Endogenous nicotinamide riboside metabolism protects against diet-induced liver damage

Audrey Sambeat, Joanna Ratajczak, Magali Joffraud, José L. Sanchez-Garcia, Maria P. Giner, Armand Valsesia, Judith Giroud-Gerbetant, Miriam Valera-Alberni, Angelique Cercillieux, Marie Boutant, Sameer S. Kulkarni, Sofia Moco and Carles Canto ()
Additional contact information
Audrey Sambeat: Nestlé Research
Joanna Ratajczak: Nestlé Research
Magali Joffraud: Nestlé Research
José L. Sanchez-Garcia: Nestlé Research
Maria P. Giner: Nestlé Research
Armand Valsesia: Nestlé Research
Judith Giroud-Gerbetant: Nestlé Research
Miriam Valera-Alberni: Nestlé Research
Angelique Cercillieux: Nestlé Research
Marie Boutant: Nestlé Research
Sameer S. Kulkarni: Nestlé Research
Sofia Moco: Nestlé Research
Carles Canto: Nestlé Research

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12262-x

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