rate-limiting and essential for NR-induced NAD+ synthesis in hepatic cells. To understand the relevance of hepatic NR metabolism, we generated whole body and liver-specific NRK1 knockout mice. Here, we show that NRK1 deficiency leads to decreased gluconeogenic potential and impaired mitochondrial function. Upon high-fat feeding, NRK1 deficient mice develop glucose intolerance, insulin resistance and hepatosteatosis. Furthermore, they are more susceptible to diet-induced liver DNA damage, due to compromised PARP1 activity. Our results demonstrate that endogenous NR metabolism is critical to sustain hepatic NAD+ levels and hinder diet-induced metabolic damage, highlighting the relevance of NRK1 as a therapeutic target for metabolic disorders.

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Endogenous nicotinamide riboside metabolism protects against diet-induced liver damage

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