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Endogenous nicotinamide riboside metabolism protects against diet-induced liver damage

2019; Nature Portfolio; Volume: 10; Issue: 1 Linguagem: Inglês

10.1038/s41467-019-12262-x

2041-1723

Audrey Sambeat, Joanna Ratajczak, Magali Joffraud, José Luis Sánchez, Maria Pilar Giner, Armand Valsesia, Judith Giroud‐Gerbetant, Miriam Valera‐Alberni, Angelique Cercillieux, Marie Boutant, Sameer S. Kulkarni, Sofia Moco, Carles Cantó,

PARP inhibition in cancer therapy

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.